Patent application title: Novel genes encoding novel proteolytic enzymes

Inventors: Luppo Edens Andreas Fritz Dieter Maier Christian Wagner Ulrike Folkers Fabio Spreafico Alard Van Albertus Dijk Phillip Krubasik Kaj Albermann Alexander Stock Erik Kimpel Sabrine Klaubauer Wilk Von Gustedt Oliver Henrich Sylvia Hopper Wolfram Kemmner Pamela Tan Josephine Stiebler Ricahrd Albang
Agents: NIXON & VANDERHYE, PC
Assignees: DSM IP ASSETS B.V.
Origin: ARLINGTON, VA US
IPC8 Class: AC12N948FI
USPC Class: 435 691
Patent application number: 20090275079

Abstract:

The invention relates to newly identified gene sequences that encode novel proteases obtainable from Aspergillus niger. The invention features the full length gene sequence of the novel genes, their cDNA sequences as well as the full-length functional protein and fragments thereof. The invention also relates to methods of using these enzymes in industrial processes and methods of diagnosing fungal infections. Also included in the invention are cells transformed with DNA according to the invention and cells wherein a protease according to the invention is genetically modified to enhance or reduce its activity and/or level of expression.

Claims:

1. An isolated polynucleotide that encodes a tripeptidyl peptidase wherein said polynucleotide hybridizes to the full length complement of a nucleotide sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:8; SEQ ID NO:11; SEQ ID NO:13 to SEQ ID NO:25; SEQ ID NO:27 to SEQ ID NO:34; SEQ ID NO:36 to SEQ ID NO:49; SEQ ID NO:51 to SEQ ID NO:57; SEQ ID NO:58 to SEQ ID NO:65; SEQ ID NO:68; SEQ ID NO:70 to SEQ ID NO:82; SEQ ID NO:84 to SEQ ID NO:91; SEQ ID NO:93 to SEQ ID NO:106; and SEQ ID NO:108 to SEQ ID NO:115 under hybridization conditions of 5.times.SSC, 5.times.Denhardt's solution, and 1.0% SDS at 68.degree. C. and wash conditions of 0.2.times.SSC and 0.1% SDS at room temperature.

2. The isolated polynucleotide of claim 1, which comprises a nucleotide sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:8; SEQ ID NO:11; SEQ ID NO:13 to SEQ ID NO:25; SEQ ID NO:27 to SEQ ID NO:34; SEQ ID NO:36 to SEQ ID NO:49; SEQ ID NO:51 to SEQ ID NO:57; SEQ ID NO:58 to SEQ ID NO:65; SEQ ID NO:68; SEQ ID NO:70 to SEQ ID NO:82; SEQ ID NO:84 to SEQ ID NO:91; SEQ ID NO:93 to SEQ ID NO:106; and SEQ ID NO:108 to SEQ ID NO:115.

3. The isolated polynucleotide of claim 1 obtainable from a filamentous fungus.

4. The isolated polynucleotide of claim 3 obtainable from Aspergillus niger.

5. An isolated polynucleotide encoding a polypeptide having tripeptidyl peptidase-activity, which is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:115 to SEQ ID NO:122; SEQ ID NO:125; SEQ ID NO:127 to SEQ ID NO:139; SEQ ID NO:141 to SEQ ID NO:148; SEQ ID NO:150 to SEQ ID NO:163; and SEQ ID NO:165 to SEQ ID NO:171.

6. The isolated polynucleotide of claim 7 wherein said polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:115 to SEQ ID NO:122; SEQ ID NO:125; SEQ ID NO:127 to SEQ ID NO:139; SEQ ID NO:141 to SEQ ID NO:148; SEQ ID NO:150 to SEQ ID NO:163; and SEQ ID NO:165 to SEQ ID NO:171.

7. The isolated polynucleotide of claim 1, which hybridizes to the full length of a nucleotide sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:8; SEQ ID NO:11; SEQ ID NO:13 to SEQ ID NO:25; SEQ ID NO:27 to SEQ ID NO:34; SEQ ID NO:36 to SEQ ID NO:49; SEQ ID NO:51 to SEQ ID NO:57; SEQ ID NO:58 to SEQ ID NO:65; SEQ ID NO:68; SEQ ID NO:70 to SEQ ID NO:82; SEQ ID NO:84 to SEQ ID NO:91; SEQ ID NO:93 to SEQ ID NO:106; and SEQ ID NO:108 to SEQ ID NO:115.

8. A vector comprising the polynucleotide sequence of claim 1.

9. The vector of claim 8 wherein said polynucleotide sequence is operatively linked with regulatory sequences suitable for expression of said polynucleotide sequence in a suitable host cell.

10. The vector of claim 9 wherein said suitable host cell is a filamentous fungus.

11. An isolated recombinant host cell comprising the vector of claim 9.

12. A method to prepare a tripeptidyl peptidase comprising the steps of culturing a host cell comprising the vector of claim 9 and isolating said tripeptidyl peptidase from said host cell.

13. A vector comprising the polynucleotide sequence of claim 5.

14. The vector of claim 13 wherein said polynucleotide sequence is operatively linked with regulatory sequences suitable for expression of said polynucleotide sequence in a suitable host cell.

15. The vector of claim 14 wherein said suitable host cell is a filamentous fungus.

16. An isolated recombinant host cell comprising the vector of claim 14.

17. A method to prepare a tripeptidyl peptidase comprising the steps of culturing a host cell comprising the vector of claim 14 and isolating said tripeptidyl peptidase from said host cell.

18. An isolated polypeptide having tripeptidyl peptidase activity, which comprises an amino acid sequence at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:115 to SEQ ID NO:122; SEQ ID NO:125; SEQ ID NO:127 to SEQ ID NO:139; SEQ ID NO:141 to SEQ ID NO:148; SEQ ID NO:150 to SEQ ID NO:163; and SEQ ID NO:165 to SEQ ID NO:171.

19. The isolated polypeptide of claim 18 wherein said polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:115 to SEQ ID NO:122; SEQ ID NO:125; SEQ ID NO:127 to SEQ ID NO:139; SEQ ID NO:141 to SEQ ID NO:148; SEQ ID NO:150 to SEQ ID NO:163; and SEQ ID NO:165 to SEQ ID NO:171.

20. An isolated polypeptide obtainable by expressing the polynucleotide of claim 1 in a host cell.

21. An isolated polypeptide obtainable by expressing the polynucleotide of claim 5 in a host cell.

22. An isolated recombinant host cell expressing the polypeptide of claim 18.

23. A fusion protein comprising the amino acid sequence according to claim 18.

24. A fusion protein comprising the amino acid sequence of the polypeptide according to claim 20.

25. A fusion protein comprising the amino acid sequence of the polypeptide according to claim 21.

Description:

FIELD OF THE INVENTION

[0001]The invention relates to newly identified polynucleotide sequences comprising genes that encode novel proteases isolated from Aspergillus niger. The invention features the full length nucleotide sequence of the novel genes, the cDNA sequences comprising the full length coding sequences of the novel proteases as well as the amino acid sequences of the full-length functional proteins and fragments and variants thereof. The invention also relates to methods of using these enzymes in industrial processes and methods of diagnosing fungal infections. Also included in the invention are cells transformed with a polynucleotide according to the invention and cells wherein a protease according to the invention is genetically modified to enhance or reduce its activity and/or level of expression.

BACKGROUND OF THE INVENTION

Proteolytic Enzymes

[0002]Proteins can be regarded hetero-polymers that consist of amino acid building blocks connected by a peptide bond. The repetitive unit in proteins is the central alpha carbon atom with an amino group and a carboxyl group. Except for glycine, a so-called amino acid side chain substitutes one of the two remaining alpha carbon hydrogen atoms. The amino acid side chain renders the central alpha carbon asymmetric. In general, in proteins the L-enantiomer of the amino acid is found. The following terms describe the various types of polymerized amino acids. Peptides are short chains of amino acid residues with defined sequence. Although there is not really a maximum to the number of residues, the term usually indicates a chain which properties are mainly determined by its amino acid composition and which does not have a fixed three-dimensional conformation. The term polypeptide is usually used for the longer chains, usually of defined sequence and length and in principle of the appropriate length to fold into a three-dimensional structure. Protein is reserved for polypeptides that occur naturally and exhibit a defined three-dimensional structure. In case the proteins main function is to catalyze a chemical reaction it usually is called an enzyme. Proteases are the enzymes that catalyze the hydrolysis of the peptide bond in (poly)peptides and proteins.

[0003]Under physiological conditions proteases catalyse the hydrolysis of the peptide bond. The International Union of Biochemistry and Molecular Biology (1984) has recommended to use the term peptidase for the subset of peptide bond hydrolases (Subclass E.C 3.4.). The terms protease and peptide hydrolase are synonymous with peptidase and may also be used here. Proteases comprise two classes of enzymes: the endo-peptidases and the exo-peptidases, which cleave peptide bonds at points within the protein and remove amino acids sequentially from either N or C-terminus respectively. Proteinase is used as a synonym for endo-peptidase. The peptide bond may occur in the context of di-, tri-, tetra-peptides, peptides, polypeptides or proteins. In general the amino acid composition of natural peptides and polypeptides comprises 20 different amino acids, which exhibit the L-configuration (except for glycine which does not have a chiral centre). However the proteolytic activity of proteases is not limited to peptides that contain only the 20 natural amino acids. Peptide bonds between so-called non-natural amino acids can be cleaved too, as well as peptide bonds between modified amino acids or amino acid analogues. Some proteases do accept D enantiomers of amino acids at certain positions. In general the remarkable stereo-selectivity of proteases makes them very useful in the process of chemical resolution. Many proteases exhibit interesting side activities such as esterase activity, thiol esterase activity and (de)amidase activity. These side activities are usually not limited to amino acids only and might turn out to be very useful in bioconversions in the area of fine chemicals.

[0004]There are a number of reasons why proteases of filamentous fungi, eukaryotic microorganisms, are of particular interest. The basic process of hydrolytic cleavage of peptide bonds in proteins appears costly and potentially detrimental to an organism if not properly controlled. The desired limits to proteolytic action are achieved through the specificity of proteinases, by compartmentalization of proteases and substrates within the cell, through modification of the substrates allowing recognition by the respective proteases, by regulation via zymogen activation, and the presence or absence of specific inhibitors, as well through the regulation of protease gene expression. In fungi, proteases are also involved in other fundamental cellular processes, including intracellular protein turnover, processing, translocation, sporulation, germination and differentiation. In fact, Aspergillus nidulans and Neurospora crassa have been used as model organisms for analyzing the molecular basis of a range of physiological and developmental processes. Their genetics enable direct access to biochemical and genetical studies, under defined nutrient and cultivation conditions. Furthermore, a large group of fungi pathogenic to humans, live-stock and crop, has been isolated and proteolysis has been suggested to play a role in their pathogenicity (host penetration, countering host defense mechanisms and/or nutrition during infection). Proteases are also frequently used in laboratory, clinical and industrial processes; both microbial and non-microbial proteases are widely used in the food industry (baking, brewing, cheese manufacturing, meat tenderizing), in tanning industry and in the manufacture of biological detergents (Aunstrup, 1980). The commercial interest in exploiting certain filamentous fungi, especially the Aspergilli, as hosts for the production of both homologous and heterologous proteins, has also recently renewed interests in fungal proteases (van Brunt, 1986ab). Proteases often cause problems in heterologous expression and homologous overexpression of proteins in fungi. In particular, heterologous expression is hampered by the proteolytic degradation of the expressed products by homologous proteases. These commercial interests have resulted in detailed studies of proteolytic spectra and construction of protease deficient strains and have improved the knowledge about protease expression and regulation in these organisms. Consequently there is a great need to identify and eliminate novel proteases in filamentous fungi.

[0005]Micro-organisms such as for example fungi are particularly useful in the large scale production of proteins. In particular when such proteins are secreted into the medium. Proteolytic enzymes play a role in these production processes. On the one hand particular proteolytic enzymes are in general required for proper processing of the target protein and the metabolic well-being of the production host. On the other hand proteolytic degradation may significantly decrease the yield of secreted proteins. Poor folding in the secretion pathway may lead to degradation by intracellular proteases. This might be a particular problem with producing heterologous proteins. The details of the proteolytic processes, which are responsible for the degradation of the proteins that are diverted from the secretory process in fungi are not exactly known. In eukaryotes the degradation of cellular proteins is achieved by a proteasome and usually involves ubiquitin labelling of proteins to be degraded. In fungi, proteasomal and vacuolar proteases are also likely candidates for the proteolytic degradation of poorly folded secretory proteins. The proteolytic degradation is likely cytoplasmic, but endoplamatic reticulum resident proteases cannot be excluded. From the aspect of production host strain improvement the proteolytic system may be an interesting target for genetic engineering and production strain improvement. Additional copies of protease genes, over-expression of certain proteases, modification of transcriptional control, as well as knock out procedures for deletion of protease genes may provide a more detailed insight in the function a given protease. Deletion of protease encoding genes can be a valuable strategy for host strain improvement in order to improve production yield for homologous as well as heterologous proteins.

[0006]Eukaryotic microbial proteases have been reviewed by North (1982). More recently, Suarez Rendueles and Wolf (1988) have reviewed the S. cerevisiae proteases and their function.

[0007]Apart from the hydrolytic cleavage of bonds, proteases may also be applied in the formation of bonds. Bonds in this aspect comprise not only peptide and amide bonds but also ester bonds. Whether a protease catalyses the cleavage or the formation of a particular bond does in the first place depend on the thermodynamics of the reaction. An enzyme such as a protease does not affect the equilibrium of the reaction. The equilibrium is dependent on the particular conditions under which the reaction occurs. Under physiological conditions the thermodynamics of the reactions is in favour of the hydrolysis of the peptide due to the thermodynamically very stable structure of the zwitterionic product. By application of physical-chemical principles to influence the equilibrium, or by manipulating the concentrations or the nature of the reactants and products, or by exploiting the kinetic parameters of the enzyme reaction it is possible to apply proteases for the purpose of synthesis of peptide bonds. The addition of water miscible organic solvents decreases the ektent of ionisation of the carboxyl component, thereby increasing the concentration of substrate available for the reaction. Biphasic systems, water mimetics, reverse micelles, anhydrous media, or modified amino and carboxyl groups to invoke precipitation of products are often employed to improve yields. When the proteases with the right properties are available the application of proteases for synthesis offers substantial advantages. As proteases are stereo-selective as well as regio-selective, sensitive groups on the reactants do usually not need protection and reactants do not need to be optically pure. As conditions of enzymatic synthesis are mild, racemization and decomposition of labile reactants or products can be prevented. Apart from bonds between amino acids, also other compounds exhibiting a primary amino group, a thiol group or a carboxyl group may be linked by properly selected proteases. In addition esters, thiol esters and amides may be synthesized by certain proteases. Protease have been shown to exhibit regioselectively in the acylation of mono, di- and tri-saccharides, nucleosides, and riboflavin. Problems with stability under the sometimes harsh reaction conditions may be prevented by proper formulation. Encapsulation and immobilisation do not only stabilise enzymes but also allow easy recovery and separation from the reaction medium. Extensive crosslinking, treatment with aldehydes or covering the surface with certain polymers such as dextrans, polyethyleneglycol, polyimines may substantially extend the lifetime of the biocatalyst.

The Natural Roles of Proteases

[0008]Traditionally, proteases have been regarded as degrading enzymes, capable of cleaving proteins into small peptides and/or amino acids, and whose role it is to digest nutrient protein or to participate in the turnover of cellular proteins. In addition, it has been shown that proteases also play key roles in a wide range of cellular processes, via mechanisms of selective modification by limited proteolysis, and thus can have essential regulatory functions (Holzer and Tschensche 1979; Holzer and Heinrich, 1980). The specificity of a proteinase is assumed to be closely related to its physiological function and its mode of expression. With respect to the function of a particular protease, its localisation is often very important; for example, a lot of the vacuolar and periplasmic proteases are involved in protein degradation, while many of the membrane-bound proteases are important in protein processing (Suarez Rendueles and Wolf, 1988). The different roles of proteases in many cellular processes can be divided into four main functions of proteases: 1) protein degradation, 2) posttranslational processing and (in)activation of specific proteins, 3) morphogenesis, and 4) pathogenesis.

[0009]An obvious role for proteases in organisms which utilise protein as a nutrient source is in the hydrolysis of nutrients. In fungi, this would involve the degradation outside the cells by extracellular broad specificity proteases. Protein degradation is also important for rapid turnover of cellular proteins and allows the cell to remove abnormal proteins and to adapt their complement of protein to changing physiological conditions. Generally, proteases of rather broad specificity should be extremely well-controlled in order to protect the cell from random degradation of other than correct target proteins.

[0010]Contrary to the hydrolysis the synthesis of polypeptides occurs in vivo by an ATP driven process on the ribosome. Ultimately the sequence in which the amino acids are linked is dictated by the information derived from the genome. This process is known as the transcription. Primary translation products are often longer than the final functional products, and after the transcription usually further processing of such precursor proteins by proteases is required. Proteases play a key role in the maturation of such precursor proteins to obtain the final functional protein. In contrast to the very controlled trimming and reshaping of proteins, proteases can also be very destructive and may completely degrade polypeptides into peptides and amino acids. In order to avoid that proteolytic activity is unleashed before it is required, proteases are subject to extensive regulation. Many proteases are synthesized as larger precursors known as zymogens, which become activated when required. Remarkably this activation always occurs by proteolysis. Apart from direct involvement in the processing, selective activation and inactivation of individual proteins are well-known phenomena catalyzed by specific proteases.

[0011]The selectivety of limited proteolysis appears to reside more directly in the proteinase-substrate interaction. Specificity may be derived from the proteolytic enzyme which recognizes only specific amino acid target sequences. On the other hand, it may also be the result of selective exposure of the `processing site` under certain conditions such as pH, ionic strength or secondary modifications, thus allowing an otherwise non-specific protease to catalyze a highly specific event. The activation of vacuolar zymogens by limited proteolysis gives an example of the latter kind.

[0012]Morphogenesis or differentiation can be defined as a regulated series of events leading to changes from one state to another in an organism. Although direct relationships between proteases and morphological effects could not be established in many cases, the present evidence suggests a significant involvement of proteases in fungal morphogenesis; apart form the observed extensive protein turnover during differentiation, sporulation and spore germination, proteases are thought to be directly involved in normal processes as hyphal tip branching and septum formation, (Deshpande, 1992).

[0013]Species of Aspergillus, in particular A. fumigatus and A. flavus, have been implicated as the causative agents of a number of diseases in humans and animals called aspergillosis (Bodey and Vartivarian, 1989). It has been repeatedly suggested that proteases are involved in virulence of A. fumigatus and A. flavus like there are many studies linking secreted proteases and virulence of bacteria. In fact, most human infections due to Aspergillus species are characterised by an extensive degradation of the parenchyma of the lung which is mainly composed of collagen and elastin (Campbell et al., 1994). Research has been focussed on the putative role of the secreted proteases in virulence of A. fumigatus and A. flavus which are the main human pathogens and are known to possess elastinolytic and collagenic activities (Kolattukudy et al., 1993). These elastinolytic activities were shown to correlate in vitro with infectivity in mice (Kothary et al., 1984). Two secreted proteases are known to be produced by A. fumigatus and A. flavus, an alkaline serine protease (ALP) and a neutral metallo protease (MEP). In A. fumigatus both the genes encoding these proteases were isolated, characterised and disrupted (Reicherd et al., 1990; Tang et al, 1992, 1993; Jaton-Ogay et al., 1994). However, alp mep double mutants showed no differences in pathogenecity when compared with wild type strains. Therefore, it must be concluded that the secreted A. fumigatus proteases identified in vitro are not essential factors for the invasion of tissue (Jaton Ogay et al., 1994). Although A. fumigatus accounts for only a small proportion of the airborne mould spores, it is the most frequently isolated fungus from lung and sputem (Schmitt et al., 1991). Other explanations for the virulence of the fungus could be that the conditions in the bronchia (temperature and nutrients) are favourable for the parasitic growth of A. fumigatus. As a consequence, invasive apergillosis could be a circumstancial event, when the host pathogenic defences have been weakened by immunosuppressive treatments or diseases like AIDS.

[0014]Four major classes of proteases are known and are designated by the principal functional groups in their active site: the `serine`, the `thiol` or `cysteine`, the `aspartic` or `carboxyl` and the `metallo` proteases. A detailed state of the art review on these major classes of proteases, minor classes and unclassified proteases can be found in Methods in Enzymology part 244 and 248 (A. J. Barrett ed, 1994 and 1995).

Specificity of Proteases

[0015]Apart from the catalytic machinery of proteases another important aspect of proteolytic enzymes is the specificity of proteases. The specificity of a protease indicates which substrates the protease is likely to hydrolyze. The twenty natural amino acids offer a large number of possibilities to make up peptides. Eg with twenty amino acids one can make up already 400 dipeptides and 800 different tripeptide, and so on. With longer peptides the number of possibilities will become almost unlimited. Certain proteases hydrolyze only particular sequences at a very specific position. The interaction of the protease with the peptide substrate may encompass one up to ten amino acid residues of the peptide substrate. With large proteinacious substrates there may be even more residues of the substrate that interact with the proteases. However this likely involves less specific interactions with protease residues outside the active site binding cleft. In general the specific recognition is restricted to the linear peptide, which is bound in the active site of the protease.

[0016]The nomenclature to describe the interaction of a substrate with a protease has been introduced in 1967 by Schechter and Berger (Biochem. Biophys. Res. Com., 1967, 27, 157-162) and is now widely used in the literature. In this system, it is considered that the amino acid residues of the polypeptide substrate bind to so-called sub-sites in the active site. By convention, these sub-sites on the protease are called S (for sub-sites) and the corresponding amino acid residues are called P (for peptide). The amino acid residues of the N-terminal side of the scissile bond are numbered P3, P2, P1 and those residues of the C-terminal side are numbered P1', P2', P3'. The P1 or P1' residues are the amino acid residues located near the scissile bond. The substrate residues around the cleavage site can then be numbered up to P8. The corresponding sub-sites on the protease that complement the substrate binding residues are numbered S3, S2, S1, S1', S2', S3', etc, etc. The preferences of the sub-sites in the peptide binding site determine the preference of the protease for cleaving certain specific amino acid sequences at a particular spot. The amino acid sequence of the substrate should conform with the preferences exhibited by the sub-sites. The specificity towards a certain substrate is clearly dependant both on the binding affinity for the substrate and on the velocity at which subsequently the scissile bond is hydrolysed. Therefore the specificity of a protease for a certain substrate is usually indicated by its kcat/Km ratio, better known as the specificity constant. In this specificity constant kcat represents the turn-over rate and Km is the dissociation constant.

[0017]Apart from amino acid residues involved in catalysis and binding, proteases contain many other essential amino acid residues. Some residues are critical in folding, some residues maintain the overall three dimensional architecture of the protease, some residues may be involved in regulation of the proteolytic activity and some residue may target the protease for a particular location. Many proteases contain outside the active site one or more binding sites for metal ions. These metal ions often play a role in stabilizing the structure. In addition secreted eukaryotic microbial proteases may be extensively glycosylated. Both N- and O-linked glycosylation occurs. Glycosylation may aid protein folding, may increase solubility, prevent aggregation and as such stabilize the mature protein. In addition the extent of glycosylation may influence secretion as well as water binding by the protein.

Regulation of Proteolytic Activity

[0018]A substantial number of proteases are subject to extensive regulation of the proteolytic activity in order to avoid undesired proteolytic damage. To a certain extent this regulation takes place at transcription level. For example in fungi the transcription of secreted protease genes appears to be sensitive to external carbon and nitrogen sources, whereas genes encoding intracellular proteases are insensitive. The extracellular pH is sensed by fungi and some genes are regulated by pH. In this process transcriptional regulator proteins play a crucial role. Proteolytic processing of such regulator proteins is often the switch that turns the regulator proteins either on or off.

[0019]Proteases are subject to intra- as well as intermolecular regulation. This implies certain amino acids in the proteolytic enzyme molecule that are essential for such regulation. Proteases are typically synthesized as larger precursors known as zymogens, which are catalytically inactive. Usually the peptide chain extension rendering the precursor protease inactive is located at the amino terminus of the protease. The precursor is better known as pro-protein. As many of the proteases processed in this way are secreted from the cells they contain in addition a signal sequence (pre sequence) so that the complete precursor is synthesized as a pre-pro-protein. Apart from rendering the protease inactive the pro-peptide often is essential for mediating productive folding. Examples of proteases include serine proteases (alpha lytic protease, subtilisin, aqualysin, prohormone convertase), thiol proteases (cathepsin L and cruzian), aspartic proteases (proteinase A and cathepsin D) and metalloproteases. In addition the pro-peptide might play a role in cellular transport either alone or in conjunction with signal peptides. It may facilitate interaction with cellular chaperones or it may facilitate transport over the membrane. The size of the extension in the precursor pre-pro-protein may vary substantially, ranging from a short peptide fragment to a polypeptide, which can exist as an autonomous folding unit. In particular these larger extensions are often observed to be strong inhibitors of the protease even after cleavage from the protease. It was observed that even after cleavage such pro-peptides could assist in proper folding of the proteases. As such pro-peptides can be considered to function as molecular chaperones and separate or additional co-expression of such pro-peptides could be advantageous for protease production.

[0020]There is substantial difference in the level of regulation between proteases that are secreted into the medium and proteases that remain intracellular. Proteases secreted into the medium are usually after activation no longer subject to control and therefore are usually relatively simple in their molecular architecture consisting of one globular module. Intracellular proteases are necessarily subject to continuous control in order to avoid damage to the cells. In contrast with zymogens of secreted proteases in more complex regulatory proteases very large polypeptide segments may be inserted between the signal and the zymogen activation domain of the proteolytic module. Structure-function studies indicate that such non-protease parts may be involved in interactions with macroscopic structures, membranes, cofactors, substrates, effectors, inhibitors, ions, that regulate activity and activation of the proteolytic module(s) or its (their) zymogens. The non-proteolytic modules exhibit remarkable variation in size and structure. Many of the modules can exist as such independently from the proteolytic module. Therefore such modules can be considered to correspond to independent structural and functional units that are autonomous with respect to folding. The value of such a modular organization is that acquisition of new modules can endow the recipient protease with new novel binding specificities and can lead to dramatic changes in its activity, regulation and targeting. The principle of modular organized proteolytic enzymes may also be exploited by applying molecular biology tools in order to create novel interactions, regulation, specificity, and/or targeting by shuffling of modules. Although in general such additional modules are observed as N or C terminal extension, also large insertions within the exterior loops of the catalytic domain have been observed. It is believed that also in this case the principal fold of the protease represents still the essential topology to form a functional proteolytic entity and that the insertion can be regarded as substructure folded onto the surface of the proteolytic module.

Molecular Structure

[0021]In principle the modular organization of larger proteins is a general theme in nature. In particular within the larger multimodular frameworks typical proteolytic modules show sizes of 100 to 400 amino acids on the average. This corresponds with the average size of most of the globular proteolytic enzymes that are secreted into the medium. As discussed above polypeptide modules are polypeptide fragments, which can fold and function as independent entities. Another term for such modules is domains. However domain is used in a broader context than module. The term domain as used herein refers usually to a part of the polypeptide chain that depicts in the three-dimensional structure a typical folding topology. In a protein domains interact to varying extents, but less extensively than do the structural elements within domains. Other terms such as subdomain and folding unit are also used in literature. As such it is observed that many proteins that share a particular functionality may share the same domains. Such domains can be recognized from the primary structure that may show certain sequence patterns, which are typical for a particular domain. Typical examples are the mononucleotide binding fold, cellulose binding domains, helix-turn-helix DNA binding motif, zinc fingers, EF hands, membrane anchors. Modules refer to those domains which are expected to be able to fold and function autonomously. A person skilled in the art knows how to identify particular domains in a primary structure by applying commonly available computer software to said structure and homologous sequences from other organisms or species.

[0022]Although multimodular or multidomain proteins may appear as a string of beads, assemblies of substantial more complex architecture have been observed. In case the various beads reside on the same polypeptide chain the beads are generally called modules or domains. When the beads do not reside on one and same polypeptide chain but form assemblies via non-covalent interactions then the term subunit is used to designate the bead. Subunits may be transcribed by one and the same gene or by different genes. The multi-modular protein may become proteolytically processed after transcription leading to multiple subunits. Individual subunits may consist of multiple domains. Typically the smaller globular proteins of 100-300 amino acids usually consist only of one domain.

Molecular Classification of Proteolytic Enzymes

[0023]In general proteases are classified according to their molecular properties or according to their functional properties. The molecular classification is based on the primary structure of the protease. The primary structure of a protein represents its amino acid sequence, which can be derived from the nucleotide sequence of the corresponding gene. Tracing extensively the similarities in the primary structures may allow for the notice of similarities in catalytic mechanism and other properties, which even may extend to functional properties. The term family is used to describe a group of proteases that show evolutionary relationship based on similarity between their primary structures. The members of such a family are believed to have arisen by divergent evolution from the same ancestor. Within a family further sub-grouping of the primary structures based on more detailed refinement of sequence comparisons results in subfamilies. Classification according to three-dimensional fold of the proteases may comprise secondary structure, tertiary structure and quarternary structure. In general the classification on secondary structure is limited to content and gross orientation of secondary structure elements. Similarities in tertiary structure have led to the recognition of superfamilies or clans. A superfamily or a clan is a group of families that are thought to have common ancestry, as they show a common 3-dimensional fold. In general tertiary structure is more conserved than the primary structure. As a consequence similarity of the primary structure does not always reflect similar functional properties. In fact functional properties may have diverged substantially resulting in interesting new properties. At present quarternary structure has not been applied to classify various proteases. This might be due to a certain bias of the structural databases towards simple globular proteases. Many proteolytic systems that are subject to activation, regulation, or complex reaction cascades are likely to consist of multiple domains or subunits. General themes in the structural organization of such protease systems may lead to new types of classification.

Classification According to Specificity.

[0024]In absence of sequence information proteases haven been subject to various type of functional classification. The classification and naming of enzymes by reference to the reactions which are catalyzed is a general principle in enzyme nomenclature. This approach is also the underlying principle of the EC numbering of enzymes (Enzyme Nomenclature 1992 Academic Press, Orlando). Two types of proteases (EC 3.4) can be recognized within Enzyme Nomenclature 1992, those of the exo-peptidases (EC 3.4.11-19) and those of the endo-peptidases (EC 3.4.21-24, 3.4.99). Endo-peptidases cleave peptide bonds in the inner regions of the peptide chain, away from the termini. Exo-peptidases cleave only residues from the ends of the peptide chain. The exo-peptidases acting at the free N-terminus may liberate a single amino acid residue, a dipeptide or a tripeptide and are called respectively amino peptidases (EC 3.4.11), dipeptidyl peptidases (EC 3.4.14) and tripeptidyl peptidase (EC 3.3.14). Proteases starting peptide processing from the carboxyl terminus liberating a single amino acid are called carboxy peptidase (EC 3.4.16-18). Peptidyl-dipeptidases (EC 3.4.15) remove a dipeptide from the carboxyl terminus. Exo- and endo-peptidase in one are the dipeptidases (EC 3.4.13), which cleave specifically only dipeptides in their two amino acid halves. Omega peptidases (EC 3.4.19) remove terminal residues that are either substituted, cyclic, or linked by isopeptide bonds

[0025]Apart from the position where the protease cleaves a peptide chain, for each type of protease a further division is possible based on the nature of the preferred amino acid residues in the substrate. In general one can distinguish proteases with broad, medium and narrow specificity. Some proteases are simply named after the specific proteins or polypeptides that they hydrolyze, e.g. keratinase, collagenase, elastase. A narrow specificity may pin down to one particular amino acid or one particular sequence which is removed or which is cleaved respectively. When the protease shows a particular preference for one amino acid in the P1 or P1' position the name of this amino acid may be a qualifier. For example prolyl amino peptidase removes proline from the amino terminus of a peptide (proline is the P1 residue). X-Pro or proline is used when the bond on the imino side of the proline is cleaved (proline is P1' residue), eg proline carboxypeptidase removes proline from the carboxyl terminus. Prolyl endopeptidase (or Pro-X) cleaves behind proline while proline endopeptidase (X-Pro) cleaves in front of a proline. Amino acid residue in front of the scissile peptide bond refers to the amino acid residue that contributes the carboxyl group to the peptide bond. The amino acids residue behind the scissile peptide bond refers to the amino acid residue that contributes the amino group to the peptide bond. According to the general convention an amino acid chain runs from amino terminus (the start) to the carboxyl terminus (the end) and is numbered accordingly. Endo proteases may also show clear preference for a particular amino acid in the P1 or P1' position, eg glycyl endopeptidase, peptidyl-lysine endopeptidase, glutamyl endopeptidase. In addition proteases may show a preference for a certain group of amino acids that share a certain resemblance. Such a group of preferred amino acids may comprise the hydrophobic amino acids, only the bulky hydrophobic amino acids, small hydrophobic, or just small amino acids, large positively charged amino acids, etc, etc. Apart from preferences for P1 and P1' residues also particular preferences or exclusions may exist for residues preferred by other subsites on the protease. Such multiple preferences can result in proteases that are very specific for only those sequences that satisfy multiple binding requirements at the same time. In general it should be realized that protease are rather promiscuous enzymes. Even very specific protease may cleave peptides that do not comply with the generally observed preference of the protease. In addition it should be realized that environmental conditions such as pH, temperature, ionic strength, water activity, presence of solvents, presence of competing substrates or inhibitors may influence the preferences of the proteases. Environmental condition may not only influence the protease but also influence the way the proteinacious substrate is presented to the protease.

Classification by Catalytic Mechanism.

[0026]Proteases can be subdivided on the basis of their catalytic mechanism. It should be understood that for each catalytic mechanism the above classification based on specificity leads to further subdivision for each type of mechanism. Four major classes of proteases are known and are designated by the principal functional group in the active site: the serine proteases (EC 3.4.21 endo peptidase, EC 3.4.16 carboxy peptidase), the thiol or cysteine proteases (EC 3.4.22 endo peptidase, EC 3.4.18 carboxy peptidase), the carboxyl or aspartic proteases (EC 3.4.23 endo peptidase) and metallo proteases (EC 3.4.24 endo peptidase, EC 3.4.18 carboxy peptidase). There are characteristic inhibitors of the members of each catalytic type of protease. These small inhibitors irreversibly modify an amino acid residue of the protease active site. For example, the serine protease are inactivated by Phenyl Methane Sulfonyl Fluoride (PMSF) and Diisopropyl Fluoro Phosphate (DFP), which react with the active Serine whereas the chloromethylketone derivatives react with the Histidine of the catalytic triad. Phosphoramidon and 1,10 Phenanthroline typically inhibit metallo proteases. Inhibition by Pepstatin generally indicates an aspartic protease. E64 inhibits thiol protease specifically. Amastatin and Bestatin inhibit various aminopeptidases. Substantial variations in susceptibility of the proteases to the inhibitors are observed, even within one catalytic class. To a certain extent this might be related to the specificity of the protease. In case binding site architecture prevents a mechanism based inhibitor to approach the catalytic site, then such a protease escapes from inhibition and identification of the type of mechanism based on inhibition is prohibited. Chymostation for example is a potent inhibitor for serine protease with chymotrypsin like specificity, Elastatinal inhibits elastase like serine proteases and does not react with trypsin or chymostrypsin, 4 amido PMSF (APMSF) inhibits only serine proteases with trypsin like specificity. Extensive accounts of the use of inhibitors in the classification of proteases include Barret and Salvesen, Proteinase Inhibitors, Elsevier Amstardam, 1986; Bond and Beynon (eds), Proteolytic Enzymes, A Practical Approach, IRL Press, Oxford, 1989; Methods in Enzymology, eds E. J. Barret, volume 244, 1994 and volume 248, 1995; E. Shaw, Cysteinyl proteinases and their selective inactivation, Adv Enzymol. 63:271-347 (1990)

Classification According to Optimal Performance Conditions.

[0027]The catalytic mechanism of a proteases and the requirement for its conformational integrity determine mainly the conditions under which the protease can be utilized. Finding the protease that performs optimal under application conditions is a major challenge. Often conditions at which proteases have to perform are not optimal and do represent a compromise between the ideal conditions for a particular application and the conditions which would suit the protease best. Apart from the particular properties of the protease it should be realized that also the presentation of a proteinacious substrates is dependant on the conditions, and as such determines also which conditions are most effective for proteolysis. Specifications for the enzyme that are relevant for application comprise for example the pH dependence, the temperature dependence, sensitivity for or the dependence of metal ions, ionic strength, salt concentration, solvent compatibility. Another factor of major importance is the specific activity of a protease. The higher the enzyme's specific activity, the less enzyme is needed for a specific conversion. Lower enzyme requirements imply lower costs and lower protein contamination levels.

[0028]The pH is a major parameter that determines protease performance in an application. Therefor pH dependence is an important parameter to group proteases. The major groups that are recognized are the acid proteases, the neutral proteases, the alkaline proteases and the high alkaline proteases. The optimum pH matches only to some extent the proteolytic mechanism, eg aspartic protease show often an optimum at acidic pH, metalloproteases and thiol proteases often perform optimal around neutral pH to slightly alkaline, serine peptidases are mainly active in the alkaline and high alkaline region. For each class exceptions are known. In addition the overall water activity of the system plays a role. The pH optimum of a protease is defined as the pH range where the protease exhibits an optimal hydrolysis rate for the majority of its substrates in a particular environment under particular conditions. This range can be narrow, e.g. one pH unit, as well as quite broad, 3-4 pH units. In general the pH optimum is also dependant on the nature of the proteinacious substrate. Both the turnover rate as well as the specificity may vary as a function of pH. For a certain efficacy it can be desirable to use the protease far from its pH optimum because production of less desired peptides is avoided. Less desired peptides might be for example very short peptides or peptides causing a bitter taste. In addition a more narrow specificity can be a reason to choose conditions that deviate from optimal conditions with respect to turnover rate. Dependant on the pH the specificity may be narrow, e.g. only cleaving the peptide chain in one particular position or before or after one particular amino acid, or broader, e.g. cleaving a chain at multiple positions or cleaving before or after more different types of amino acids. In fact the pH dependence might be an important tool to regulate the proteolytic activity in an application. In case the pH shifts during the process the proteolysis might cease spontaneously without the need for further treatment to inactivate the protease. In some cases the proteolysis itself may be the driver of the pH shift.

[0029]Very crucial for application of proteases is their handling and operating stability. As protease stability is strongly affected by the working temperature, stability is often also referred to as thermostability. In general the stability of a protease indicates how long a protease retains its proteolytic activity under particular conditions. Particular conditions may comprise fermentation conditions, conditions during isolation and down stream processing of the enzyme, storage conditions, formulation and operating or application conditions. In case particular conditions encompass elevated temperatures stability in general refers to thermostability. Apart from the general causes for enzyme inactivation such as chemical modification, unfolding, aggregation etc, main problem with proteases is that they are easy subject to autodegradation. Especially for the utilization of proteases the temperature optimum is a relevant criterion to group proteases. Although there are different definitions, economically the most useful definition is the temperature or the temperature range in which the protease is most productive in a certain application. Protease productivity is a function of both the stability and the turnover rate. Where elevated temperature in general will increase the turnover rate, rapid inactivation will counteract the increase in turnover rate and ultimately lead to low productivity. The conformational stability of the protease under a given process condition will determine its maximum operating temperature. The temperature at which the protease looses it active conformation, often indicated as unfolding or melting point, can be determined according various methods, for example NMR, Circular Dichroism Spectroscopy, Differential Scanning Calorimetry etc. For protease unfolding is usually accompanied by a tremendous increase in autodegradation rate.

[0030]In applications where low temperatures are required protease may be selected with emphasis on a high intrinsic activity at low to moderate temperature. As under such conditions inactivation is relatively slow, under these conditions activity might largely determine productivity. In processes where only during a short period protease activity is required, the stability of the protease might be used as a switch to turn the protease off. In such case more labile instead of very thermostable protease might be preferred.

[0031]Other environmental parameters which may play a role in selecting the appropriate protease may be its sensitivity to salts. The compatibility with metal ions which are found frequently at low concentrations in various natural materials can be crucial for certain applications. In particular with metallo proteases certain ions may replace the catalytic metal ion and reduce or even abolish activity completely. In some applications metal ions have to be added on purpose in order to prevent the washout of the metal ions coordinated to the protease. It is well known that for the sake of enzyme stability and life-time, calcium ions have to be supplied in order to prevent dissociation of protein bound calcium.

[0032]Most microorganisms show a certain tolerance with respect to adapting to changes in the environmental condition. As a consequence at least the proteolytic spectrum that the organism is able to produce are likely to show at least similar tolerances. Such a proteolytic spectrum might be covered by many proteases covering together the hole spectrum or by only a few proteases of a broad spectrum. Taking into account the whole proteolytic spectrum of a microorganism it can be very important to take the location into account.

Cellular Localisation and Characterization of Proteolytic Processing and Degradation

[0033]From an industrial point of view the proteases which are excreted from the cell have specific advantages with respect to producibility at a large scale and stress tolerance as they have to survive without protection of the cell. The large group of cellular protease can be further subdivided in soluble and membrane bound. Membrane bound may comprise protease at the inside as well the outside of the membrane. Intracellular soluble protease may be subdivided further according to specific compartments of the cell where they do occur. As the cell shields the proteases to some extent from the environment and because the cell controls the conditions in the cell, intracellular protease might be more sensitive to large environmental changes and their optima might correlate better with the specific intracelluar conditions. Knowing the conditions of the cellular department where the protease resides might indicate their preferences. Where extracellular protease in general do not require any regulation any more once excreted from the cell, intracellular proteases are often subject to more complicated control and regulation.

[0034]With respect to the function of a particular protease, its localisation is often very important; for example, a lot of the vacuolar and periplasmic proteases are involved in protein degradation, while many of the membrane-bound proteases are important in protein processing (Suarez Rendueles and Wolf, 1988).

[0035]A comprehensive review on the biological properties and evolution of proteases has been published in van den Hombergh: Thesis Landbouwuniversiteit Wageningen: An analysis of the proteolytic system in Aspergillus in order to improve protein production ISBN 90-5485-545-2, which is hereby incorporated by reference herein.

The Protease Problem

[0036]An important reason for the interest in microbial proteases are protease related expression problems observed in several expression hosts used in bioprocess industry. The increasing use of heterologous hosts for the production of proteins, by recombinant DNA technology, has recently brought this problem into focus, since it seems that heterologous proteins are more prone to proteolysis (Archer et al., 1992; van den Hombergh et al., 1996b).

[0037]In S. cerevisiae, already in the early eighties the protease problem and the involvement of several proteases, thus complicating targeted gene disruption approaches to overcome this problem, was recognised. During secretion a protein is exposed to several proteolytic activities residing in the secretory pathway. Additionally, in a prototrophic microorganism as Aspergillus secreted proteins can be exposed to several extracellular proteolytic activities

[0038]The problem of degradation of heterologously expressed proteins is well documented in Aspergillus (van den Hombergh Thesis Landbouwuniversiteit Wageningen: An analysis of the proteolytic system in Aspergillus in order to improve protein production ISBN 90-5485-545-2) and has been reported in the expression of cow prochymosin, human interferon .alpha.-2 tPA, GMCSF, IL6, lactoferrin, chicken egg-white lysosyme, porcine plA2, A. niger pectin lyase B, E. coli enterotoxin B and .beta.-glucoronidase, and Erwinia carotovora pectate lyase 3.

[0039]The problem of proteolysis may be addressed at several stages in protein production. Bioprocess engineers may address the problem of proteolysis by downstream processing at low temperatures, by early separation of product and protease(s) or by use of protease inhibitors. These may all lead to successful reduction of the problem. However it is certainly not eliminated, because much of the degradation occurs in vivo during the production of the protein.

[0040]In understanding how proteolysis is controlled in the cell, a major question concerns the recognition mechanism by which proteolysis is triggered. Into what extent are proteolytically susceptable (heterologous) proteins recognised as aberrant because of misfolding or, if correctly folded, as `foreign`, because they do not posses features essential for stability which are specific to the host. Various types of stress can cause the overall proteolysis in a cell to increase significantly. Factors known to increase rate of proteolysis include nutrient starvation and various other types of stress (i.e. elevation of temperature, osmotic stress, toxic substances and expression of certain heterologous proteins). To deal with proteolysis-related expression problems in vivo, several approaches have been proven successful as will be discussed below. However, we have to keep in mind that true `non-proteolytic cells` cannot exist, since proteolysis by intracellular proteases is involved in many essential metabolic and `housekeeping` reactions. Reducing proteolysis will therefore always be a process in which the changed genetical background which results in decreased proteolytic has to be analysed for potential secondary effects which could lead to reduced protein production (e.g. reduced growth rate or sporulation).

Disruption of Proteases in Filamentous Fungal Expression Hosts

[0041]Berka and coworkers (1990) describe the cloning and disruption of the A. awamori pepA gene. More recently, three disrupted aspartyl proteases in A. niger have been described. Disruptants for both the major extracellular aspartyl proteases and the major vacuolar aspartyl protease were described. Double and triple disruptants were generated via recombination and tested for protease spectra and expression and secretion of the A. niger pectin lyase PELB protein, which is very susceptable to proteolytic degradation (van den Hombergh et al., 1995). Disruption of pepA and pepB resulted both in reduction of extracellular protease activities, 80% and 6%, respectively. In the .DELTA.pepE disruptant also other (vacuolar) protease activities were severely affected caused by inactivating of the proteolytic cascade for other vacuolar proteases. Reduced extracellular activities correlated with reduced in vitro degradation of PELB and improved in vivo expression of pelB (van den Hombergh et al., 1996f).

Protease Deficient (prt) Mutants Filamentous Fungi

[0042]Several Aspergillus protease deficient mutants have been studied whether protein production is improved. Archer and coworkers describe the reduced proteolysis of Hen egg white lysozyme in supernatants of an A. niger double prt mutant generated by Mattern and coworkers (1992) and conclude that although the degradation is not absent, it is significantly reduced. Van den Hombergh et al. (1995) show that the in vitro degradation of A. niger PELB is reduced in all seven prt complementation groups they have isolated. Virtually no degradation is observed in the prtB, prtF and prtG mutants. Recently, the expression of the pelB gene was shown to be improved in six complementation groups tested (prtA-F) and highest expression levels were observed in the prtB, prtF and prtG mutants. In addition to the single mutants, which contained residual extracellular proteolytic activities varying from 2-80% compared to wild type activity, double mutants were generated both by recombination and by additional rounds of mutagenesis. Via this approach several double prt mutants were selected and further characterised, which showed a further reduction of PELB degradation compared to their parental strains.

[0043]Instead of elimination of protease activities via disruption or mutagenesis, reduced proteolysis can also be achieved via down-regulation of the interfering proteolytic activities. This may be achieved by genetically altering the promoter or other regulatory sequences of the gene. As shown by Fraissinet-Tachet and coworkers (1996) the extracellular proteases in A. niger are all regulated by carbon catabolite repression and nitrogen metabolite repression. Nutrient starvation also causes the overall proteolysis rate in a cell to increase strongly, which makes sense for a cell that lacks nutrients but posses proteins, that under starvation conditions are not needed or needed only in smaller amounts. In expression strategies which allow high expression on media containing high glucose and ammonium concentrations reduced proteolysis has been reported. Several constitutive glycolytic promoters (gpd and pkiA) are highly expressed under these conditions and can also be used to drive (heterologous) gene expression in continuous fermentations. The type of nutrient starvation imposed can influence different proteases to varying extent, which means that the importance of nutrient conditions in a given process depend on the type of proteolysis that is involved. Specific proteolysis may therefore be induced by conditions of substrate limitation which are frequently used in many large-scale fermentation processes.

[0044]The protease problem can nowadays be addressed in part by one or more of the above strategies. However, the residual proteolytic activity of yet unidentified proteolytic enzymes still constitutes a major problem in the art. In order to further reduce the level of unwanted proteolysis, there is a great need in the art to identify novel proteases responsible for degradation of homologously and heterologously expressed proteins. This invention provides such novel protease gene sequences encoding novel proteases. Once the primary sequence of a novel protease gene is known, one or more of the above recombinant DNA strategies may be employed to produce (knock-out) mutants with reduced proteolytic activity.

[0045]Despite the widespread applications of proteases in a great number of industrial processes, current enzymes also have significant shortcomings with respect to at least one of the following properties.

[0046]When added to animal feed, current proteases are not sufficiently resistant to digestive enzymes present in the gastrointestinal (GI) tract of e.g. pigs and poultry.

[0047]With respect to another aspect, the currently available enzymes are not sufficiently resistant to specific (high) temperatures and (high) pressure conditions that are applied during extrusion or pelleting operations.

[0048]Also, the current enzymes are not sufficiently active in a pH range of 3-7, conditions prevailing in many food, beverage products as well as in the GI tract of most animals.

[0049]According to yet another aspect the specificity of the currently available proteases is very limited which results in the inability of the existing enzymes to degrade or to dissolve certain "protease resistant" proteins thus resulting in low peptide or amino acid yields. Moreover proteases with new specificities allow the synthesis of new peptides.

[0050]Yet another drawback of the currently available enzymes is their low specific activity.

[0051]It is therefore clear that for a large number of applications a strong desire exists for proteases that are more resistant to digestive enzymes, high temperature and/or pressure and which exhibit novel specificities regarding their sites of hydrolysis. The present invention provides such enzymes.

OBJECT OF THE INVENTION

[0052]It is an object of the invention to provide novel polynucleotides encoding novel proteases. A further object is to provide naturally and recombinantly produced proteases as well as recombinant strains producing these. Such strains may also be used to produce classical fermentation products faster or with higher yields. Yet another object of the invention is to provide a filamentous fungus strain defective in producing a protease according to the invention. Such strains may be used for a more efficient production of heterologous or homologous proteins. Also antibodies and fusion polypeptides are part of the invention as well as methods of making and using the polynucleotides and polypeptides according to the invention.

SUMMARY OF THE INVENTION

[0053]The invention provides for novel polynucleotides encoding novel proteases.

[0054]More in particular, the invention provides for polynucleotides having a nucleotide sequence that hybridises (preferably under highly stringent conditions) to a sequence according to a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or to a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114. Consequently, the invention provides nucleic acids that are about 60%, preferably 65%, more preferably 70%, even more preferably 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% homologous to the sequences according to a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114.

[0055]In a more preferred embodiment the invention provides for such an isolated polynucleotide obtainable from a filamentous fungus, preferably Aspergilli, in particular A. niger is preferred.

[0056]In one embodiment, the invention provides for an isolated polynucleotide comprising a nucleic acid sequence encoding a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171 or functional equivalents thereof.

[0057]In a further preferred embodiment, the invention provides an isolated polynucleotide encoding at least one functional domain of a polypeptide according to a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171 or functional equivalents thereof.

[0058]In a preferred embodiment the invention provides a protease gene according to a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57. In another aspect the invention provides a polynucleotide, preferably a cDNA encoding an A. niger protease selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171 or variants or fragments of that polypeptide. In a preferred embodiment the cDNA has a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114 or functional equivalents thereof.

[0059]A genomic clone encoding a polypeptide according to the invention may also be obtained by selecting suitable probes to specifically amplify a genomic region corresponding to any of the sequences according to SEQ ID NO: 1 to SEQ ID NO: 57 or fragments thereof, hybridising that probe under suitable conditions to genomic DNA obtained from a suitable organism, such as Aspergillus, e.g. A. niger, amplifying the desired fragment e.g. by PCR (polymerase chain reaction) followed by purifying and cloning of the amplified fragment.

[0060]In an even further preferred embodiment, the invention provides for a polynucleotide comprising the coding sequence of the genomic polynucleotides according to the invention, preferred is a polynucleotide sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114.

[0061]In another preferred embodiment, the invention provides a cDNA obtainable by cloning and expressing a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 into a suitable host organism, such as A. niger.

[0062]A polypeptide according to the invention may also be obtained by cloning and expressing a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 into a suitable host organism, such as A. niger.

[0063]The invention also relates to vectors comprising a polynucleotide sequence according to the invention and primers, probes and fragments that may be used to amplify or detect the DNA according to the invention.

[0064]In a further preferred embodiment, a vector is provided wherein the polynucleotide sequence according to the invention is functionally linked with regulatory sequences suitable for expression of the encoded amino acid sequence in a suitable host cell, such as A. niger or A. oryzea. The invention also provides methods for preparing polynucleotides and vectors according to the invention.

[0065]The invention also relates to recombinantly produced host cells that contain heterologous or homologous polynucleotides according to the invention.

[0066]In one embodiment, the invention provides recombinant host cells wherein the expression of a protease according to the invention is significantly reduced or wherein the activity of the protease is reduced or wherein the protease is even inactivated. Such recombinants are especially useful for the expression of homologous or heterologous proteins.

[0067]In another embodiment, the invention provides recombinant host cells wherein the expression of a protease according to the invention is significantly increased or wherein the activity of the protease is increased. Such recombinants are especially useful for the expression of homologous or heterologous proteins where maturation is seriously hampered in case the required proteolytic cleavage becomes the rate limiting step.

[0068]In another embodiment the invention provides for a recombinantly produced host cell that contains heterologous or homologous DNA according to the invention, preferably DNA encoding proteins bearing signal sequences and wherein the cell is capable of producing a functional protease according to the invention, preferably a cell capable of over-expressing the protease according to the invention, for example an Aspergillus strain comprising an increased copy number of a gene or cDNA according to the invention.

[0069]In another embodiment the invention provides for a recombinantly produced host cell that contains heterologous or homologous DNA according to the invention and wherein the cell is capable of secreting a functional protease according to the invention, preferably a cell capable of over-expressing and secreting the protease according to the invention, for example an Aspergillus strain comprising an increased copy number of a gene or cDNA according to the invention.

[0070]In yet another aspect of the invention, a purified polypeptide is provided. The polypeptides according to the invention include the polypeptides encoded by the polynucleotides according to the invention. Especially preferred is a polypeptide according to a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171 or functional equivalents thereof.

[0071]The invention also provides for antibodies reactive with a polypeptide according to the invention. These antibodies may be polyclonal, yet especially preferred are monoclonal antibodies. Such antibodies are particularly useful for purifying the polypeptides according to the invention.

[0072]Fusion proteins comprising a polypeptide according to the invention are also within the scope of the invention. The invention also provides methods of making the polypeptides according to the invention.

[0073]The invention further relates to a method for diagnosing aspergillosis either by detecting the presence of a polypeptide according to the invention or functional equivalents thereof, or by detecting the presence of a DNA according to the invention or fragments or functional equivalents thereof.

[0074]The invention also relates to the use of the protease according to the invention in an industrial process as described herein

DETAILED DESCRIPTION OF THE INVENTION

Polynucleotides

[0075]The present invention provides polynucleotides encoding proteases having an amino acid sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171 or functional equivalents thereof. The sequence of these genes was determined by sequencing a genomic clone obtained from Aspergillus niger. The invention provides polynucleotide sequences comprising the gene encoding these proteases as well as their complete cDNA sequence and its coding sequence. Accordingly, the invention relates to an isolated polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114 or functional equivalents thereof.

[0076]More in particular, the invention relates to an isolated polynucleotide hybridisable under stringent conditions to a polynucleotide selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114 preferably under highly stringent conditions. Advantageously, such polynucleotides may be obtained from filamentous fungi, in particular from Aspergillus niger. More specifically, the invention relates to an isolated polynucleotide having a nucleotide sequence according to a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114.

[0077]The invention also relates to an isolated polynucleotide encoding at least one functional domain of a polypeptide according to a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171 or functional equivalents thereof.

[0078]As used herein, the terms "gene" and "recombinant gene" refer to nucleic acid molecules which may be isolated from chromosomal DNA, which include an open reading frame encoding a protein, e.g. an A. niger protease. A gene may include coding sequences, non-coding sequences, introns and regulatory sequences. Moreover, a gene refers to an isolated nucleic acid molecule as defined herein.

[0079]A nucleic acid molecule of the present invention, such as a nucleic acid molecule having the nucleotide sequence of a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114 or a functional equivalent thereof, can be isolated using standard molecular biology techniques and the sequence information provided herein. For example, using all or portion of the nucleic acid sequence of a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or the nucleotide sequence of a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114 as a hybridization probe, nucleic acid molecules according to the invention can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook, J., Fritsh, E. F., and Maniatis, T. Molecular Cloning: A Laboratory Manual. 2nd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989).

[0080]Moreover, a nucleic acid molecule encompassing all or a portion of a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114 can be isolated by the polymerase chain reaction (PCR) using synthetic oligonucleotide primers designed based upon the sequence information contained in a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114.

[0081]A nucleic acid of the invention can be amplified using cDNA, mRNA or alternatively, genomic DNA, as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis.

[0082]Furthermore, oligonucleotides corresponding to or hybridisable to nucleotide sequences according to the invention can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer.

[0083]In a preferred embodiment, an isolated nucleic acid molecule of the invention comprises the nucleotide sequence shown in a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114. The sequence of a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114 corresponds to the coding region of the A. niger protease cDNA. This cDNA comprises sequences encoding the A. niger protease polypeptide according to a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171.

[0084]In another preferred embodiment, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule which is a complement of the nucleotide sequence shown in a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114 or a functional equivalent of these nucleotide sequences.

[0085]A nucleic acid molecule which is complementary to another nucleotide sequence is one which is sufficiently complementary to the other nucleotide sequence such that it can hybridize to the other nucleotide sequence thereby forming a stable duplex.

[0086]One aspect of the invention pertains to isolated nucleic acid molecules that encode a polypeptide of the invention or a functional equivalent thereof such as a biologically active fragment or domain, as well as nucleic acid molecules sufficient for use as hybridisation probes to identify nucleic acid molecules encoding a polypeptide of the invention and fragments of such nucleic acid molecules suitable for use as PCR primers for the amplification or mutation of nucleic acid molecules.

[0087]An "isolated polynucleotide" or "isolated nucleic acid" is a DNA or RNA that is not immediately contiguous with both of the coding sequences with which it is immediately contiguous (one on the 5' end and one on the 3' end) in the naturally occurring genome of the organism from which it is derived. Thus, in one embodiment, an isolated nucleic acid includes some or all of the 5' non-coding (e.g., promotor) sequences that are immediately contiguous to the coding sequence. The term therefore includes, for example, a recombinant DNA that is incorporated into a vector, into an autonomously replicating plasmid or virus, or into the genomic DNA of a prokaryote or eukaryote, or which exists as a separate molecule (e.g., a cDNA or a genomic DNA fragment produced by PCR or restriction endonuclease treatment) independent of other sequences. It also includes a recombinant DNA that is part of a hybrid gene encoding an additional polypeptide that is substantially free of cellular material, viral material, or culture medium (when produced by recombinant DNA techniques), or chemical precursors or other chemicals (when chemically synthesized). Moreover, an "isolated nucleic acid fragment" is a nucleic acid fragment that is not naturally occurring as a fragment and would not be found in the natural state.

[0088]As used herein, the terms "polynucleotide" or "nucleic acid molecule" are intended to include DNA molecules (e.g., cDNA or genomic DNA) and RNA molecules (e.g., mRNA) and analogs of the DNA or RNA generated using nucleotide analogs. The nucleic acid molecule can be single-stranded or double-stranded, but preferably is double-stranded DNA. The nucleic acid may be synthesized using oligonucleotide analogs or derivatives (e.g., inosine or phosphorothioate nucleotides). Such oligonucleotides can be used, for example, to prepare nucleic acids that have altered base-pairing abilities or increased resistance to nucleases.

[0089]Another embodiment of the invention provides an isolated nucleic acid molecule which is antisense to a protease nucleic acid molecule, e.g., the coding strand of a protease nucleic acid molecule. Also included within the scope of the invention are the complement strands of the nucleic acid molecules described herein.

Sequencing Errors

[0090]The sequence information as provided herein should not be so narrowly construed as to require inclusion of erroneously identified bases. The specific sequences disclosed herein can be readily used to isolate the complete gene from filamentous fungi, in particular A. niger which in turn can easily be subjected to further sequence analyses thereby identifying sequencing errors.

[0091]Unless otherwise indicated, all nucleotide sequences determined by sequencing a DNA molecule herein were determined using an automated DNA sequencer and all amino acid sequences of polypeptides encoded by DNA molecules determined herein were predicted by translation of a DNA sequence determined as above. Therefore, as is known in the art for any DNA sequence determined by this automated approach, any nucleotide sequence determined herein may contain some errors. Nucleotide sequences determined by automation are typically at least about 90% identical, more typically at least about 95% to at least about 99.9% identical to the actual nucleotide sequence of the sequenced DNA molecule. The actual sequence can be more precisely determined by other approaches including manual DNA sequencing methods well known in the art. As is also known in the art, a single insertion or deletion in a determined nucleotide sequence compared to the actual sequence will cause a frame shift in translation of the nucleotide sequence such that the predicted amino acid sequence encoded by a determined nucleotide sequence will be completely different from the amino acid sequence actually encoded by the sequenced DNA molecule, beginning at the point of such an insertion or deletion.

[0092]The person skilled in the art is capable of identifying such erroneously identified bases and knows how to correct for such errors.

Nucleic Acid Fragments, Probes and Primers

[0093]A nucleic acid molecule according to the invention may comprise only a portion or a fragment of the nucleic acid sequence shown in a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114, for example a fragment which can be used as a probe or primer or a fragment encoding a portion of a protease protein. The nucleotide sequence determined from the cloning of the protease gene and cDNA allows for the generation of probes and primers designed for use in identifying and/or cloning other protease family members, as well as protease homologues from other species. The probe/primer typically comprises substantially purified oligonucleotide which typically comprises a region of nucleotide sequence that hybridizes preferably under highly stringent conditions to at least about 12 or 15, preferably about 18 or 20, preferably about 22 or 25, more preferably about 30, 35, 40, 45, 50, 55, 60, 65, or 75 or more consecutive nucleotides of a nucleotide sequence shown in a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114 or of a functional equivalent thereof.

[0094]Probes based on the protease nucleotide sequences can be used to detect transcripts or genomic protease sequences encoding the same or homologous proteins for instance in other organisms. In preferred embodiments, the probe further comprises a label group attached thereto, e.g., the label group can be a radioisotope, a fluorescent compound, an enzyme, or an enzyme cofactor. Such probes can also be used as part of a diagnostic test kit for identifying cells which express a protease protein.

Identity & Homology

[0095]The terms "homology" or "percent identity" are used interchangeably herein. For the purpose of this invention, it is defined here that in order to determine the percent identity of two amino acid sequences or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity=number of identical positions/total number of positions (i.e. overlapping positions).times.100).

[0096]Preferably, the two sequences are the same length.

[0097]The skilled person will be aware of the fact that several different computer programs are available to determine the homology between two sequences. For instance, a comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at http://www.gcg.com), using either a Blossom 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. The skilled person will appreciate that all these different parameters will yield slightly different results but that the overall percentage identity of two sequences is not significantly altered when using different algorithms.

[0098]In yet another embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http://www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. In another embodiment, the percent identity two amino acid or nucleotide sequence is determined using the algorithm of E. Meyers and W. Miller (CABIOS, 4:11-17 (1989) which has been incorporated into the ALIGN program (version 2.0) (available at http://vega/igh.cnrs.fr/bin/align-guess.cgi), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

[0099]The nucleic acid and protein sequences of the present invention can further be used as a "query sequence" to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to protease nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to protease protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25(17):3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http://www.ncbi.nlm.nih.gov.

Hybridisation

[0100]As used herein, the term "hybridizing" is intended to describe conditions for hybridization and washing under which nucleotide sequences at least about 50%, at least about 60%, at least about 70%, more preferably at least about 80%, even more preferably at least about 85% to 90%, more preferably at least 95% homologous to each other typically remain hybridized to each other.

[0101]A preferred, non-limiting example of such hybridization conditions are hybridization in 6.times. sodium chloride/sodium citrate (SSC) at about 45.degree. C., followed by one or more washes in 1.times.SSC, 0.1% SDS at 50.degree. C., preferably at 55.degree. C., preferably at 60.degree. C. and even more preferably at 65.degree. C.

[0102]Highly stringent conditions include, for example, hybridizing at 68.degree. C. in 5.times.SSC/5.times.Denhardt's solution/1.0% SDS and washing in 0.2.times.SSC/0.1% SDS at room temperature. Alternatively washing may be performed at 42.degree. C.

[0103]The skilled artisan will know which conditions to apply for stringent and highly stringent hybridisation conditions. Additional guidance regarding such conditions is readily available in the art, for example, in Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, N.Y.; and Ausubel et al. (eds.), 1995, Current Protocols in Molecular Biology, (John Wiley & Sons, N.Y.).

[0104]Of course, a polynucleotide which hybridizes only to a poly A sequence (such as the 3' terminal poly(A) tract of mRNAs), or to a complementary stretch of T (or U) resides, would not be included in a polynucleotide of the invention used to specifically hybridize to a portion of a nucleic acid of the invention, since such a polynucleotide would hybridize to any nucleic acid molecule contain a poly (A) stretch or the complement thereof (e.g., practically any double-stranded cDNA clone).

Obtaining Full Length DNA from Other Organisms

[0105]In a typical approach, cDNA libraries constructed from other organisms, e.g. filamentous fungi, in particular from the species Aspergillus can be screened.

[0106]For example, Aspergillus strains can be screened for homologous protease polynucleotides by Northern blot analysis. Upon detection of transcripts homologous to polynucleotides according to the invention, cDNA libraries can be constructed from RNA isolated from the appropriate strain, utilizing standard techniques well known to those of skill in the art. Alternatively, a total genomic DNA library can be screened using a probe hybridisable to a protease polynucleotide according to the invention.

[0107]Homologous gene sequences can be isolated, for example, by performing PCR using two oligonucleotide primers or two degenerate oligonucleotide primer pools designed on the basis of nucleotide sequences as taught herein.

[0108]The template for the reaction can be cDNA obtained by reverse transcription of mRNA prepared from strains known or suspected to express a polynucleotide according to the invention. The PCR product can be subcloned and sequenced to ensure that the amplified sequences represent the sequences of a new protease nucleic acid sequence, or a functional equivalent thereof.

[0109]The PCR fragment can then be used to isolate a full length cDNA clone by a variety of known methods. For example, the amplified fragment can be labeled and used to screen a bacteriophage or cosmid cDNA library. Alternatively, the labeled fragment can be used to screen a genomic library.

[0110]PCR technology also can be used to isolate full length cDNA sequences from other organisms. For example, RNA can be isolated, following standard procedures, from an appropriate cellular or tissue source. A reverse transcription reaction can be performed on the RNA using an oligonucleotide primer specific for the most 5' end of the amplified fragment for the priming of first strand synthesis.

[0111]The resulting RNA/DNA hybrid can then be "tailed" (e.g., with guanines) using a standard terminal transferase reaction, the hybrid can be digested with RNase H, and second strand synthesis can then be primed (e.g., with a poly-C primer). Thus, cDNA sequences upstream of the amplified fragment can easily be isolated. For a review of useful cloning strategies, see e.g., Sambrook et al., supra; and Ausubel et al., supra.

Vectors

[0112]Another aspect of the invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding a protease protein or a functional equivalent thereof. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as "expression vectors". In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. The terms "plasmid" and "vector" can be used interchangeably herein as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.

[0113]The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vector includes one or more regulatory sequences, selected on the basis of the host cells to be used for expression, which is operatively linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, "operatively linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner which allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). The term "regulatory sequence" is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signal). Such regulatory sequences are described, for example, in Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those which direct constitutive expression of a nucleotide sequence in many types of host cells and those which direct expression of the nucleotide sequence only in a certain host cell (e.g. tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, encoded by nucleic acids as described herein (e.g. protease proteins, mutant forms of protease proteins, fragments, variants or functional equivalents thereof, fusion proteins, etc.).

[0114]The recombinant expression vectors of the invention can be designed for expression of protease proteins in prokaryotic or eukaryotic cells. For example, protease proteins can be expressed in bacterial cells such as E. coli, insect cells (using baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

[0115]Expression vectors useful in the present invention include chromosomal-, episomal- and virus-derived vectors e.g., vectors derived from bacterial plasmids, bacteriophage, yeast episome, yeast chromosomal elements, viruses such as baculoviruses, papova viruses, vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses and retroviruses, and vectors derived from combinations thereof, such as those derived from plasmid and bacteriophage genetic elements, such as cosmids and phagemids.

[0116]The DNA insert should be operatively linked to an appropriate promoter, such as the phage lambda PL promoter, the E. coli lac, trp and tac promoters, the SV40 early and late promoters and promoters of retroviral LTRs, to name a few. Other suitable promoters will be known to the skilled person. In a specific embodiment, promoters are preferred that are capable of directing a high expression level of proteases in filamentous fungi. Such promoters are known in the art. The expression constructs may contain sites for transcription initiation, termination, and, in the transcribed region, a ribosome binding site for translation. The coding portion of the mature transcripts expressed by the constructs will include a translation initiating AUG at the beginning and a termination codon appropriately positioned at the end of the polypeptide to be translated.

[0117]Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms "transformation" and "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, transduction, infection, lipofection, cationic lipid mediated transfection or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (Molecular Cloning: A Laboratory Manual, 2.sup.nd, ed. Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), Davis et al., Basic Methods in Molecular Biology (1986) and other laboratory manuals.

[0118]For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Preferred selectable markers include those which confer resistance to drugs, such as G418, hygromycin and methatrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding a protease protein or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g. cells that have incorporated the selectable marker gene will survive, while the other cells die).

[0119]Expression of proteins in prokaryotes is often carried out in E. coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, e.g. to the amino terminus of the recombinant protein. Such fusion vectors typically serve three purposes: 1) to increase expression of recombinant protein; 2) to increase the solubility of the recombinant protein; and 3) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognation sequences, include Factor Xa, thrombin and enterokinase.

[0120]As indicated, the expression vectors will preferably contain selectable markers. Such markers include dihydrofolate reductase or neomycin resistance for eukarotic cell culture and tetracyline or ampicilling resistance for culturing in E. coli and other bacteria. Representative examples of appropriate host include bacterial cells, such as E. coli, Streptomyces and Salmonella typhimurium; fungal cells, such as yeast; insect cells such as Drosophila S2 and Spodoptera Sf9; animal cells such as CHO, COS and Bowes melanoma; and plant cells. Appropriate culture mediums and conditions for the above-described host cells are known in the art.

[0121]Among vectors preferred for use in bacteria are pQE70, pQE60 and PQE-9, available from Qiagen; pBS vectors, Phagescript vectors, Bluescript vectors, pNH8A, pNH16A, pNH18A, pNH46A, available from Stratagene; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 available from Pharmacia. Among preferred eukaryotic vectors are PWLNEO, pSV2CAT, pOG44, pZT1 and pSG available from Stratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia. Other suitable vectors will be readily apparent to the skilled artisan.

[0122]Among known bacterial promotors for use in the present invention include E. coli lacI and lacZ promoters, the T3 and T7 promoters, the gpt promoter, the lambda PR, PL promoters and the trp promoter, the HSV thymidine kinase promoter, the early and late SV40 promoters, the promoters of retroviral LTRs, such as those of the Rous sarcoma virus ("RSV"), and metallothionein promoters, such as the mouse metallothionein-I promoter.

[0123]Transcription of the DNA encoding the polypeptides of the present invention by higher eukaryotes may be increased by inserting an enhancer sequence into the vector. Enhancers are cis-acting elements of DNA, usually about from 10 to 300 bp that act to increase transcriptional activity of a promoter in a given host cell-type. Examples of enhancers include the SV40 enhancer, which is located on the late side of the replication origin at bp 100 to 270, the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers.

[0124]For secretion of the translated protein into the lumen of the endoplasmic reticulum, into the periplasmic space or into the extracellular environment, appropriate secretation signal may be incorporated into the expressed polypeptide. The signals may be endogenous to the polypeptide or they may be heterologous signals.

[0125]The polypeptide may be expressed in a modified form, such as a fusion protein, and may include not only secretion signals but also additional heterologous functional regions. Thus, for instance, a region of additional amino acids, particularly charged amino acids, may be added to the N-terminus of the polypeptide to improve stability and persistence in the host cell, during purification or during subsequent handling and storage. Also, peptide moieties may be added to the polypeptide to facilitate purification.

Polypeptides According to the Invention

[0126]The invention provides an isolated polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171, an amino acid sequence obtainable by expressing a polynucleotide according to the invention or in a preferred embodiment of a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 in an appropriate host, as well as an amino acid sequence obtainable by expressing a polynucleotide sequences selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114 in an appropriate host. Also, a peptide or polypeptide comprising a functional equivalent of the above polypeptides is comprised within the present invention. The above polypeptides are collectively comprised in the term "polypeptides according to the invention"

[0127]The terms "peptide" and "oligopeptide" are considered synonymous (as is commonly recognized) and each term can be used interchangeably as the context requires to indicate a chain of at least two amino acids coupled by peptidyl linkages. The word "polypeptide" is used herein for chains containing more than seven amino acid residues. All oligopeptide and polypeptide formulas or sequences herein are written from left to right and in the direction from amino terminus to carboxy terminus. The one-letter code of amino acids used herein is commonly known in the art and can be found in Sambrook, et al. (Molecular Cloning: A Laboratory Manual, 2.sup.nd, ed. Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989)

[0128]By "isolated" polypeptide or protein is intended a polypeptide or protein removed from its native environment. For example, recombinantly produced polypeptides and proteins expressed in host cells are considered isolated for purpose of the invention as are native or recombinant polypeptides which have been substantially purified by any suitable technique such as, for example, the single-step purification method disclosed in Smith and Johnson, Gene 67:31-40 (1988).

[0129]The protease according to the invention can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. For analytical purposes most preferably, high performance liquid chromatography ("HPLC") is employed for purification.

[0130]Polypeptides of the present invention include naturally purified products, products of chemical synthetic procedures, and products produced by recombinant techniques from a prokaryotic or eukaryotic host, including, for example, bacterial, yeast, higher plant, insect and mammalian cells. Depending upon the host employed in a recombinant production procedure, the polypeptides of the present invention may be glycosylated or may be non-glycosylated. In addition, polypeptides of the invention may also include an initial modified methionine residue, in some cases as a result of host-mediated processes.

[0131]Moreover, a protein according to the invention may be a precursor protein such as a zymogen, a hybrid protein, a protein obtained as a pro sequence or pre-pro sequence, or any other type of immature form.

Protein Fragments

[0132]The invention also features biologically active fragments of the polypeptides according to the invention.

[0133]Biologically active fragments of a polypeptide of the invention include polypeptides comprising amino acid sequences sufficiently identical to or derived from the amino acid sequence of the protease protein (e.g., the amino acid sequence of a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171), which include fewer amino acids than the full length protein, and exhibit at least one biological activity of the corresponding full-length protein. Typically, biologically active fragments comprise a domain or motif with at least one activity of the protease protein. A biologically active fragment of a protein of the invention can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acids in length. Moreover, other biologically active portions, in which other regions of the protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the biological activities of the native form of a polypeptide of the invention.

[0134]The invention also features nucleic acid fragments which encode the above biologically active fragments of the protease protein.

Fusion Proteins

[0135]The proteins of the present invention or functional equivalents thereof, e.g., biologically active portions thereof, can be operatively linked to a non-protease polypeptide (e.g., heterologous amino acid sequences) to form fusion proteins. As used herein, a protease "chimeric protein" or "fusion protein" comprises a protease polypeptide operatively linked to a non-protease polypeptide. A "protease polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a polypeptide sequence according to the invention, whereas a "non-protease polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a protein which is not substantially homologous to a protein according to the invention, e.g., a protein which is different from the protease protein and which is derived from the same or a different organism. Within a protease fusion protein the protease polypeptide can correspond to all or a portion of a protein according to the invention. In a preferred embodiment, a protease fusion protein comprises at least one biologically active fragment of a protein according to the invention. In another preferred embodiment, a protease fusion protein comprises at least two biologically active portions of a protein according to the invention. Within the fusion protein, the term "operatively linked" is intended to indicate that the protease polypeptide and the non-protease polypeptide are fused in-frame to each other. The non-protease polypeptide can be fused to the N-terminus or C-terminus of the protease polypeptide.

[0136]For example, in one embodiment, the fusion protein is a GST-protease fusion protein in which the protease sequences are fused to the C-terminus of the GST sequences.

[0137]Such fusion proteins can facilitate the purification of recombinant protease. In another embodiment, the fusion protein is a protease protein containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian and Yeast host cells), expression and/or secretion of protease can be increased through use of a heterologous signal sequence.

[0138]In another example, the gp67 secretory sequence of the baculovirus envelope protein can be used as a heterologous signal sequence (Current Protocols in Molecular Biology, Ausubel et al., eds., John Wiley & Sons, 1992). Other examples of eukaryotic heterologous signal sequences include the secretory sequences of melittin and human placental alkaline phosphatase (Stratagene; La Jolla, Calif.). In yet another example, useful prokaryotic heterologous signal sequences include the phoA secretory signal (Sambrook et al., supra) and the protein A secretory signal (Pharmacia Biotech; Piscataway, N.J.).

[0139]A signal sequence can be used to facilitate secretion and isolation of a protein or polypeptide of the invention. Signal sequences are typically characterized by a core of hydrophobic amino acids which are generally cleaved from the mature protein during secretion in one or more cleavage events. Such signal peptides contain processing sites that allow cleavage of the signal sequence from the mature proteins as they pass through the secretory pathway. The signal sequence directs secretion of the protein, such as from a eukaryotic host into which the expression vector is transformed, and the signal sequence is subsequently or concurrently cleaved. The protein can then be readily purified from the extracellular medium by art recognized methods. Alternatively, the signal sequence can be linked to the protein of interest using a sequence which facilitates purification, such as with a GST domain. Thus, for instance, the sequence encoding the polypeptide may be fused to a marker sequence, such as a sequence encoding a peptide, which facilitates purification of the fused polypeptide. In certain preferred embodiments of this aspect of the invention, the marker sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (Qiagen, Inc.), among others, many of which are commercially available. As described in Gentz et al, Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance, hexa-histidine provides for convenient purification of the fusion protein. The HA tag is another peptide useful for purification which corresponds to an epitope derived of influenza hemaglutinin protein, which has been described by Wilson et al., Cell 37:767 (1984), for instance.

[0140]Preferably, a protease chimeric or fusion protein of the invention is produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, for example by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, for example, Current Protocols in Molecular Biology, eds. Ausubel et al. John Wiley & Sons: 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g, a GST polypeptide). A protease-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the protease protein.

Functional Equivalents

[0141]The terms "functional equivalents" and "functional variants" are used interchangeably herein. Functional equivalents of a DNA according to the invention are isolated DNA fragments that encode a polypeptide that exhibits a particular function of an A. niger protease as defined herein. A functional equivalent of a polypeptide according to the invention is a polypeptide that exhibits at least one function of an A. niger protease as defined herein.

[0142]Functional protein or polypeptide equivalents may contain only conservative substitutions of one or more amino acids of a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171 or substitutions, insertions or deletions of non-essential amino acids. Accordingly, a non-essential amino acid is a residue that can be altered in a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171 without substantially altering the biological function. For example, amino acid residues that are conserved among the protease proteins of the present invention, are predicted to be particularly unamenable to alteration. Furthermore, amino acids conserved among the protease proteins according to the present invention and other proteases are not likely to be amenable to alteration.

[0143]The term "conservative substitution" is intended to mean that a substitution in which the amino acid residue is replaced with an amino acid residue having a similar side chain. These families are known in the art and include amino acids with basic side chains (e.g. lysine, arginine and hystidine), acidic side chains (e.g. aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagines, glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine tryptophan, histidine).

[0144]Functional nucleic acid equivalents may typically contain silent mutations or mutations that do not alter the biological function of encoded polypeptide. Accordingly, the invention provides nucleic acid molecules encoding protease proteins that contain changes in amino acid residues that are not essential for a particular biological activity. Such protease proteins differ in amino acid sequence from a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171 yet retain at least one biological activity. In one embodiment the isolated nucleic acid molecule comprises a nucleotide sequence encoding a protein, wherein the protein comprises a substantially homologous amino acid sequence of at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more homologous to the amino acid sequence shown in a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171.

[0145]For example, guidance concerning how to make phenotypically silent amino acid substitutions is provided in Bowie, J. U. et al., Science 247:1306-1310 (1990) wherein the authors indicate that there are two main approaches for studying the tolerance of an amino acid sequence to change. The first method relies on the process of evolution, in which mutations are either accepted or rejected by natural selection. The second approach uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene and selects or screens to identify sequences that maintain functionality. As the authors state, these studies have revealed that proteins are surprisingly tolerant of amino acid substitutions. The authors further indicate which changes are likely to be permissive at a certain position of the protein. For example, most buried amino acid residues require non-polar side chains, whereas few features of surface side chains are generally conserved. Other such phenotypically silent substitutions are described in Bowie et al, supra, and the references cited therein.

[0146]An isolated nucleic acid molecule encoding a protease protein homologous to the protein selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171 can be created by introducing one or more nucleotide substitutions, additions or deletions into the coding nucleotide sequences according to a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114 such that one or more amino acid substitutions, deletions or insertions are introduced into the encoded protein. Such mutations may be introduced by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis.

[0147]The term "functional equivalents" also encompasses orthologues of the A. niger protease protein. Orthologues of the A. niger protease protein are proteins that can be isolated from other strains or species and possess a similar or identical biological activity. Such orthologues can readily be identified as comprising an amino acid sequence that is substantially homologous to a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO:171.

[0148]As defined herein, the term "substantially homologous" refers to a first amino acid or nucleotide sequence which contains a sufficient or minimum number of identical or equivalent (e.g., with similar side chain) amino acids or nucleotides to a second amino acid or nucleotide sequence such that the first and the second amino acid or nucleotide sequences have a common domain. For example, amino acid or nucleotide sequences which contain a common domain having about 60%, preferably 65%, more preferably 70%, even more preferably 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identity or more are defined herein as sufficiently identical.

[0149]Also, nucleic acids encoding other protease family members, which thus have a nucleotide sequence that differs from a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114, are within the scope of the invention. Moreover, nucleic acids encoding protease proteins from different species which thus have a nucleotide sequence which differs from a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114 are within the scope of the invention.

[0150]Nucleic acid molecules corresponding to variants (e.g. natural allelic variants) and homologues of the protease DNA of the invention can be isolated based on their homology to the protease nucleic acids disclosed herein using the cDNAs disclosed herein or a suitable fragment thereof, as a hybridisation probe according to standard hybridisation techniques preferably under highly stringent hybridisation conditions.

[0151]In addition to naturally occurring allelic variants of the protease sequence, the skilled person will recognise that changes can be introduced by mutation into the nucleotide sequences of a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114 thereby leading to changes in the amino acid sequence of the protease protein without substantially altering the function of the protease protein.

[0152]In another aspect of the invention, improved protease proteins are provided. Improved protease proteins are proteins wherein at least one biological activity is improved. Such proteins may be obtained by randomly introducing mutations along all or part of the protease coding sequence, such as by saturation mutagenesis, and the resulting mutants can be expressed recombinantly and screened for biological activity. For instance, the art provides for standard assays for measuring the enzymatic activity of proteases and thus improved proteins may easily be selected.

[0153]In a preferred embodiment the protease protein has an amino acid sequence according to a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171. In another embodiment, the protease polypeptide is substantially homologous to the amino acid sequence according to a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171 and retains at least one biological activity of a polypeptide according to a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171, yet differs in amino acid sequence due to natural variation or mutagenesis as described above.

[0154]In a further preferred embodiment, the protease protein has an amino acid sequence encoded by an isolated nucleic acid fragment capable of hybridising to a nucleic acid according to a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57 or a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114, preferably under highly stringent hybridisation conditions.

[0155]Accordingly, the protease protein is a protein which comprises an amino acid sequence at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more homologous to the amino acid sequence shown in a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171 and retains at least one functional activity of the polypeptide according to a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171.

[0156]Functional equivalents of a protein according to the invention can also be identified e.g. by screening combinatorial libraries of mutants, e.g. truncation mutants, of the protein of the invention for protease activity. In one embodiment, a variegated library of variants is generated by combinatorial mutagenesis at the nucleic acid level. A variegated library of variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential protein sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display). There are a variety of methods that can be used to produce libraries of potential variants of the polypeptides of the invention from a degenerate oligonucleotide sequence. Methods for synthesizing degenerate oligonucleotides are known in the art (see, e.g., Narang (1983) Tetrahedron 39:3; Itakura et al. (1984) Annu. Rev. Biochem. 53:323; Itakura et al. (1984) Science 198:1056; Ike et al. (1983) Nucleic Acid Res. 11:477).

[0157]In addition, libraries of fragments of the coding sequence of a polypeptide of the invention can be used to generate a variegated population of polypeptides for screening a subsequent selection of variants. For example, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of the coding sequence of interest with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form double stranded DNA which can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with S1 nuclease, and ligating the resulting fragment library into an expression vector. By this method, an expression library can be derived which encodes N-terminal and internal fragments of various sizes of the protein of interest.

[0158]Several techniques are known in the art for screening gene products of combinatorial libraries made by point mutations of truncation, and for screening cDNA libraries for gene products having a selected property. The most widely used techniques, which are amenable to high through-put analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation of the vector encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a technique which enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify variants of a protein of the invention (Arkin and Yourvan (1992) Proc. Natl. Acad. Sci. USA 89:7811-7815; Delgrave et al. (1993) Protein Engineering 6(3):327-331).

[0159]In addition to the protease gene sequence shown in a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57, it will be apparent for the person skilled in the art that DNA sequence polymorphisms that may lead to changes in the amino acid sequence of the protease protein may exist within a given population. Such genetic polymorphisms may exist in cells from different populations or within a population due to natural allelic variation. Allelic variants may also include functional equivalents.

[0160]Fragments of a polynucleotide according to the invention may also comprise polynucleotides not encoding functional polypeptides. Such polynucleotides may function as probes or primers for a PCR reaction. Such polynucleotides may also be useful when it is desired to abolish the functional activity of a protease in a particular organism (knock-out mutants).

[0161]Nucleic acids according to the invention irrespective of whether they encode functional or non-functional polypeptides, can be used as hybridization probes or polymerase chain reaction (PCR) primers. Uses of the nucleic acid molecules of the present invention that do not encode a polypeptide having a protease activity include, inter alia, (1) isolating the gene encoding the protease protein, or allelic variants thereof from a cDNA library e.g. from other organisms than A. niger; (2) in situ hybridization (e.g. FISH) to metaphase chromosomal spreads to provide precise chromosomal location of the protease gene as described in Verma et al., Human Chromosomes: a Manual of Basic Techniques, Pergamon Press, New York (1988); (3) Northern blot analysis for detecting expression of protease mRNA in specific tissues and/or cells and 4) probes and primers that can be used as a diagnostic tool to analyse the presence of a nucleic acid hybridisable to the protease probe in a given biological (e.g. tissue) sample.

[0162]Also encompassed by the invention is a method of obtaining a functional equivalent of a protease gene or cDNA. Such a method entails obtaining a labelled probe that includes an isolated nucleic acid which encodes all or a portion of the sequence according to a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171 or a variant thereof; screening a nucleic acid fragment library with the labelled probe under conditions that allow hybridisation of the probe to nucleic acid fragments in the library, thereby forming nucleic acid duplexes, and preparing a full-length gene sequence from the nucleic acid fragments in any labelled duplex to obtain a gene related to the protease gene.

[0163]In one embodiment, a protease nucleic acid of the invention is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more homologous to a nucleic acid sequence shown in a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 57, a sequence selected from the group consisting of SEQ ID NO: 58 to SEQ ID NO: 114 or the complement thereof.

[0164]In another preferred embodiment a protease polypeptide of the invention is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more homologous to the amino acid sequence shown in a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171.

Host Cells

[0165]In another embodiment, the invention features cells, e.g., transformed host cells or recombinant host cells that contain a nucleic acid encompassed by the invention. A "transformed cell" or "recombinant cell" is a cell into which (or into an ancestor of which) has been introduced, by means of recombinant DNA techniques, a nucleic acid according to the invention. Both prokaryotic and eukaryotic cells are included, e.g., bacteria, fungi, yeast, and the like, especially preferred are cells from filamentous fungi, in particular Aspergillus niger.

[0166]A host cell can be chosen that modulates the expression of the inserted sequences, or modifies and processes the gene product in a specific, desired fashion. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may facilitate optimal functioning of the protein.

[0167]Various host cells have characteristic and specific mechanisms for post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems familiar to those of skill in the art of molecular biology and/or microbiology can be chosen to ensure the desired and correct modification and processing of the foreign protein expressed. To this end, eukaryotic host cells that possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product can be used. Such host cells are well known in the art.

[0168]Host cells also include, but are not limited to, mammalian cell lines such as CHO, VERO, BHK, HeLa, COS, MDCK, 293, 3T3, WI38, and choroid plexus cell lines.

[0169]If desired, the polypeptides according to the invention can be produced by a stably-transfected cell line. A number of vectors suitable for stable transfection of mammalian cells are available to the public, methods for constructing such cell lines are also publicly known, e.g., in Ausubel et al. (supra).

Antibodies

[0170]The invention further features antibodies, such as monoclonal or polyclonal antibodies, that specifically bind protease proteins according to the invention.

[0171]As used herein, the term "antibody" (Ab) or "monoclonal antibody" (Mab) is meant to include intact molecules as well as antibody fragments (such as, for example, Fab and F(ab').sub.2 fragments) which are capable of specifically binding to protease protein. Fab and F(ab').sub.2 fragments lack the Fc fragment of intact antibody, clear more rapidly from the circulation, and may have less non-specific tissue binding of an intact antibody (Wahl et al, J. Nucl. Med. 24:316-325 (1983)). Thus, these fragments are preferred.

[0172]The antibodies of the present invention may be prepared by any of a variety of methods. For example, cells expressing the protease protein or an antigenic fragment thereof can be administered to an animal in order to induce the production of sera containing polyclonal antibodies. In a preferred method, a preparation of protease protein is prepared and purified to render it substantially free of natural contaminants. Such a preparation is then introduced into an animal in order to produce polyclonal antisera of greater specific activity.

[0173]In the most preferred method, the antibodies of the present invention are monoclonal antibodies (or protease protein binding fragments thereof). Such monoclonal antibodies can be prepared using hybridoma technology (Kohler et al., Nature 256':495 (1975); Kohler et al., Eur. J. Immunol. 6:511 (1976); Hammerling et al., In: Monoclonal Antibodies and T-Cell Hybridomas, Elsevier, N.Y., pp. 563-681 (1981)). In general, such procedures involve immunizing an animal (preferably a mouse) with a protease protein antigen or, with a protease protein expressing cell. The splenocytes of such mice are extracted and fused with a suitable myeloma cell line. Any suitable myeloma cell line may be employed in accordance with the present invention; however, it is preferably to employ the parent myeloma cell line (SP.sub.2O), available from the American Type Culture Collection, Rockville, Md. After fusion, the resulting hybridoma cells are selectively maintained in HAT medium, and then cloned by limiting dilution as described by Wands et al. (Gastro-enterology 80.225-232 (1981)). The hybridoma cells obtained through such a selection are then assayed to identify clones which secrete antibodies capable of binding the protease protein antigen. In general, the polypeptides can be coupled to a carrier protein, such as KLH, as described in Ausubel et al., supra, mixed with an adjuvant, and injected into a host mammal.

[0174]In particular, various host animals can be immunized by injection of a polypeptide of interest. Examples of suitable host animals include rabbits, mice, guinea pigs, and rats. Various adjuvants can be used to increase the immunological response, depending on the host species, including but not limited to Freund's (complete and incomplete), adjuvant mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, dinitrophenol, BCG (bacille Calmette-Guerin) and Corynebacterium parvum. Polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of the immunized animals.

[0175]Such antibodies can be of any immunoglobulin class including IgG, IgM, IgE, IgA, IgD, and any subclass thereof. The hybridomas producing the mAbs of this invention can be cultivated in vitro or in vivo.

[0176]Once produced, polyclonal or monoclonal antibodies are tested for specific recognition of an protease polypeptide or functional equivalent thereof in an immunoassay, such as a Western blot or immunoprecipitation analysis using standard techniques, e.g., as described in Ausubel et al., supra. Antibodies that specifically bind to protease proteins or functional equivalents thereof are useful in the invention. For example, such antibodies can be used in an immunoassay to detect protease in pathogenic or non-pathogenic strains of Aspergillus (e.g., in Aspergillus extracts).

[0177]Preferably, antibodies of the invention are produced using fragments of the protease polypeptides that appear likely to be antigenic, by criteria such as high frequency of charged residues. For example, such fragments may be generated by standard techniques of PCR, and then cloned into the pGEX expression vector (Ausubel et al., supra). Fusion proteins may then be expressed in E. coli and purified using a glutathione agarose affinity matrix as described in Ausubel, et al., supra. If desired, several (e.g., two or three) fusions can be generated for each protein, and each fusion can be injected into at least two rabbits. Antisera can be raised by injections in a series, typically including at least three booster injections. Typically, the antisera are checked for their ability to immunoprecipitate a recombinant protease polypeptide or functional equivalents thereof whereas unrelated proteins may serve as a control for the specificity of the immune reaction.

[0178]Alternatively, techniques described for the production of single chain antibodies (U.S. Pat. Nos. 4,946,778 and 4,704,692) can be adapted to produce single chain antibodies against a protease polypeptide or functional equivalents thereof. Kits for generating and screening phage display libraries are commercially available e.g. from Pharmacia.

[0179]Additionally, examples of methods and reagents particularly amenable for use in generating and screening antibody display library can be found in, for example, U.S. Pat. No. 5,223,409; PCT Publication No. WO 92/18619; PCT Publication No. WO 91/17271; PCT Publication No. WO 20791; PCT Publication No. WO 92/20791; PCT Publication No. WO 92/15679; PCT Publication No. WO 93/01288; PCT Publication No. WO 92/01047; PCT Publication No. WO 92/09690; PCT Publication No. WO 90/02809; Fuchs et al. (1991) Bio/Technology 9:1370-1372; Hay et al. (1992) Hum. Antibod. Hybridomas 3:81-85; Huse et al. (1989) Science 246; 1275-1281; Griffiths et al. (1993) EMBO J. 12:725-734.

[0180]Polyclonal and monoclonal antibodies that specifically bind protease polypeptides of functional equivalents thereof can be used, for example, to detect expression of a protease gene or a functional equivalent thereof e.g. in another strain of Aspergillus.

[0181]For example, protease polypeptide can be readily detected in conventional immunoassays of Aspergillus cells or extracts. Examples of suitable assays include, without limitation, Western blotting, ELISAs, radioimmune assays, and the like.

[0182]By "specifically binds" is meant that an antibody recognizes and binds a particular antigen, e.g., a protease polypeptide, but does not substantially recognize and bind other unrelated molecules in a sample.

[0183]Antibodies can be purified, for example, by affinity chromatography methods in which the polypeptide antigen is immobilized on a resin.

[0184]An antibody directed against a polypeptide of the invention (e.g., monoclonal antibody) can be used to isolate the polypeptide by standard techniques, such as affinity chromatography or immunoprecipitation. Moreover, such an antibody can be used to detect the protein (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the polypeptide. The antibodies can also be used diagnostically to monitor protein levels in cells or tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen or in the diagnosis of Aspergillosis.

[0185]Detection can be facilitated by coupling the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, .beta.-galactosidase, or acetylcholinesterase; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and acquorin, and examples of suitable radioactive materials include .sup.125I, .sup.131I, .sup.35S or .sup.3H.

[0186]Preferred epitopes encompassed by the antigenic peptide are regions that are located on the surface of the protein, e.g., hydrophilic regions. Hydrophobicity plots of the proteins of the invention can be used to identify hydrophilic regions.

[0187]The antigenic peptide of a protein of the invention comprises at least 7 (preferably 10, 15, 20, or 30) contiguous amino acid residues of the amino acid sequence of a sequence selected from the group consisting of SEQ ID NO: 115 to SEQ ID NO: 171 and encompasses an epitope of the protein such that an antibody raised against the peptide forms a specific immune complex with the protein.

[0188]Preferred epitopes encompassed by the antigenic peptide are regions of protease that are located on the surface of the protein, e.g., hydrophilic regions, hydrophobic regions, alpha regions, beta regions, coil regions, turn regions and flexible regions.

Immunoassays

[0189]Qualitative or quantitative determination of a polypeptide according to the present invention in a biological sample can occur using any art-known method. Antibody-based techniques provide special advantages for assaying specific polypeptide levels in a biological sample.

[0190]In these, the specific recognition is provided by the primary antibody (polyclonal or monoclonal) but the secondary detection system can utilize fluorescent, enzyme, or other conjugated secondary antibodies. As a result, an immunocomplex is obtained.

[0191]Accordingly, the invention provides a method for diagnosing whether a certain organism is infected with Aspergillus comprising the steps of: [0192]Isolating a biological sample from said organism suspected to be infected with Aspergillus, [0193]reacting said biological sample with an antibody according to the invention, [0194]determining whether immunocomplexes are formed.

[0195]Tissues can also be extracted, e.g., with urea and neutral detergent, for the liberation of protein for Western-blot or dot/slot assay. This technique can also be applied to body fluids.

[0196]Other antibody-based methods useful for detecting protease gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). For example, protease-specific monoclonal antibodies can be used both as an immunoabsorbent and as an enzyme-labeled probe to detect and quantify the protease protein. The amount of protease protein present in the sample can be calculated by reference to the amount present in a standard preparation using a linear regression computer algorithm. In another ELISA assay, two distinct specific monoclonal antibodies can be used to detect protease protein in a biological fluid. In this assay, one of the antibodies is used as the immuno-absorbent and the other as the enzyme-labeled probe.

[0197]The above techniques may be conducted essentially as a "one-step" or "two-step" assay. The "one-step" assay involves contacting protease protein with immobilized antibody and, without washing, contacting the mixture with the labeled antibody. The "two-step" assay involves washing before contacting the mixture with the labeled antibody. Other conventional methods may also be employed as suitable. It is usually desirable to immobilize one component of the assay system on a support, thereby allowing other components of the system to be brought into contact with the component and readily removed from the sample.

[0198]Suitable enzyme labels include, for example, those from the oxidase group, which catalyze the production of hydrogen peroxide by reacting with substrate. Activity of an oxidase label may be assayed by measuring the concentration of hydrogen peroxide formed by the enzyme-labelled antibody/substrate reaction.

[0199]Besides enzymes, other suitable labels include radioisotopes, such as iodine (.sup.125I, .sup.121I), carbon (.sup.14C), sulphur (.sup.35S), tritium (.sup.3H), indium (.sup.112In), and technetium (.sup.99mTc), and fluorescent labels, such as fluorescein and rhodamine, and biotin.

[0200]Specific binding of a test compound to a protease polypeptide can be detected, for example, in vitro by reversibly or irreversibly immobilizing the protease polypeptide on a substrate, e.g., the surface of a well of a 96-well polystyrene microtitre plate. Methods for immobilizing polypeptides and other small molecules are well known in the art. For example, the microtitre plates can be coated with a protease polypeptide by adding the polypeptide in a solution (typically, at a concentration of 0.05 to 1 mg/ml in a volume of 1-100 ul) to each well, and incubating the plates at room temperature to 37.degree. C. for 0.1 to 36 hours. Polypeptides that are not bound to the plate can be removed by shaking the excess solution from the plate, and then washing the plate (once or repeatedly) with water or a buffer. Typically, the polypeptide is contained in water or a buffer. The plate is then washed with a buffer that lacks the bound polypeptide. To block the free protein-binding sites on the plates, the plates are blocked with a protein that is unrelated to the bound polypeptide. For example, 300 ul of bovine serum albumin (BSA) at a concentration of 2 mg/ml in Tris-HCl is suitable. Suitable substrates include those substrates that contain a defined cross-linking chemistry (e.g., plastic substrates, such as polystyrene, styrene, or polypropylene substrates from Corning Costar Corp. (Cambridge, Mass.), for example). If desired, a beaded particle, e.g., beaded agarose or beaded sepharose, can be used as the substrate.

[0201]Binding of the test compound to the polypeptides according to the invention can be detected by any of a variety of art known methods. For example, a specific antibody can be used in an immunoassay. If desired, the antibody can be labeled (e.g., fluorescently or with a radioisotope) and detected directly (see, e.g., West and McMahon, J. Cell Biol. 74:264, 1977). Alternatively, a second antibody can be used for detection (e.g., a labeled antibody that binds the Fc portion of an anti-AN97 antibody). In an alternative detection method, the protease polypeptide is labeled, and the label is detected (e.g., by labeling a protease polypeptide with a radioisotope, fluorophore, chromophore, or the like). In still another method, the protease polypeptide is produced as a fusion protein with a protein that can be detected optically, e.g., green fluorescent protein (which can be detected under UV light). In an alternative method, the protease polypeptide can be covalently attached to or fused with an enzyme having a detectable enzymatic activity, such as horse radish peroxidase, alkaline phosphatase, a-galactosidase, or glucose oxidase. Genes encoding all of these enzymes have been cloned and are readily available for use by those of skill in the art. If desired, the fusion protein can include an antigen, and such an antigen can be detected and measured with a polyclonal or monoclonal antibody using conventional methods. Suitable antigens include enzymes (e.g., horse radish peroxidase, alkaline phosphatase, and a-galactosidase) and non-enzymatic polypeptides (e.g., serum proteins, such as BSA and globulins, and milk proteins, such as caseins).

Epitopes, Antigens and Immunogens.

[0202]In another aspect, the invention provides a peptide or polypeptide comprising an epitope-bearing portion of a polypeptide of the invention. The epitope of this polypeptide portion is an immunogenic or antigenic epitope of a polypeptide of the invention. An "immunogenic epitope" is defined as a part of a protein that elicits an antibody response when the whole protein is the immunogen. These immunogenic epitopes are believed to be confined to a few loci on the molecule. On the other hand, a region of a protein molecule to which an antibody can bind is defined as an "antigenic epitope." The number of immunogenic epitopes of a protein generally is less than the number of antigenic epitopes. See, for instance, Geysen, H. M. et al., Proc. Natl. Acad. Sci. USA 81:3998-4002 (1984).

[0203]As to the selection of peptides or polypeptides bearing an antigenic epitope (i.e., that contain a region of a protein molecule to which an antibody can bind), it is well known in that art that relatively short synthetic peptides that mimic part of a protein sequence are routinely capable of eliciting an antiserum that reacts with the partially mimicked protein. See, for instance, Sutcliffe, J. G. et al., Science 219:660-666 (1984). Peptides capable of eliciting protein-reactive sera are frequently represented in the primary sequence of a protein, can be characterized by a set of simple chemical rules, and are confined neither to immunodominant regions of intact proteins (i.e., immunogenic epitopes) nor to the amino or carboxyl terminals. Peptides that are extremely hydrophobic and those of six or fewer residues generally are ineffective at inducing antibodies that bind to the mimicked protein; longer, soluble peptides, especially those containing proline residues, usually are effective. Sutcliffe et al., supra ?. For instance, 18 of 20 peptides designed according to these guidelines, containing 8-39 residues covering 75% of the sequence of the influenza virus hemagglutinin HAI polypeptide chain, induced antibodies that reacted with the HA1 protein or intact virus; and 12/12 peptides from the MuLV polymerase and 18/18 from the rabies glycoprotein induced antibodies that precipitated the respective proteins.

[0204]Antigenic epitope-bearing peptides and polypeptides of the invention are therefore useful to raise antibodies, including monoclonal antibodies, that bind specifically to a polypeptide of the invention. Thus, a high proportion of hybridomas obtained by fusion of spleen cells from donors immunized with an antigen epitope-bearing peptide generally secrete antibody reactive with the native protein. Sutcliffe et al., supra, at 663. The antibodies raised by antigenic epitope bearing peptides or polypeptides are useful to detect the mimicked protein, and antibodies to different peptides may be used for tracking the fate of various regions of a protein precursor which undergoes posttranslation processing. The peptides and anti-peptide antibodies may be used in a variety of qualitative or quantitative assays for the mimicked protein, for instance in competition assays since it has been shown that even short peptides (e.g., about 9 amino acids) can bind and displace the larger peptides in immunoprecipitation assays. See, for instance, Wilson, I. A. et al., Cell 37:767-778 at 777 (1984). The anti-peptide antibodies of the invention also are useful for purification of the mimicked protein, for instance, by adsorption chromatography using methods well known in the art.

[0205]Antigenic epitope-bearing peptides and polypeptides of the invention designed according to the above guidelines preferably contain a sequence of at least seven, more preferably at least nine and most preferably between about 15 to about 30 amino acids contained within the amino acid sequence of a polypeptide of the invention. However, peptides or polypeptides comprising a larger portion of an amino acid sequence of a polypeptide of the invention, containing about 30 to about 50 amino acids, or any length up to and including the entire amino acid sequence of a polypeptide of the invention, also are considered epitope-bearing peptides or polypeptides of the invention and also are useful for inducing antibodies that react with the mimicked protein. Preferably, the amino acid sequence of the epitope-bearing peptide is selected to provide substantial solubility in aqueous solvents (i.e., the sequence includes relatively hydrophilic residues and highly hydrophobic sequences are preferably avoided); and sequences containing proline residues are particularly preferred.

[0206]The epitope-bearing peptides and polypeptides of the invention may be produced by any conventional means for making peptides or polypeptides including recombinant means using nucleic acid molecules of the invention. For instance, a short epitope-bearing amino acid sequence may be fused to a larger polypeptide which acts as a carrier during recombinant production and purification, as well as during immunization to produce anti-peptide antibodies.

[0207]Epitope-bearing peptides also may be synthesized using known methods of chemical synthesis. For instance, Houghten has described a simple method for synthesis of large numbers of peptides, such as 10-20 mg of 248 different 13 residue peptides representing single amino acid variants of a segment of the HAI polypeptide which were prepared and characterized (by ELISA-type binding studies) in less than four weeks. Houghten, R. A., Proc. Natl. Acad. Sci. USA 82:5131-5135 (1985). This "Simultaneous Multiple Peptide Synthesis (SMPS)" process is further described in U.S. Pat. No. 4,631,211 to Houghten et al. (1986). In this procedure the individual resins for the solid-phase synthesis of various peptides are contained in separate solvent-permeable packets, enabling the optimal use of the many identical repetitive steps involved in solid-phase methods.

[0208]A manual procedure allows 500-1000 or more syntheses to be conducted simultaneously. Houghten et al., supra, at 5134.

[0209]Epitope-bearing peptides and polypeptides of the invention are used to induce antibodies according to methods well known in the art. See, for instance, Sutcliffe et al., supra; Wilson et al., supra; Chow, M. et al., Proc. Natl. Acad. Sci. USA 82:910-914; and Bittle, F. J. et al., J. Gen. Virol. 66:2347-2354 (1985).

[0210]Generally, animals may be immunized with free peptide; however, anti-peptide antibody titer may be boosted by coupling of the peptide to a macromolecular carrier, such as keyhole limpet hemocyanin (KLH) or tetanus toxoid. For instance, peptides containing cysteine may be coupled to carrier using a linker such as maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), while other peptides may be coupled to carrier using a more general linking agent such as glutaraldehyde.

[0211]Animals such as rabbits, rats and mice are immunized with either free or carrier coupled peptides, for instance, by intraperitoneal and/or intradermal injection of emulsions containing about 100 ug peptide or carrier protein and Freund's adjuvant. Several booster injections may be needed, for instance, at intervals of about two weeks, to provide a useful titer of anti-peptide antibody which can be detected, for example, by ELISA assay using free peptide adsorbed to a solid surface. The titer of anti-peptide antibodies in serum from an immunized animal may be increased by selection of anti-peptide antibodies, for instance, by adsorption to the peptide on a solid support and elution of the selected antibodies according to methods well known in the art.

[0212]Immunogenic epitope-bearing peptides of the invention, i.e., those parts of a protein that elicit an antibody response when the whole protein is the immunogen, are identified according to methods known in the art. For instance, Geysen et al., 1984, supra, discloses a procedure for rapid concurrent synthesis on solid supports of hundreds of peptides of sufficient purity to react in an enzyme-linked immunosorbent assay. Interaction of synthesized peptides with antibodies is then easily detected without removing them from the support. In this manner a peptide bearing an immunogenic epitope of a desired protein may be identified routinely by one of ordinary skill in the art. For instance, the immunologically important epitope in the coat protein of foot-and-mouth disease virus was located by Geysen et al. with a resolution of seven amino acids by synthesis of an overlapping set of all 208 possible hexapeptides covering the entire 213 amino acid sequence of the protein. Then, a complete replacement set of peptides in which all 20 amino acids were substituted in turn at every position within the epitope were synthesized, and the particular amino acids conferring specificity for the reaction with antibody were determined. Thus, peptide analogs of the epitope-bearing peptides of the invention can be made routinely by this method. U.S. Pat. No. 4,708,781 to Geysen (1987) further describes this method of identifying a peptide bearing an immunogenic epitope of a desired protein.

[0213]Further still, U.S. Pat. No. 5,194,392 to Geysen (1990) describes a general method of detecting or determining the sequence of monomers (amino acids or other compounds) which is a topological equivalent of the epitope (i.e., a "mimotope") which is complementary to a particular paratope (antigen binding site) of an antibody of interest. More generally, U.S. Pat. No. 4,433,092 to Geysen (1989) describes a method of detecting or determining a sequence of monomers which is a topographical equivalent of a ligand which is complementary to the ligand binding site of a particular receptor of interest. Similarly, U.S. Pat. No. 5,480,971 to Houghten, R. A. et al. (1996) on Peralkylated Oligopeptide Mixtures discloses linear C1-C7-alkyl peralkylated oligopeptides and sets and libraries of such peptides, as well as methods for using such oligopeptide sets and libraries for determining the sequence of a peralkylated oligopeptide that preferentially binds to an acceptor molecule of interest. Thus, non-peptide analogs of the epitope-bearing peptides of the invention also can be made routinely by these methods.

Removal or Reduction of Protease Activity

[0214]The present invention also relates to methods for producing a mutant cell of a parent cell, which comprises disrupting or deleting a nucleic acid sequence encoding the protease or a control sequence thereof, which results in the mutant cell producing less of the protease than the parent cell.

[0215]The construction of strains which have reduced protease activity may be conveniently accomplished by modification or inactivation of a nucleic acid sequence necessary for expression of the protease activity in the cell. The nucleic acid sequence to be modified or inactivated may be, for example, a nucleic acid sequence encoding the protease or a part thereof essential for exhibiting protease activity, or the nucleic acid sequence may have a regulatory function required for the expression of the protease from the coding sequence of the nucleic acid sequence. An example of such a regulatory or control sequence may be a promoter sequence or a functional part thereof, i.e., a part which is sufficient for affecting expression of the protease. Other control sequences for possible modification include, but are not limited to, a leader, a polyadenylation sequence, a propeptide sequence, a signal sequence, and a termination site.

[0216]Modification or inactivation of the nucleic acid sequence may be performed by subjecting the cell to mutagenesis and selecting for cells in which the protease producing capability has been reduced or eliminated. The mutagenesis, which may be specific or random, may be performed, for example, by use of a suitable physical or chemical mutagenizing agent, by use of a suitable oligonucleotide, or by subjecting the DNA sequence to PCR generated mutagenesis. Furthermore, the mutagenesis may be performed by use of any combination of these mutagenizing agents. Examples of a physical or chemical mutagenizing agent suitable for the present purpose include ultraviolet (UV) irradiation, hydroxylamine, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), O-methyl hydroxylamine, nitrous acid, ethyl methane sulphonate (EMS), sodium bisulphite, formic acid, and nucleotide analogues. When such agents are used, the mutagenesis is typically performed by incubating the cell to be mutagenized in the presence of the mutagenizing agent of choice under suitable conditions, and selecting for cells exhibiting reduced or no expression of protease activity.

[0217]Modification or inactivation of production of a protease of the present invention may be accomplished by introduction, substitution, or removal of one or more nucleotides in the nucleic acid sequence encoding the protease or a regulatory element required for the transcription or translation thereof. For example, nucleotides may be inserted or removed so as to result in the introduction of a stop codon, the removal of the start codon, or a change of the open reading frame. Such modification or inactivation may be accomplished by site-directed mutagenesis or PCR generated mutagenesis in accordance with methods known in the art.

[0218]Although, in principle, the modification may be performed in vivo, i.e., directly on the cell expressing the nucleic acid sequence to be modified, it is preferred that the modification be performed in vitro as exemplified below.

[0219]An example of a convenient way to inactivate or reduce production by a host cell of choice is based on techniques of gene replacement or gene interruption. For example, in the gene interruption method, a nucleic acid sequence corresponding to the endogenous gene or gene fragment of interest is mutagenized in vitro to produce a defective nucleic acid sequence which is then transformed into the host cell to produce a defective gene. By homologous recombination, the defective nucleic acid sequence replaces the endogenous gene or gene fragment. It may be desirable that the defective gene or gene fragment also encodes a marker which may be used for selection of transformants in which the gene encoding the protease has been modified or destroyed.

[0220]Alternatively, modification or inactivation of the nucleic acid sequence encoding a protease of the present invention may be performed by established anti-sense techniques using a nucleotide sequence complementary to the protease encoding sequence. More specifically, production of the protease by a cell may be reduced or eliminated by introducing a nucleotide sequence complementary to the nucleic acid sequence encoding the protease which may be transcribed in the cell and is capable of hybridizing to the protease mRNA produced in the cell. Under conditions allowing the complementary antisense nucleotide sequence to hybridize to the protease mRNA, the amount of protease translated is thus reduced or eliminated.

[0221]It is preferred that the cell to be modified in accordance with the methods of the present invention is of microbial origin, for example, a fungal strain which is suitable for the production of desired protein products, either homologous or heterologous to the cell.

[0222]The present invention further relates to a mutant cell of a parent cell which comprises a disruption or deletion of a nucleic acid sequence encoding the protease or a control sequence thereof, which results in the mutant cell producing less of the protease than the parent cell.

[0223]The protease-deficient mutant cells so created are particularly useful as host cells for the expression of homologous and/or heterologous polypeptides. Therefore, the present invention further relates to methods for producing a homologous or heterologous polypeptide comprising (a) culturing the mutant cell under conditions conducive for production of the polypeptide; and (b) recovering the polypeptide. In the present context, the term "heterologous polypeptides" is defined herein as polypeptides which are not native to the host cell, a native protein in which modifications have been made to alter the native sequence, or a native protein whose expression is quantitatively altered as a result of a manipulation of the host cell by recombinant DNA techniques.

[0224]The methods of the present invention for producing an essentially protease-free product is of particular interest in the production of eukaryotic polypeptides, in particular fungal proteins such as enzymes. The protease-deficient cells may also be used to express heterologous proteins of interest for the food industry, or of pharmaceutical interest.

Use of Proteases in Industrial Processes

[0225]The invention also relates to the use of the protease according to the invention in a selected number of industrial and pharmaceutical processes. Despite the long term experience obtained with these processes, the protease according to the invention features a number of significant advantages over the enzymes currently used. Depending on the specific application, these advantages can include aspects like lower production costs, higher specificity towards the substrate, less antigenic, less undesirable side activities, higher yields when produced in a suitable microorganism, more suitable pH and temperature ranges, better tastes of the final product as well as food grade and kosher aspects.

[0226]In large scale industrial applications aimed at food or feed production, proteolytic enzymes are commonly used to improve aspects like protein solubility, extraction yields, viscosity or taste, texture, nutritional value, minimalisation of antigenicity or antinutritional factors, colour or functionality as well as processing aspects like filterability of the proteinaceous raw material. In these applications the proteinaceous raw material can be of animal or vegetable origin and examples include vegetable proteins such as soy protein, wheat gluten, rape seed protein, pea protein, alfalfa protein, sunflower protein, fabaceous bean protein, cotton or sesame seed protein, maize protein, barley protein, sorghum protein, potato protein, rice protein, coffee proteins, and animal derived protein such as milk protein (e.g. casein, whey protein), egg white, fish protein, meat protein including gelatin, collagen, blood protein (e.g. haemoglobin), hair, feathers and fish meal.

[0227]An important aspect of the proteases according to the invention is that they cover a whole range of pH and temperature optima which are ideally suited for a variety of applications. For example many large scale processes benefit from relatively high processing temperatures of 50 degrees C. or higher to control the risks of microbial infections. Several proteases according to the invention comply with this demand but at the same time exhibit no extreme heat stabilities so that they resist attempts to inactivate the enzyme by an additional heat treatment. The latter feature allows production routes that yield final products free of residual proteolytic activity. Similarly many feed and food products have slightly acidic pH values so that for their processing proteases with acidic or near neutral pH optima are preferred. A protease according to the invention complies with this requirement as well.

[0228]The specificity of endoproteases is usually defined in terms of preferential cleavages of bonds between the carboxyl of the amino acid residue in position P1 and the amino group of the residue in position P1' respectively. The preference may be conditioned predominantly either by P1 (e.g. positively charged residues in substrates for trypsin), by P1' (e.g. hydrophobic residues in cleavages by thermolysin) or by both P1 and P2 (e.g. specific cleavages between two positively charged residues by adrenal medulla serine endoprotease). In some cases more distant residues may determine the cleavage preference, e.g. P2 for streptococcal peptidase A. Some residues are known to influence cleavages negatively; it is well known that bonds with proline in position P1' are resistant to the action of many proteases. Most endoproteases cleave preferentially either in a hydrophobic environment or in the proximity of negatively charged residues. For example, industrially available endoproteases like chymotrypsin (obtained from bovine pancreas) or subtilisin, neutral metallo endoprotease or thermolysin (all obtained from Bacillus species) tend to favour cleavage "behind" hydrophobic amino acids like -Phe, -Leu and -Tyr. Other industrially available endoproteases are trypsin (obtained from bovine pancreas) preferring cleavage behind -Arg and -Lys and papain (a complex mixture of various enzymes including proteases obtained from papaya fruits) preferring cleavage behind -Arg.

[0229]In contrast, peptide bonds formed by small sized residues such as Ala, Gly, Ser, Thre as well as Ile and Pro are poor substrates (Keil, B et al.; Protein Seq Data Anal (1993) 5; 401-407). This situation has a profound implications for the pharmaceutical, the food and beverages, the agro and even the chemical industry. A protease according to the invention exhibits uncommon cleavage preferences.

[0230]The exopeptidases act only near the ends of polypeptide chains. Those acting at a free N-terminus liberate a single amino acid residue (socalled aminopeptidases) or a dipeptide or a tripeptide (socalled dipeptidyl-peptidases and tripeptidyl-peptidases) Those acting at a free C-terminus liberate a single residue (socalled carboxypeptidases) or a dipeptide (socalled peptidyl-dipeptidases) The carboxypeptidases are allocated to three groups on the basis of catalytic mechanism i.e. serine-type carboxypeptidases, metallocarboxypeptidases and cystein-type carboxypeptidases. Other exopeptidases are specific for dipeptides (socalled dipeptidases) or are able to cleave peptide linkages other than those of alpha-carboxyl or alpha-amino groups (socalled omega peptidases). Examples of such new omega peptidases are the pyroglutamyl-peptidase and the acylaminoacyl-peptidase as identified in the present invention (see Table 1, genes 18 and 45 respectively).

[0231]Typical examples of industrial application which depend on the use of pure endoproteases and in which the protease according to the invention can be expected to deliver a superior performance include the processing of materials of vegetable or animal origin. These processing steps can be aimed at modifying a large array of characteristics of either the crude material or the (partially) purified protein fraction. For example, these processing steps can be aimed at maximising product solubilities, filterabilities, separabilities, protein extraction yields and digestibilities or minimising toxicities, off-tastes and viscosities. Furthermore the treatment can be directed at altering physico-chemical characteristics of the crude material or the purified (or partially purified) protein. These advantages apply not only if the endoprotease according to the invention is applied as a processing aid in industrial applications but also if applied as an active enzyme component in animal feed. Specifically the endoprotease according to the invention can be applied as bread improver in the bakery industry, e.g. to retard the staling of bread or to diminishing the viscosity of doughs. Or the endoprotease can be used in the beer and wine industry to prevent or to minimise the formation of undesirable protein hazes. Alternatively it can be used in the beer industry to optimise the protein extraction yields of cereals used in the preparation of the wort. Furthermore, it can also be advantageously used in the dairy industry as a milk clotting agent with superior characteristics or to optimise the texturising, foaming or setting characteristics of various milk components. Another application in the dairy industry is the use of the new protease in the preparation of Enzyme Modified Cheeses (EMC's).

[0232]Moreover, various proteinaceous substrates can be subjected to an endoprotease according to the invention, usually in combination with other proteolytic enzymes to obtain hydrolysates for medical or non-medical applications. Here the endoprotease according to the invention is surprisingly effective in achieving a complete hydrolysis of the proteinaceous substrate so that even protease resistant parts are fully hydrolysed, the endoprotease is also surprisingly active in minimising the allergenicity of the final hydrolysate or in suppressing the formation of bitter off-tastes.

[0233]More specifically the endoprotease according to the invention is characterised by its preference for cleaving proteins at unusual peptide bonds, especially with the small size amino acid residues of Ala, Gly, Ser and Thr, or the residues Ile and Pro in either the P1 or the P1' position (Keil, B et al.; Protein Seq Data Anal (1993) 5; 401-407). As the result those fractions of the proteinaceous starting materials that resist hydrolysis upon using prior art endoproteases, can be dissolved and hydrolysed using the endoprotease according to the invention. Non limiting examples of such protease resistant fractions include socalled extensins in plant materials and collagen, gelatin but also specific milk components in material of animal origen.

[0234]Various feedstuffs such as e.g. soybeans contain trypsin inhibitors. These proteins inhibit trypsin activity in the GI-tract of e.g. pigs and poultry. This trypsin inhibiting activity results in sub-optimal protein digestibility in these animals resulting in increased waste production and poor economics. This problem may partly be overcome by toasting soybeans at high temperatures. Two different types of trypsin inhibitors have been identified in soybeans, i.e. the Bowman-Birk type trypsin inhibitors and the Kunitz type trypsin inhibitors.

[0235]This invention now provides an alternative way to degrade trypsin inhibiting activity over toasting, in that it provides a cysteine proteases (EC 3.4.22, table 1) capable of cleaving at Leucine176-Aspartate177 peptide bond near the carboxyl-terminus of the Kunitz type trypsin inhibitor (as reviewed by Wilson (1988) in CRC Critical Reviews in Biotechnology 8 (3): 197-216). This results in inactivation of this trypsin inhibitor in soybean. It was surprisingly found that the cysteine proteases secreted by the fungus Aspergillus niger fulfilled these criteria far better than similar enzymes derived from other organisms.

[0236]Proteases are also widely used in the art of cheese-making. In the production of cheese it is necessary to coagulate the cheese milk to be able to separate the cheese matters e.g. casein from the whey. Several milk coagulating enzymes, also referred to as coagulants, have been described and include (bovine) chymosin, bovine pepsin, porcine pepsin as well as microbial enzymes like Rhizomucor miehei protease, Rhizomucor pusillus protease and Cryptonectria parasitica protease. Chymosin can be obtained from calf stomachs but can also be produced microbially by for example Kluyveromyces lactis. All these enzymes are characterized by having specificity for the peptide bond between residue 105 (phenylalanine) and residue 106 (methionine) or the bond adjacent to that in K-casein. This means that by employing these enzymes in cheese making, the K-casein is split at the junction between para-K-casein and the macro-peptide moiety called glycomacropeptide (GMP) carrying the negative charges. When this occurs the macropeptide diffuses into the whey, its stabilizing effect on the solubility of the casein micelles is lost, and the casein micelles can start to aggregate once sufficient kappa-casein has been hydrolyzed. For further elaboration on the enzymatic coagulation of milk (e.g. D. G. Dalaleish in Advanced Dairy Chemistry vol. 1 ed by P. F. Fox, Elsevier, London, 1992.

[0237]The currently available coagulants allow for a rather high yield of cheese, however, it should be realised that due to the enormous volumes of cheese produced, an increased yield in the order of magnitude of tenths of percent points may constitute a substantial economical advantage. Consequently there is a great need in the art for coagulants with an (even slightly) improved yield.

[0238]Coagulants are characterized by their high substrate specificity, which is, however, dependent on pH and temperature. In a typical cheese making process the pH will change from the initial pH 6.3 to lower pH values in the range of 4.5-5.5, the end-value depends on the conditions used during the cheese production process. Some coagulants are more sensitive to pH changes than others. The Rhizomucor pusillus protease for example is more sensitive to pH changes than chymosin. Besides pH, also other parameters like temperature and water content may affect the protease specificity. It is well known that most coagulants show a changing substrate specificity with changing pH, resulting in altered proteolytic activity in later stages of the cheese making process. It is also well known that coagulants differ in the extent of casein proteolysis; they may also show differences in the peptide patterns produced during proteolysis. These are relevant factors during cheese ripening and may affect cheese properties like taste, flavor and texture. In some cases coagulants give rise to undesired effects like the formation of bitter tasting peptides or off-taste. In addition, changes in proteolytic specificity may lead to a reduction in yield. Pepsin, a well known component in many bovine chymosin preparations, is an example of a protease that gives rise to lower yields and taste effects as compared to pure chymosin. There is still a need for coagulants with give rise to new, improved cheese texture and taste. Such new coagulants result in the accelerated development of taste and texture profiles related to cheese aging, therewith providing a substantial economical benefit.

[0239]It is well known that free amino acids are very important in taste and flavour generation. Especially the amino acids leucine, phenylalanine, methionine and valine play an important role in the generation of typical cheese taste and flavor components. The free amino acids are converted via fermentation by micro organisms that are added during the cheese manufacturing process into the actual flavor and taste generating compounds like methanediol, dimethyldisulphide, methylpropanoic acid and methylpropanal. Exo-peptidases play an important role in the generation of free amino acids. They can only be effective, however, when they are combined with an endo-protease of appropriate specificity. Appropriate combinations of exo- and endo-peptidases can be used in cheese making, resulting in the manufacture of cheeses with new and improved taste profiles.

[0240]The enzymes according to the invention may be used to hydrolyze proteinaceous materials of animal origin such as whole milk, skim milk, casein, whey protein or mixtures of casein and whey protein. Such mixtures of casein and whey protein may be used, for example, in ratios similar to those found in human milk. Furthermore, the enzyme mixture according to the invention may be used to hydrolyze proteinaceous materials of plant origin such as, for example, wheat gluten malted or unmalted barley or other cereals used for making beer, soy milk, concentrates or isolates thereof, maize protein concentrates and isolates thereof, and rice proteins.

[0241]Within the area of large scale industrial processes, some applications rely on the use of endoproteases only whereas in other applications combinations of endoproteases with exoproteases are essential. Typical examples which depend on the use of pure endoproteases and in which the protease according to the invention can deliver a superior performance include applications like the processing of soy or peas or cereals proteins aimed at minimising viscosities or optimising foaming or other physics-chemical characteristics, bread improvers in the bakery industry also aimed at diminishing the viscosity of doughs, processing aids in the beer and wine industry aimed at the prevention of protein hazes or optimising the extraction yields of cereals, feed additives in the bio industry aimed at enhancing intestinal absorption or modulating microbial activities in the gut, processing aids in the dairy industry aimed at optimising the clotting, foaming or setting characteristics of various milk components. Moreover, v For specific market segments proteins derived from milk or soy or collagen are exposed to proteases to produce socalled protein hydrolysates. Although the main outlets for these protein hydrolysates are infant formula and food products for hospitalised persons, products intended for persons with non-medical needs, such as athletes or people on a slimming diet form a rapidly growing segment. In all of these applications protein hydrolysates offer attractive advantages such as lowered allergenicities, facilitated, gastro-intestinal uptake, less chemical deterioration of desirable amino acids like glutamine and cystein and finally, absence of proteinaceous precipitations in acid beverages during prolonged storage periods. All these advantages can be combined if the hydrolysate is offered as a mixture of di- and tripeptides. However, currently all commercially available hydrolysates are produced by combining several endoproteases. The latter approach implies a non-uniform and incomplete degradation of the protein. To obtain the desired mixture of di- and tripeptides, a hydrolysis process involving a combination of various di- and tripeptidylpeptidases would be ideal. Unfortunately, only few of these enzymes from food grade and industrially acceptable microorganisms are known, let alone industrially available. According to the invention several of highly useful di- and tripeptidylpeptidases are economically obtainable in a relatively pure state. Preferred are those di- or tripeptidylpeptidases that exhibit a low selectivity towards the substrate to be cleaved, i.e. exhibit minimal amino acid residue cleavage preferences only. Preferred are combinations of those di- or tripeptidylpeptidases that hydrolyse high percentage of the naturally occurring peptide bonds. Despite this high activity to naturally occurring peptide bonds, a total hydrolysis to free amino acids is prevented by the nature of the di- and tripeptidylpeptidases. Also preferred are those di- or tripeptidylpeptidases that are optimally active between pH 4 to B and exhibit adequate temperature stability. Adequate temperature stability implies that at least 40%, preferably at least 60%, more preferably between 70 and 100% of the initial hydrolytic activity survives after heating the enzyme together with the substrate for 1 hour at 50 degrees C.

[0242]Although the process towards an efficient production of mixtures di- or tripeptides or di- and tripeptides hinges on the availability of the enzymes according to the invention, the first enzyme incubation with the proteinaceous substrate will usually be an endoprotease. Preferably an endoprotease with a broad spectrum endopeptidase suited for the situation, e.g. subtilisin (Delvolase from DSM), neutral metallo protease (Neutrase from NOVO) or thermolysin (Thermoase from Daiwa Kasei) for the near neutral conditions and pepsin or aspergillopepsin (e.g. Sumizyme A P from Shin Nihon, Japan) for the acidic conditions. Aim of this first digestion is to improve the solubility, to reduce the viscosity and to reduce the heat setting characteristics of the water/protein mixture. Furthermore this pretreatment with an endonuclease is essential to create enough starting points for the di- and tripeptidylpeptidases hereby accelerating the process of di- or tripeptide formation. Optionally a protease intended for debittering of the hydrolysate can be included in this stage of the process or later, together with the di- or tripeptidylpeptidases.

[0243]Main aim of the latter hydrolysates is to minimize the allergenicity of the product or to facilitate gastrointestinal uptake. In the production of such hydrolysates the use of dipeptidyl- and tripeptidyl-peptidases is of special importance as hese s offer an efficient way for producing hydrolysates.

[0244]Other applications in these food and feed industries totally rely upon combinations of one or more endoprotease(s) with one or more exoprotease(s). Such combinations of an endoprotease with an exoprotease are typically used in industries to improve aspects like taste and colour of the final product. The reason for this is that the development of taste and colour is largely dependent upon the presence of free amino acids. Free amino acids can not only be obtained by exoproteases such as carboxypeptidases and aminopeptidases but also by peptidyl-dipeptidases. If combined with endoproteases or even dipeptidyl- or tripeptidyl-peptidases, carboxypeptidases, aminopeptidases and peptidyl-dipeptidases can create larger quantities of free amino acids in less time. However, in all of these processes an uncontrolled release of amino acids or even non-proteinaceous components should be avoided to minimise undesirable side reactions.

[0245]Though free amino acids as such, can elicit a number of taste impressions, these taste impressions are very basic (bitter, sweet, sour and "umami") and the amino acid concentration required for perceiving these tastes are high. Despite these high threshold values, free amino acids are able to create major sensory effects at much lower concentration ranges through a number of flavour enhancing mechanisms. One of these mechanism involves the combination of free amino acids with sugars in so-called Maillard reactions. Compared with free amino acids, with these Maillard products overwhelmingly complex flavour and odour systems can develop with threshold values that are several orders of magnitude lower than those recorded for the free amino acids. Maillard products are formed at elevated temperatures usually during cooking, baking or roasting when preparing food or feed products. During these treatments both colour and a large array of aromas develop. In these reactions amino groups react with reducing compounds as a first step and ultimately leading to a whole family of reaction pathways. In foods or feeds the amino compounds involved are predominantly free amino acids which are released from the proteinaceous raw material by various proteases and the required reducing compounds primarily represent reducing sugars. The implication is that during the processsing of the raw material undesired release of free amino acids and sugars should be avoided to minimise off tastes that could be generated during subsequent heating steps as e.g. during spray drying or sterilisation. The latter notion emphasises once more the benefits of superior purity and low in-use costs of the enzyme according to the invention.

[0246]Apart from Maillard reactions, amino acids can also undergo important chemical transitions at ambient temperatures. The latter type of transitions are enzyme dependent and are quite common in fermented foods such as beer, yoghurt, cheese ripening and meat and wine maturation processes. In these fermentation processes, free amino acids are liberated from the raw materials used by the proteases added or by proteolytic enzyme activity from the raw material or the microbial starters used. During the maturation phase microbial metabolic activity then converts the free amino acids into derivatives with increased sensoric properties. For example, L-leucine, L-isoleucine and L-valine lead to the formation of valuable fusel alcohols like amylalcohols and isobutanol in beer fermentation. Similarly cheese volatiles such as methanethiol and dimethyldisulphide have been traced back to the occurrence of methionine in cheese as well as methylpropanoic acid and methylpropanal to valine. Finally the free amino acid glutamate and can create strong savoury enhancing effects because of its synergy with the breakdown products of RNA, so-called 5'-ribonucleotides. If combined with proper concentrations of 5'-ribonucleotides such as 5'-IMP and 5'-GMP, the detection threshold of the umami taste generated by glutamate is known to be lowered by almost two orders of magnitude.

[0247]In order to obtain pronounced and precise taste effects in all of these processes, the proteinaceous substrates should be hydrolysed using a combination of an endo- and an exoprotease, wherein at least one of the endo or exoprotease, preferably both the endo- and exoprotease, are pure and preferably selective towards a specific set of amino acid(s) or preferentially release the preferred amino acid(s). So preferred proteases are characterised by a high selectivity towards the amino acid sequences that can be cleaved which notion makes the enzyme category in Aspergillus known as "maturases" of particular importance.

[0248]Apart from the food and feed industries, proteases are also commonly applied by the chemical, pharmaceutical, diagnostic and personal care industries.

[0249]In the personal care industry proteases are used to create peptides which are added to a variety of products to improve aspects like skin feel, gloss or protection. Moreover there is a new tendency towards direct topical application of the protease. Very similar to the enzyme use in the leather industry, the prime aim in the latter application is to clean, dehair and soften the skin.

[0250]In the chemical and pharmaceutical industry proteases are being developed as valuable tools in producing costly ingredients or intermediates. In these industries proteases are not only used because of their hydrolytic capacity but also because of their capacity to synthesise peptides from natural or non-natural amino acids. The latter option is clearly demonstrated by the possibility to synthesize aspartame from its amino acid based building blocks by using an endoprotease like thermolysin.

[0251]Unlike the situation in the food and feed industry, the stereo- and regioselectivity of proteases are also considered important assets although unusual reaction conditions may be needed to accomplish the desired chemical transformation. Typical examples of the application of proteases in this industry include the use of endoproteases, aminopeptidases as well as carboxypeptidases in the production of various intermediates for drugs like insulin, antibiotics, renin and ACE-inhibitors An overview of such uses is presented in Industrial Biotransformations, A. Liese, K. Seelbach, C. Wandrey, Wiley-VCH; ISBN 3-527-30094-5.

[0252]In view of the desired specificities, stereo- and regioselectivities, the absence of side activities and resistance to unusual reaction conditions such as high solvent concentrations, the improved performance of the protease according to the invention offers substantial advantages.

[0253]From a pharmaceutical point of view the role of proteases is illustrated by a substantial number of references in Martindale's, "The Extra Pharmacopoeia" (Pharmaceutical Press, London, UK). Moreover the important role of very specific proteases in regulating all kinds of biological processes is illustrated by the fact that many hormones become active only after the processing of an, mostly inactive, precursor molecule by such a very specific protease. Inhibitors active towards certain categories of such specific proteases have been implicated in the development of all kinds of new drugs. Therefore new and effective inhibitors for protease may now be identified using the sequences provided herein.

[0254]The entire disclosure of each document cited herein is hereby incorporated by reference

TABLE-US-00001 TABLE 1 SEQ ID number Gene cDNA Protein Function of encoded protein EC number 1 58 115 Pepsin A.sub.3 EC3.4.23.1 2 59 116 Metalloprotease EC3.4.24.56 3 60 117 acylaminoacyl-peptidase EC3.4.19.1 4 61 118 Tripeptidylaminopeptidase EC3.4.14.- 5 62 119 serine carboxypeptidase EC3.4.16.6 6 63 120 Serine endoprotease EC3.4.21.- 7 64 121 Carboxypeptidase Y EC3.4.16.5 8 65 122 aspergillopepsin II - hom EC3.4.23.19 9 66 123 Tripeptidyl peptidase EC3.4.14.9 10 67 124 Tripeptidyl peptidase EC3.4.14.9 11 68 125 aspergillopepsin II - hom EC3.4.23.19 12 69 126 Tripeptidyl peptidase EC3.4.14.9 13 70 127 Metalloprotease EC3.4.24.- 14 71 128 aspergillopepsin I EC3.4.23.18 15 72 129 Pepsinogen E EC3.4.23.25 16 73 130 aspergillopepsin I - hom EC3.4.23.18 17 74 131 aspergillopepsin II EC3.4.23.19 18 75 132 Pyro-Glu peptidase EC3.4.19.3 19 76 133 dipeptidyl peptidase EC3.4.14.2 20 77 134 Secr. aminopeptidase EC3.4.11.10 21 78 135 alkaline D-peptidase EC3.4.16.4 22 79 136 Carboxypeptidase EC3.4.16.1 23 80 137 Carboxypeptidase EC3.4.16.1 24 81 138 Carboxypeptidase-II EC3.4.16.1 25 82 139 aspartic proteinase EC3.4.23.- 26 83 140 Tripeptidyl peptidase EC3.4.14.9 27 84 141 Carboxypeptidase EC3.4.16.1 28 85 142 cysteine proteinase EC3.4.22.- 29 86 143 Metallocarboxypeptidase EC3.4.17.- 30 87 144 Subtilisin hom. EC3.4.21.62 31 88 145 Carboxypeptidase Y EC3.4.16.5 32 89 146 Metalloprotease EC3.4.24.- 33 90 147 Carboxypeptidase Y EC3.4.16.5 34 91 148 Metalloprotease EC3.4.24.- 35 92 149 Tripeptidyl peptidase EC3.4.14.9 36 93 150 Aspartic protease EC3.4.23.24 37 94 151 Aspartic protease EC3.4.23.24 38 95 152 Pepsin A.sub.3 EC3.4.23.1 39 96 153 Aspartic protease EC3.4.23.24 40 97 154 Aspartic protease EC3.4.23.24 41 98 155 Kex EC3.4.21.61 42 99 156 Serine protease EC3.4.21.- 43 100 157 Glutamyl endoprotease EC3.4.21.82 44 101 158 aspergillopepsin II - hom EC3.4.23.19 45 102 159 acylaminoacyl-peptidase EC3.4.19.1 46 103 160 Tripeptidylaminopeptidase EC3.4.14.- 47 104 161 serine carboxypeptidase EC3.4.16.6 48 105 162 Gly-X carboxypeptidase EC3.4.17.4 49 106 163 aspartic proteinase EC3.4.23.- 50 107 164 Tripeptidyl peptidase EC3.4.14.9 51 108 165 Carboxypeptidase-I EC3.4.16.1 52 109 166 serine carboxypeptidase EC3.4.16.6 53 110 167 serine carboxypeptidase EC3.4.16.6 54 111 168 Secr. aminopeptidase EC3.4.11.10 55 112 169 Prolyl endopeptidase EC3.4.21.26 56 113 170 aspergillopepsin I - hom EC3.4.23.18 57 114 171 Aminopeptidase EC 3.4.11.-

EXAMPLES

Example 1

Assaying Proteolytic Activity and Specificity

[0255]Protease specificity may be explored by using various peptide substrates. Synthetic substrates are widely used to detect proteolytic enzymes in screening, in fermentation, during isolation, to assay enzyme activity, to determine enzyme concentrations, to investigate specificity and to explore interaction with inhibitors. Peptide p-nitroanilides are preferably used to assay protease activity as the activity can be followed continuously and therefore allow for kinetic measurement. The cleavage of peptide p-nitroanilides can be followed by measuring the increase in adsorption at 410 nm upon release of the 4-nitroanilide. Paranitroanilide substrates are generally used for serine and cysteine proteases. In addition peptide thioesters and 7-amino-p-methylcoumarin peptide derivates are used. Peptide thioesters are very sensitive substrates for serine and metalloproteases that exhibit relatively high turnover rate since the thioester bond is easier to cleave than the amide bond. Cleavage of thiolesters may be followed with a thiol reagent such 4,4-dithiopyridine (324 nm) or 5,5-dithiobis 2-nitrobenzoic acid (405 nm). The same increased turnover rate is usually observed for the cleavage of ester bonds relative to amide bond. The most well known substrates to assay the esterase activity of proteases are p-nitrophenol derivates. The release of p-nitrophenol can be monitored at different wavelength dependent on the pH that is used, eg around neutral pH a wavelength of 340 nm is used while above pH 9 monitoring is done around 405 nm. In addition the hydrolysis of esters can also be followed by titration using pH-stat equipment. In case of qualitative measurement of esterase activity pH sensitive dyes can be applied.

[0256]As an alternative, peptides may be attached to a fluorescent leaving group. Proteolysis is accompanied by an increase in fluorescence when monitored at the appropriate wavelengths. Peptidyl 2-naphtylamides and peptidyl 4-methyl-7-coumarylamides are commonly used. The release of for example 7-amino-4 methylcoumarin is measured using an excitation wavelength of 350 nm and an emission wavelength of 460 nm. The use of 7-amino-4 trifluoromethylcoumarin has the advantage of the leaving group being both chromogenic (absorbtion 380 nm) as well as fluorogenic (excitation 400 nm, emission 505 nm). When it is essential that at both sides of the scissile bond an amino acid is present, the introduction of a group that quenches the fluorescence might be useful. The general characteristics of such substrates is that the peptide sequence separates a fluorescent donor group from an acceptor group that acts as a quencher of fluorescence. Cleavage of a peptide bond between the quenching group and the fluorophore will lead to substantial increase in fluorescence. Several donor-acceptor pairs have been reported, including o-aminobenzoic acid (Abz) as the donor and 2, 4 dinitrophenyl (Dnp) as the acceptor, 5-[(2'aminoethyl)-amino]naphtalenesulfonic acid (EDANS) as the donor and 4-[[4'-(dimethylamino)phenyl]azo]-benzoic acid (DABCYL) as the acceptor. The Abz/EDDnp represents a very convenient donor-aceptor pair since after total hydrolysis, the fluorescence increases by a factor 7 to 100 and the absorption spectrum of EDDnp does not change with pH. Moreover, the peptide sequence may contain up to 10 residues without loss of the quenching effect. As the size of the connecting peptides increases, the position of the scissile bond may become less specific. Therefore in addition to establishing whether proteolysis occurred, additional analysis of the products may be required. This may be done by analysing and separating the produced peptides by HPLC and determining the amino acid sequence of the fragments. In addition the peptide composition of the digest may be directly analysed by using combined HPLC/mass-spectroscopy technique.

[0257]Apart from using peptides of a defined sequence also synthetic peptide libraries can be used to study protease specificity. Peptides are synthesised by solid phase synthesis in random or semi-random fashion. E.g. Meldal et al. (PNAS USA 91, 3314, 1994) report the preparation of a family of protease substrates by starting with H-Lys(Abz)-resin, extending the resin with peptides to a length of six aminoacids, and finally coupling Tyr(NO2) to the peptides. Each resin bead has a unique sequence and on treatment with the proteases the most susceptible becomes fluorescent as the Tyr(NO2) containing peptide is released. Sequence analysis of the peptides on the susceptible will give information on the specificity of the protease.

[0258]Protease activity is usually expressed in units. Generally the international standard unit (IU) is defined as the amount of enzyme, which under defined conditions transfers one micromole of substrate per minute. Specifically with proteases the IU would relate to the hydrolysis of one micromole peptide bond per minute. However in the case of protease units deviations of the international definition are more rule than exception. Where with the model peptides, which are cleaved specifically at one bond the calculation of IU's is strait-forward, for proteinacious substrates where the protease can cleave at various positions to a various degree many deviating unit definition are used. Apart from a definition of the unit used, any hydrolysis experiment requires an adequate description of the conditions under which the units are measured. Such conditions comprise e.g. the substrate concentration, the enzyme-substrate ratio, the pH and temperature. Typical assays for determining the specific activity of a proteases comprise a proteinacious substrate such as for example denaturated hemoglobin, insulin or casein. The polypeptide substrate is digested by a protease at fixed conditions during a fixed time interval. Undigested and large polypeptides are precipitated with TCA and TCA soluble product is determined by measuring absorbance at 220 or 280 nm, or by titrating the soluble peptides with folin reagent, ninhydrin, fluoro 2,4, dinitrobenzene/dansylchloride, TNBS method or fluorescein. Instead of labeling the product after hydrolysis, also polypeptide substrates may be used which are already labeled by specific dyes or fluorophores such as for example fluorescein. In addition standard methods of amino acid analysis may be applied using standard laboratory analyzers. In order to hget insight in the size distribution of the peptides generated by a protease, gel chromatography experiments may be performed. In addition to this HPLC using reverse phase techniques is applied in order to get better resolution of the peptide patterns generated by the protease.

[0259]The course of the hydrolysis of proteinacious substrates is usually expressed in the degree of hydrolysis or DH. In case pH-stat is used to follow the course of hydrolysis, DH can be derived from the base consumption during hydrolysis (Enzymatic Hydrolysis of Food Protein, J. Adler-Nissen, 1986, Elsevier Applied Science Publishers LTD). The DH is related to various useful functional properties of the hydrolysate such as solubility, emulsifying capacity, foaming and foam stability, whipping expansion, organoleptic quality. In addition taste is an important aspect of food grade hydrolysates. Bitterness can be a major problem in protein hydrolysates. Termination of the hydrolysis reaction may be done by changing the pH, heat inactivation, denaruring agents such as SDS, acetonitril etc.

[0260]Polypeptides shown in Table 1 were expressed and at least partially purified according to standard procedures known in the art. They were analysed according to at least one of the methods described above and found to have the activities listed in Table 1.

Example 2

Direct Determination of the kcat/Km Ratio for Protease Substrates

[0261]Synthetic substrates can be used to monitor the enzymatic activity during purification, to determine enzyme concentration, to determine inhibition constants or to investigate the substrate specificity. Determination of the kcat/Km ratio gives a measurement of the substrate specificity. It allows to compare the specificity of different substrates for a same enzyme or the comparison of hydrolysis rates with different enzymes cleaving the same substrate. This ratio has a unit of a second order rate constant and is then expressed as 1/(concentrationtime). Substrates having a kcat/Km ratio in the range 10.5-10.6 M-1sec-1 are considered to be very good substrates i.e good affinity and rapid turn-over. However, some substrates may be very specific with kcat/Km values in the 10.4 M-1sec-1 range.

[0262]The kcat/Km ratio may be calculated after determination of individual parameters. In that case, Km and Vm may be obtained from various linear plots (e.g Hanes or Cornish-Bowden method) or by a non-linear regression method. Knowing that Vm=kcatEt (where Et is the final active enzyme concentration then kcat=Vm/Et. Determination of the kcat/Km ratio by the previous method may be prevented when product or substrate inhibition occur, or when substrate precipitates at high concentration. It is however possible to obtain an accurate value of the kcat/Km ratio working under first-order conditions i.e at a substrate concentration far below the estimated Km. In these conditions, the Michaelis-Menten equation: v=(VmS)/(Km+S) becomes:

v=(VmS)/Km since S<<Km

or v=(Vm/Km)S=kobsS=-dS/dt

which integrates as InS=-kobst+InSo where So is the starting substrate concentration and S the substrate concentration at a given time. The velocity is proportional to the substrate concentration. In other words, the substrate hydrolysis obeys a first order process with kobs as the first-order rate constant. kobs=Vm/Km=(kcatEt)/Km since Vm=kcatEt

[0263]A continuously recording of the substrate hydrolysis will allow the graphical determination of kobs from the InS vs time graph. The kcat/Km ratio is simply inferred from kobs providing the active enzyme concentration is known:

kcat/Km=kobs/Et

[0264]Assay method: Use a starting substrate concentration far below the estimated Km and a low enzyme concentration to allow the substrate hydrolysis to be recorded. You will obtain a first-order curve for the product generation:

[0265]After total hydrolysis of the substrate, the absorbance (or fluorescence units) of the product will allow the accurate determination of So, since Pt=Sokobs is determined from the slope of the InS vs time graph or alternatively using a fitting software (Enzfitter, SigmaPlot . . . ).

[0266]NB: Do not forget to calculate the substrate concentration for any given time from the product concentration (S=So-P) since plotting P vs time would not provide the correct kobs (dP/dt=kobsS does not integrate in the same way).

[0267]Alternatively, one can measure successive t1/2 (half-time) from the product apparition curve since in a first order process:

t1/2=ln 2/lkobs=0.693/kobs then kobs=0.693/t1/2

[0268]Using this method allows to check that you have a true first order decay (identical values for the successive t1/2).

Example 3

Inactivating Protease Genes in Aspergillus

[0269]The most convenient way of inactivating protease genes in the genome of Aspergillus is the technique of gene replacement (also called "one step gene disruption"). The basics of this technique have been described by Rothstein R J in Meth. Enzymol. 101, p 202, 1983. Essentially the technique is based on homologous recombination of transformed DNA fragments with the genomic DNA of a fungal cell. Via double crossover the gene to be inactivated is (partly) replaced by the DNA fragment with which the cell is transformed. Preferably the transformed DNA fragment contains a selectable marker gene for Aspergillus niger. Basically the manipulation of DNA and generation of a inactivation construct are done using general molecular biological techniques. First, genomic DNA is isolated from the Aspergillus niger strain that is later on used for the inactivation of the protease gene. Genomic DNA of A. niger can be isolated by any of the techniques described, e.g. by the method described by de Graaff et al. (1988) Curr. Genet. 13, 315-321, and known to the person skilled in the art. This genomic DNA is used as template for amplification of the flanking regions of the protease gene by using the polymerase chain reaction (PCR; Sambrook et al. (1989) Molecular cloning, a laboratory manual, 2nd edition, Cold Spring Harbor Laboratory Press, New York). With flanking regions is meant here the non-coding regions upstream and downstream of the protease gene that will be inactivated. Preferably the flanking regions should each be more than 1.0 kb in length.

[0270]Two single stranded DNA oligonucleotides are used for the priming of the PCR amplification of each flanking region. For the 5'-flanking region, one primer is homologous to a DNA sequence upstream of the start of the coding sequence of the protease gene. Preferably the homologous region is located more than 1.0 kb upstream of the translation start site. The second primer is homologous to the complementary and inverse DNA sequence located immediately upstream of the coding sequence of the protease gene.

[0271]For the 3'-flanking region, one primer is homologous to the DNA sequence immediately downstream of the coding sequence of the protease gene. The second primer is homologous to a complementary and inverse DNA sequence located preferably more than 1.0 kb downstream of the coding sequence of the protease gene.

[0272]The DNA sequence included in all primers and homologous to the A. niger genome should be minimally 15 nucleotides in length, preferably more than 18 nucleotides in length. Most conveniently, all primers should contain a DNA sequence coding for the recognition site of suitable restriction enzymes upstream of the sequence that is homologous to the A. niger genome. These extra recognition sites facilitate the cloning process.

[0273]Both primers and the genomic DNA of A. niger are used in a PCR reaction under conditions known to those skilled in the art. The annealing temperature of the primers can be calculated from the part of the DNA sequence that is homologous to the A. niger genome. Both fragments containing the 5'-flanking region and the 3'-flanking region are cloned into a vector that can be propagated in E. coli using general molecular biological techniques. A gene that can be used as selection marker in Aspergillus niger is then cloned in between the two flanking regions. Most conveniently the marker gene is under control of a promoter that comes to expression in A. niger, preferably an endogenous A. niger promoter. The orientation of the insertion of the marker gene is preferably in the same direction as the original protease gene. The final inactivation fragment contains the 5'-flanking region, a selection marker gene preferably under control of a A. niger endogenous promoter, and the 3'-flanking region, all in this direction and orientation. DNA of the final construct is cloned into a vector that can be propagated in E. coli.

[0274]The inactivation construct is digested with suitable restriction enzymes to remove the E. coli vector sequences and the inactivation fragment is isolated using standard techniques (Sambrook et al. (1989) Molecular cloning, a laboratory manual, 2nd edition, Cold Spring Harbor Laboratory Press, New York). Finally Aspergillus niger is transformed with the inactivation fragment using a method described in literature, e.g. by the method described by Kusters-van Someren et al. (1991) Curr. Genet. 20, 293-299. Transformed cells are selected by plating the transformation mixture on agar plates that are selective for growth of Aspergillus niger strains that do express the marker gene. After purification of the transformed Aspergillus strains by replica plating, a representative number of strains is analysed by Southern blotting using standard methods (Sambrook et al. (1989) Molecular cloning, a laboratory manual, 2nd edition, Cold Spring Harbor Laboratory Press, New York). Therefore, genomic DNA of mycelium of transformed strains is isolated and digested with suitable restriction enzymes. Restriction fragments are separated using agarose gel electrophoresis, blotted to nitrocellulose membranes and probed with a labeled fragment of the marker gene. Hybridization and washing is under stringent conditions. Strains that contain labeled restriction fragments of the correct length are considered correct.

[0275]Using this method A. niger strains can be selected with an inactivated protease gene of choice.

Example 4

Isolating Proteases by Ion Exchange Chromatography

[0276]Small quanties of the protease encoded by the nucleotide sequence as provided herein are obtained by constructing an expression plasmid containing the relevant DNA sequence, transforming an A. niger strain with this plasmid and growing the A. niger strain in a suitable medium. After collecting the broth free of contaminating cells, the protease sought can be purified.

[0277]To isolate the protease as encoded by the provided nucleotide sequence in an essentially pure form several strategies can be followed. All of these strategies have been adequately described in the relevant scientific literature (see for example the Protein Purification Handbook, 18-1132-29 Edition M as published by Amersham Pharmacia Biotech, Uppsala, Sweden). A procedure which is applicable to purify proteases from complex mixtures is provided hereunder. Essential is that a suitable assay is available that is selective towards the enzyme characteristics sought. For proteases typically a chromogenic, synthetic peptide substrate is used as described in Example 1. Such peptide substrates can be selective towards endoproteases, carboxypeptidases, aminopeptidases or omega peptidases. In Example 11 the selectivity towards a specific tripeptidylpeptidase is described. By choosing the right amino acid residues in the relevant synthetic peptide, proteases with the desired specificity can be selected.

[0278]First it should be determined whether the protease is excreted into the medium, depending on the expression system chosen to produce the protease, it may be excreted or contained in the cell. If the protease is excreted into the fermentation medium, the producing cells or fragments of these cells have to be removed by centrifugation or filtration and the resulting clear or clarified medium is the starting point for further purification. In those cases in which the protease sought is not excreted, the producing cells have to be disrupted to enable purification of the protease. In such cases the collected cell mass is best ground with an abrasive, milled with beads, ultrasonicated or subjected to a French press or a Manton-Gaulin homogeniser and then filtered or centrifuged. In case the protease is hydrophobic or membrane bound, the addition of a non-ionic detergent to solubilise the protease before the filtering or centrifugation step may be necessary.

[0279]After the clarification step, a three phase purification strategy can be applied to obtain the unknown proteases in an essentially pure state. In all or some of these three phases addition of a detergent may be necessary.

[0280]In the first or capture phase the target protease is isolated, partly purified and concentrated. During the subsequent intermediate purification phase most of the bulk impurities are removed and in the final polishing phase trace amounts of remaining impurities of larger amounts of closely related substances are removed and the enzyme is dissolved in the desired buffer. Depending upon the nature and physical properties of the protease at hand, a person skilled in the art is capable of optimising the three phases using slightly modified versions of the different protein binding materials and apply these under somewhat changed conditions. However, in all cases a selective analytical assay is indispensible as it will enable the continuous monitoring of the increasingly purified proteolytic activity. Analytical assays suitable for the purpose include the use of chromogenic peptide substrates as has been mentioned before.

[0281]In the first capturing phase of the purification a strong ion exchange resin of the anionic type is preferably used to apply the clarified and desalted enzyme containing medium. To guarantee binding of the desired proteolytic activity to the resin, three or four different pH values of medium and resin are tested under low conductivity conditions. In these tests the resin is always equilibrated with a buffer of the same pH value and conductivity as the enzyme containing medium. The medium is then applied to the column under pH conditions which has been shown to allow adequate binding of the protease to the resin i.e. none of the desired enzymatic activity can be traced back in the run-through medium. Subsequently the desired enzymatic activity is eluted from the ion exchange resin using a continuous salt gradient which starts with the resin equilibration buffer and ends with this buffer to which 1 mol/liter of NaCl has been added. Eluted fractions containing the desired activity according to the assay are pooled and then prepared for an additional purification step. This additional purification step depends on the purity of the desired enzyme in the pooled fraction: if almost pure, an additional gel filtration step will proof to be adequate; if not almost pure, chromatography over a hydrophobic interaction resin is applied followed by a gel filtration step.

[0282]Chromatography over a hydrophobic interaction resin is carried out by first increasing the salt content of the pooled fraction obtained from the ion exchange resin to 4 mol/liter of NaCl and by removing any precipitate formed. If the resulting clear fraction does not contain the desired activity, this activity is obviously present in the precipitate and can be recovered in an essentially pure state. If the resulting clear fraction still exhibits the desired activity in the assay, then the liquid is applied as such to a phenyl sepharose resin (Pharmacia) equilibrated in this high salt buffer with an identical pH and conductivity. If the desired enzymatic activity binds to the phenyl sepharose resin, the activity is eluted with a continuous gradient of decreasing salt content followed by a salt free wash and, if necessary, with a chaotropic agent. Like before those fractions from the gradient that exhibit activity in the assay are pooled and finally subjected to a gel filtration step. If the desired enzymatic activity does not bind to the phenyl sepharose resin, many of the contaminants will, so the desired proteolytic activity as present in the void volume of the column requires only an additional ultrafiltration step to obtain the activity in a more concentrated form before applying it to the gel filtration column. The gel filtration column does not only remove trace contaminations but also brings the enzyme in the buffer which is required by subsequent use.

[0283]Although this method is generally applicable for the isolation and purification of proteases according to the invention, a more specific isolation technique is described in Example 4. In that Example the isolation of an Aspergillus protease is described by using immobilised bacitracin, a peptide antibiotic known for its selective interaction with various types of proteases.

Example 5

Isolating Proteases by Affinity Chromatography

[0284]An alternative method for purifying small quantities of protease is by affinity chromatography. To obtain the protease in a purified form, a 100 milliliter culture is grown in a well aerated shake flask. After centrifugation to remove any non-soluble matter, the supernatant is applied to a 40 milliliter bacitracin-Sepharose column equilibrated with 0.05 mol/litre sodium acetate pH 5.0. Proteases bound to the column are eluted using the acetate buffer supplemented with 1 mol/litre of NaCl and 10% (v/v) isopropanol (J. Appl. Biochem., 1983 pp 420-428). Active fractions are collected, dialysed against distilled water and applied on a 20 milliliter bacitracin-Sepharose column, again equilibrated with acetate buffer. As before, elution is carried out using the acetate buffer supplemented with NaCl and isopropanol. Active fractions, i.e. fractions displaying the activities sought, are collected, dialysed against a 5 millimol/litre acetate buffer pH 5.0 and then concentrated by means of ultrafiltration with a Amicon PM-10 membrane. To obtain the protease in an essentially pure state, the concentrated liquid is chromatographed over a Superdex 75 column equilibrated with the 0.05 mol/litre sodium acetate buffer pH 5.0 and supplemented with 0.5 mol/litre NaCl.

[0285]Further experiments carried out with the purified enzyme on PAGE may confirm if the molecular weight is in line with what can be expected on the basis of the available sequence data. Final confirmation can be obtained by carrying out a partial, N-terminal amino acid analysis.

Example 6

Properties of a Novel Cysteine Protease from A. niger

[0286]In this Example Aspergillus gene nr 28 was cloned and overexpressed in A. niger as described before. The enzyme obtained was purified according to procedures described in Example 4 and used to destroy trypsin inhibiting activity from soybeans under various conditions. As reference materials papain and bromelain were used. Bromelain was obtained from Sigma, papain was obtained from DSM Food Specialties Business Unit Beverage Ingredients, PO Box 1, 2600 MA Delft, the Netherlands.

[0287]Trypsin inhibition was measured according to the method of Kakade, M. L., Rackis, J. J., McGhee, J. E. and Puski, G. (1974): J. Cereal Chemistry 51: 376-382. Degradation of the substrate N-benzoyl-L-arginine-p-nitroaniline to N-benzoyl-L-arginine and p-nitroaniline was taken as a measure of trypsin activity. Trypsin was obtained from British Drug Houses Ltd and was derived from cow's pancreas containing more than 0.54 Anson Units per gram of product.

[0288]The Kunitz inhibitor for soybeans was also obtained from Sigma.

[0289]The trypsin inhibitor was pre-incubated at a concentration of 2 mg/ml with the above mentioned cysteine protease enzymes at pH 3 in 50 mM Na-acetate buffer prior to measuring trypsin inhibition. Enzymes were added at a ratio of enzyme protein to trypsin inhibitor of 1:100 (w/w). Albumin served as a negative control for the enzymes. Remaining trypsin activity was measured after incubation during 3 hours at 37.degree. C. Results are shown in Table 2.

TABLE-US-00002 TABLE 2 Effects of various cysteine proteases on the enzymatic inactivation of the Kunitz trypsin inhibitor from soybeans. 3 4 5 Remaining TI Remaining TI Remaining TI 1 2 activity after activity after activity after Enzyme Remaining TI pepsin heat treatment heat treatment tested activity (%) treatment at 75.degree. C. at 90.degree. C. Papain 25 55 78 95 Bromelain 30 62 86 99 A. niger 26 26 28 35 Albumin 100 100 100 100 (control) TI: Trypsin Inhibitor activity

[0290]Experiments were repeated in the presence of pepsin during the pre-incubation of cysteine proteases with the trypsin inhibitor. Pepsin was added at final concentration of 1.3 mg/ml. Results are shown in column 3.

[0291]Another series of experiments were conducted to check for heat stability. The cysteine proteases were incubated at 75 and 90.degree. C. during 5 minutes prior to the addition of these enzymes to the pre-incubation with the trypsin inhibitors. Results are shown in columns 4 and 5.

[0292]These results clearly demonstrate the superior activity of these novel cysteine proteases from Aspergillus niger over currently available cysteine proteases for the inactivation of trypsin inhibitors in animal feed.

Example 7

Exo-Peptidases Promoting Cheese Ripening and Cheese Taste

[0293]The amino-peptidases encoded by genes nr 20 and 54 (see Table 1) were overexpressed in A. niger according to methods described earlier. Purification of these enzymes was carried out according to procedures as described in Example 4. The activity of the purified enzyme samples was determined at pH7.2 in an aqueous phosphate buffer (50 mM) containing the para-nitro anilide derivative of a number of hydrophobic amino acids (3 mM) as the substrate. The conversion of the substrate by the amino peptidase was determined by monitoring the change in optical density at 400 nm as a result of substrate conversion, using a solution not containing the enzyme as the reference. Activity (A) was calculated as the change in OD per minute and expressed as e.g. Phe-AP, Leu-AP or Val-AP units, depending on the substrate used. Normal cheese milk was inoculated with starter culture of the Delvo-tec.TM. DX 31 range (DSM Food Specialties Delft, The Netherlands) to obtain a Gouda-type cheese and coagulating was executed with an average dosis of coagulant (50 IMCU per liter of cheese milk). In addition, 25 Phe-units of each exo-protease was added to two experimental cheeses whereas the control did not contain either one of the exo-proteases. Cheese making parameters were used conform the procedure applied for semi-hard cheese for both cheeses. A difference was noted in terms of flavor and aroma development between the experimental cheeses and control cheese to such an extent that the experimental cheeses has obtained most of its organoleptical properties after three (3) weeks whereas the control cheese has obtained a similar qualification after six (6) weeks. The level of free amino acids after three weeks was shown to be twice as high in the experimental cheeses; after six weeks of ripening the levels were comparable again. Amino acid analysis was carried out according to the Picotag method of Waters (Milford Mass., USA).

[0294]These data suggests that the product is ready for sale three weeks earlier without decreasing the keeping quality of the cheese. The organoleptic character of the experimental cheeses differed from the control to the extent that the bland cheese flavor with a slight tendency to bitterness of the control cheese was overcome in the experimental cheese in the presence of the amino-peptidase. The texture of the cheeses was found to be somewhat smoother as well.

Example 8

Novel Specificity of a Protease Encoded by Gene 55

[0295]As explained earlier, certain proteins can resist enzymatic hydrolysis as the result of specific amino acid compositions or specific tertiary structures. In such cases the quantity of peptides that can be solubilised from protease resistant proteins can be dramatically improved by using proteases exhibiting novel specificities.

[0296]Beta-casein is a protein with very limited tertiary structure but with an extraordinary high level of proline residues. Many proteases have difficulties in cleaving proline containing sequences so that the hydrolysis of beta-casein with commonly available proteases yields a hydrolysate that is relatively rich in large, protease-resistant peptides. The latter resistant peptides can attribute to a number of undesirable properties of the hydrolysate. For example, it is well known that these larger peptides have a relatively strong effect on allergenicity and bitterness. Moreover, these peptides withstand a further degradation into free amino acids so that in certain processes the occurrence of these large, protease resistant peptides are synonymous with yield losses. Therefore, the availability and use of proteases that are capable of cleaving the protease-resistant parts of the proteins, translate into serious technical and economical benefits.

[0297]Beta-casein represents one of the major casein fractions of bovine milk. The protein has been well characterised in terms of its amino acid sequence and is commercially available in an almost pure form. As such, beta-casein offers an excellent test substrate for studying the relationship between enzyme cleavage sites and the length of various peptides formed during enzyme hydrolysis.

[0298]This Example demonstrates that despite the broad spectrum cleavage character of the endoprotease subtilisin, the addition of a very specific enzyme like a prolyl endopeptidase as encoded by gene 55 (see Table 1) has a major impact on the size of the beta-casein fragments formed.

[0299]Beta-casein from bovine milk (lyophilised, essentially salt-free powder) with a minimum 90% beta-casein was obtained from Sigma. Subtilisin from B. licheniformis (Delvolase.RTM., 560 000 DU per gram) was obtained from DSM Food Specialities (Seclin, France). The proline-specific endoprotease as encoded by gene 55 was overexpressed in A. niger and purified using procedures described in Example 4.

[0300]Beta-casein powder was dissolved at a concentration of 10% (w/w) together with 0.1% (w/w) Delvolase.TM. powder in a 0.1 mol/liter phosphate buffer pH7.0. After an incubation of 24 hours at 45.degree. C. in a shaking water bath, the reaction was stopped by heating the solution for 15 minutes at 90.degree. C. To one half of the solution (1 ml containing 100 milligrams of beta-casein) 100 microliter of the proline-specific protease was added and the reaction was continued for another 24 hours at 45.degree. C. After another heat shock at 90.degree. C., samples of both the Delvolase.TM. and the Delvolase.TM.+proline-specific endoprotease treated beta-casein material were analysed by LC/MS equipment to study the precise peptide size distributions in the two samples.

LC/MS Analysis

[0301]HPLC using an ion trap mass spectrometer (Thermoquest.TM., Breda, the Netherlands) coupled to a P4000 pump (Thermoquest.TM., Breda, the Netherlands) was used in characterising the enzymatic protein hydrolysates produced by the inventive enzyme mixture. The peptides formed were separated using a PEPMAP C18 300A (MIC-15-03-C18-PM, LC Packings, Amsterdam, The Netherlands) column in combination with a gradient of 0.1% formic acid in Milli Q water (Millipore, Bedford, Mass., USA; Solution A) and 0.1% formic acid in acetonitrile (Solution B) for elution. The gradient started at 100% of Solution A and increased to 70% of solution B in 45 minutes and was kept at the latter ratio for another 5 minutes. The injection volume used was 50 microliters, the flow rate was 50 microliter per minute and the column temperature was maintained at 30.degree. C. The protein concentration of the injected sample was approx. 50 micrograms/milliliter.

[0302]Detailed information on the individual peptides was obtained by using the "scan dependent" MS/MS algorithm which is a characteristic algorithm for an ion trap mass spectrometer. Full scan analysis was followed by zoom scan analysis for the determination of the charge state of the most intense ion in the full scan mass range. Subsequent MS/MS analysis of the latter ion resulted in partial peptide sequence information, which could be used for database searching using the SEQUEST application from Xcalibur Bioworks (Thermoquest.TM., Breda, The Netherlands). Databanks used were extracted from the OWL.fasta databank, available at the NCBI (National Centre for Biotechnology informatics), containing the proteins of interest for the application used.

[0303]By using this technique as a screening method only peptides with a mass ranging from approx. 400 to 2000 Daltons were considered suitable for further analysis by MS sequencing.

[0304]Angiotensin (M=1295.6) was used to tune for optimal sensitivity in MS mode and for optimal fragmentation in MS/MS mode, performing constant infusion of 60 .mu.g/ml, resulting in mainly doubly and triply charged species in MS mode, and an optimal collision energy of about 35% in MS/MS mode.

[0305]In the sample digested with Delvolase alone, the LC/MS/MS analysis identified 40 peptides covering various parts of the beta-casein molecule. Together these peptides accounted for 79% of the total beta-casein sequence. Different retention times of the peptides on the C18 column could be traced back to peptide lengths ranging from 2 to 23 amino acid residues. Together <15% of the peptides found were smaller than 6 amino acids. The sample digested with Delvolase.TM. and the proline-specific protease also generated a large number of identifiable peptides from beta-casein. Together these peptides covered >50% of the total beta-casein protein sequence. In this sample the peptide size distribution was remarkably homogeneous, as the peptides ranged in length only between 2 and 6 residues. The results show that in the hydrolysate made with the proline-specific protease contain a large fraction of di-, tri-, up to 6 M peptides, showing the distinct beneficial effect of the co-incubation with an endoprotease featuring an unusual specificity. It is also clear from these experiments that the endoprotease according to gene 55 encodes an endoprotease that cleaves the peptide chain at the carboxy terminus of the proline residue.

Example 9

The Selective Release of Specic Amino Acids to Promote Flavour Formation

[0306]Free amino acids like leucine and phenylalanine have not only been implicated in Maillard reactions but also as precursor for desirable aromas in various food fermentations. To promote the formation of such aromas in food fermentations or during the heating, roasting or baking phase of food, it would be advantageous to incorporate into these products a protein hydrolysate that contains relatively high levels of these specific amino acids in a free form. In this Example we describe the production of yeast extracts selectively enriched t in leucine and phenylalanine. This enrichment is obtained by combining an endoprotease with a cleavage preference for a selected set of amino acid residues with an exoprotease favouring the release of a similar set of amino acid residues. The preference of the endoprotease should match with the preference of the exoprotease used. For example we have established that the aminopeptidases encoded by genes 20 and 54 (see Table 1) feature a definite preference for releasing leucine and phenylalanine residues which matches with the cleavage preferences of thermolysin. The carboxypeptidases encoded by genes 23 and 24 have a preference for releasing arginine and lysine residues which matches the cleavage preferences of trypsin. Carboxypeptidase encoded by gene 5 features a highly unusual preference for releasing glycine which could be combined with certain endoproteases present in papaine. The carboxypeptidase encoded by gene 51 is capable of removing glutamate residues which matches the glutamate specific protease encoded by gene 43.

[0307]The endoprotease thermolysin (commercially available as Thermoase) C 180 from Daiwa Kasei KK (Osaka, Japan) is known to cleave peptide bonds at the amino terminal side of bulky, hydrophobic amino acids like Leu and Phe. To liberate the thus exposed amino acids from the newly formed peptides, we used the amino-peptidases encoded by genes nr 20 and 54 (see Table 1). These genes were overexpressed in A. niger according to methods described earlier and purification of these enzymes was carried out according to procedures as described in Example 4.

[0308]To release as much leucine and phenylalanine as possible without concomitant release of undesired amino acids with this combination of enzymes, it is evident that the conditions used during enzymatic hydrolysis should be carefully selected. Moreover, the yeasts own endogeneous (and probably aspecific) proteases have to be inactivated. After a number of test incubations, a protocol was worked out that leads to a surprisingly selective and effective release of leucine and phenylalanine from the yeast proteins using these two new enzymes.

[0309]To inactivate the yeasts endogeneous proteases, the yeast suspension was kept for 5 minutes at 95 degrees C. Then the suspension was quickly cooled down to the required temperature and the pH was adjusted to 7.0 using 4N NaOH. The yeast, the thermolysin and one of the aminopeptidases were all incubated simultaneously under the following conditions. After the heat shock, the pH of the 2000 milliliters yeast suspension was adjusted to 7.0 after which 680 milligrams of Thermoase were added and, after stirring, the purified aminopeptidase. The mixture was incubated with stirring at 50 degrees C. for 3 hours and centrifuged. To stop all enzymatic activities the pH of the supernatant was adjusted to 4 and subjected to another heat treatment of 45 minutes at 95 degrees C. After another centrifugation a sample for amino acid analysis was obtained from the supernatant. Precipitated or non-dissolved matter was removed by centrifugation for 15 minutes at 3500 rpm in an Hereaus Megafuge 2.0 R centrifuge. Supernatant was removed and kept frozen at -20.degree. C.

[0310]Samples of the supernatant, were analysed for amino acid content according to the Picotag method of Waters (Milford Mass., USA) immediately after thawing.

[0311]In the amino acid analysis Trp and Cys values were omitted And Asp and Asn values were summed as one value. According to the data obtained, in the resulting hydrolysate the ratio between alanine and leucine (21.3:11.7) was 1:0.5 Commercially available yeast hydrolysates typically exhibit alanine versus leucine ratio's of 1:0.3.

[0312]In a second experiment a yeast extract was prepared that was enriched in free glutamate. To achieve this, use was made of an endoprotease exhibiting a preference for cleaving at the C-terminal end of glutamate residues (encoded by gene nr 43 in Table 1) and a carboxypeptidase (encoded by gene nr 51 in Table 1) capable of removing these glutamate residues thus exposed. The endoprotease encoded by gene nr 43 and the carboxypeptidase encoded by gene 51 (see Table 1) were overexpressed in A. niger according to methods described earlier. Purification of these enzymes was carried out according to procedures as described in Example 4.

[0313]The essential role of free glutamate in a number of aroma forming processes is well documented and MSG, the sodium salt of glutamic acid, is recognized as the single most important taste enhancing component.

[0314]In this Example the pH of the 200 ml heat shocked yeast suspension is adjusted to 8.0, then the purified enzyme product encoded by gene 43 is added and the mixture was incubated for 4 hours at 50 degrees C. Then the pH was lowered to 5.0 and the suspension was centrifuged. To 100 milliliters of supernatant the purified gene product of gene 51 is added. Incubation with this carboxypeptidase took place for 30 minutes at 50 degrees C. with continuous pH adjustments. After stopping the enzyme incubation by a heat treatment of 5 minutes by 95 degrees C., the material was again centrifuged (see above) and a sample was obtained for amino acid analysis.

[0315]According to the amino acid data obtained (see above), in the resulting hydrolysate the ratio between_alanine and glutamate (30.0:48.7) was 1:1.6. Commercially available yeast hydrolysates typically exhibit alanine versus glutamate ratio's of 1:1.

Example 10

Flavour Evaluation of Yeast Hydrolysates Enriched in Specific Amino Acids

[0316]To prove that a protein hydrolysate enriched in specific amino acids according to the invention can generate specific aroma's, a number of experiments were carried out with the yeast hydrolysates described in an earlier Example. To that end larger portions of these hydrolysates were prepared and lyophilised. The performance of the resulting powders were compared with the performance of a commercially available yeast extract (Gistex LS, obtainable from DSM Food Specialties, Delft, The Netherlands) in a standardised mixture under several reaction conditions. The standardised mixture consisted of one of the hydrolysates, base mixture and water.

[0317]The base mixture contained 22 grams of Maxarome Plus Powder (a specialised yeast extract with a high content of natural nucleotides, also obtainable from DSM Food Specialties), 29.2 grams of glucose, 9 grams of REFEL-F fat (hydrogenated soy oil, obtainable from Barentz, Hoofddorp, The Netherlands) and 0.2 grams of calcium stearoyl lactylate (emulsifier, obtainable from Abitec, Northampton, UK) thoroughly mixed in a mortar.

[0318]All standardised mixtures contained 5 grams of yeast hydrolysate powder (i.e. either the leucine or the glumate enriched material or the commercial yeast extract), 3 grams of the base mixture and 3 grams of water. After thorough mixing, these three slurries were subjected to different heating regimes i.e. either 65 minutes at 90-95 degrees C. in a reaction vial (liquid reaction) or dried at 20 millibar at 120 degrees C. in a vacuum oven (vacuum roast reaction) or heated in an open reaction vial at 120 degrees C. for 10 minutes after the dissipation of all water (roast reaction).

[0319]After the heat treatment all three products had assumed colours ranging from dark brown to almost black. In case of the vacuum roast reaction only the light coloured top layers were used. Taste evaluation of the heated products was carried out by grinding the blackened cakes into fine powders and dissolving these powders to a concentration of 2% (w/w) in water containing 0.6% (w/w) NaCl. The observations of the taste panel are specified in Table 3.

TABLE-US-00003 TABLE 3 Reference Leucine Glutamate Liquid Bouillon, Cold tea, slightly More bouillon, slightly roast flowery, yeasty meaty, yeasty Vacuum Burnt, fried Astringent, beans, Burnt, bouillon, roast potatoes yeasty yeasty Roast Dark roast, Less roast, flowery, Roast, more bouillon, bouillon, umami umami more umami

Example 11

Non-Allergenic Whey Protein Hydrolysates Formed with Tripeptidylpeptidases

[0320]The dipeptidylpeptidases encoded by the genes 19 and 55 as well as the tripeptidylpeptidases encoded by the genes 4, 9, 10, 12, 26, 35, 46, and 50 (see Table 1) may be overproduced as described and may be purified according to the methods provided in Example 4. After purification the pH optimum and the temperature stability of each individual enzyme may be established by any of the methods available and known by the skilled person. Furthermore, the specificity of each individual enzyme may be determined using the methods outlined in Example 1. The selectivity exhibited by tripeptidylpeptidases is illustrated in the following experiment.

[0321]The enzyme encoded by gene 12 was overproduced in an Aspergillus niger host cell and purified by procedures described in Example 4. The enzyme thus obtained was incubated at pH 5 and 50 degrees C. with different synthetic chromogenic substrates i.e. Ala-Ala-Phe-pNA and Ala-Phe-pNA (both from Bachem, Switserland). The incubation with the Ala-Ala-Phe-pNA substrate led to a significant increase of the absorbance at 410 nm whereas the incubation with Ala-Phe-pNA did not. This observation clearly demonstrates that tripeptidylpeptidases cleave off tripeptides and do not exhibit aminopeptidase activity that can lead to an undesirable increase of free amino acids.

[0322]Moreover, the enzyme encoded by gene 12 shows favourable enzyme stability characteristics as shown in the following experiment. Four samples of the enzyme were incubated at pH 5 for one hour at 0, 40, 50 and 60 degrees C. respectively. Then each enzyme sample was incubated with the above mentioned Ala-Ala-Phe-pNA substrate in a citrate buffer at pH5 and the residual activity in each individual sample was determined by measuring the increase in absorbance at 410 nm. With the 0 degrees C. sample showing 100% activity, the 40 degrees sample showed 96% residual activity, the 50 degrees sample 92% residual activity and the 60 degrees sample 88% residual activity.

[0323]In a typical process aimed at producing a hydrolysate with a high proportion of tripeptides, whey protein (WPC 75) may be dissolved/suspended in a concentration of 100 grams of protein/liter, in an aqueous medium having a pH of 8.5. The first enzyme incubation is with the broad spectrum endoprotease subtilisin (Delvolase.RTM., 560 000 DU per gram from DSM). After a predigestion of the whey with this enzyme in a concentration of 0.5% enzyme concentrate per gram of protein for 2 hours at 60 degrees C., the mixture is heat-treated to inactivate the endoprotease used. Then the temperature is adjusted to 50 degrees C. and the tripeptidylpeptidase is added and the whole mixture is incubated until the desired level of tripeptides is reached. Further processing steps of the hydrolysate thus obtained depend on the specific application but may incorporate microfiltration or centrifugation followed by evaporation and spray drying.

Sequence CWU 1

17112520DNAAspergillus niger 1cgcaggcgtc cgttgcgccg cgaaaacctg ccgagtgggc cgtttaggct ttgggtctcc 60ccacgatgta agcataatca ttctgtgcct gagtgtgaat tctcctgttg gaggctgcat 120cttaattctt aactgcatga aaagcacttg ggtgctattt tctttttcct ttctttcttt 180tccgtgttca tttccattcc cttgctcttc ttctttgtgt cgacatttac aaatcacatt 240tttcttatac tttcttttct tcacctcgtt tcttcctatt cactctctgt gttcagcatt 300cgttatcagc actttatctt ttgctcgtct cttttatctt cacttgtttg tgcctttcca 360ctagcaatct atcgtttgat ctttctagag cattgtcttg attgtgtcat tctgtcattg 420actccggcta tgaaatatta ttctcaatct gcctaaaacc aaattctact ctatcactac 480acatttgtat cacctgatct ggctgagata ggagagtccg gcatctcatc gtctgcatca 540gacaattgcg ataaattcat tgcttgcacc tgttattgat tcttccaagt tatgcatctc 600ccacagcgtc tcgttacagc agcgtgtctt tgcgccagtg ccacggcttt catcccatac 660accatcaaac tcgatacgtc ggacgacatc tcagcccgtg attcattagc tcgtcgtttc 720ctgccagtac caaaaccaag cgatgctcta gcagacgatt ccacctcatc tgccagcgat 780gagtccctgt cactgaacat caaaaggatt cccgttcgtc gtgacaatga tttcaagatt 840gtggtagcgg aaactccctc ttggtctaac accgccgctc tcgatcaaga tggtagcgac 900atttcataca tctctgtcgt caacattggg tctgatgaga aatctatgta catgttgctc 960gacacaggcg gctctgatac ctgggttttc ggttccaact gcacgtccac accctgcacg 1020atgcacaata ccttcggttc ggacgattct tcgacccttg aaatgacatc ggaagagtgg 1080agtgtgggct atggaactgg gtctgtcagc ggcttgctag gaaaagacaa gctcacgatt 1140gcaaatgtca ctgtacgcat gactttcgga cttgcttcca acgcatcgga taacttcgag 1200tcgtacccaa tggacggcat tctcggtctc ggtcgaacca acgatagttc ctacgacaac 1260ccaacattca tggatgccgt tgcagaaagt aacgttttca agtcgaatat cgttggcttc 1320gccctttcac gtagccccgc caaggatggc acggtcagct ttggcactac tgacaaggac 1380aagtacaccg gcgatatcac ctacaccgat accgtcggat cggacagcta ttggcgcatt 1440cccgtggacg atgtctatgt tggcggcact tcatgcgatt tctccaacaa atcagccatc 1500atcgataccg gaacttctta tgctatgctg ccttcaagcg actcgaagac gctgcacagt 1560ctcattcccg gcgccaaatc ttcggggagc taccacatta ttccgtgcaa cacaactact 1620aagctacaag tggcattctc tggtgtgaat tacaccatct cgccgaagga ctacgtggga 1680gcaacttcag gttctggatg cgtttcgaac attatcagct acgacttatt tggtgatgac 1740atctggctcc tgggtgacac gtttctcaaa aatgtgtatg ctgtgtttga ctacgatgag 1800ttacgggtcg gatttgcaga gcgttcctcg aacaccacct ctgcgtcgaa ctctacgagc 1860tctggaacaa gcagcacctc gggatccact acaacgggca gctcaacgac tacgacgagc 1920tctgctagct ctagtagttc atctgatgct gaatcaggaa gtagcatgac cattcccgct 1980cctcagtatt tcttctctgc tctggcgatt gcttccttca tgctttggct ctagttaacc 2040gcatcttact cgacgcctga acctcgggaa acatatgcat tatttacaca tgctgctgat 2100ttgtatttgc atatattctt cgagcctgga cggcgtgcgg gtcatattac cttacattcg 2160aagtccttct ctaatcaatc aacatttatt cttactccac cagttctggc tcgcaattaa 2220ccctgtctaa gaaaaagttg gtatagaaca tggcatccac tacctggaac attcaaagaa 2280ccttgtccgg gatcagtgtg tatgacttcg ggtacgattc tgacatgaca gttagcgtcc 2340atcctgagga ttcatcctga tctccttacc tagtatggac ttatcaaagt ccttgacgct 2400attgtaccct cccacagcca tcaggatatc gaaatcggcc aacagcgact tcatcacatg 2460gcgaacaccc tcctcaccca tgatactgag gccccagatc cagagccggc cgacgaaaac 252025001DNAAspergillus niger 2taggaaaatc agaggcgaca atttgctccg atactggata agtaccatcg gtcacgaaat 60tcagcaccga ctggcttatg tcctgctccg ataccttagc ggacattatg ttagtagttc 120taagcaagag cccttggttc ttggtaatcg gcggatcaaa aacgtaaaga agacaaacag 180aagcgccaca ctaggctctg cctccctctt acagaagatc tgccaggtat cgatccacaa 240agatatacca aggactccaa tgcagcagat cgcaaccgaa agggaaggcg agctgtcaac 300accgccatgt gacttcaccg ctcaccgcct tagctgcgat gggcaagacc acgaacgatc 360tcgctcttcc ccagggccag actgaggccg attatatgat ttttttcttt cttttccgtg 420tgtctcgtct gctgctatat tcttattttt ctgttcggta aagatacctc ctaagaatag 480acacgggttg tttttttgtg aattatctgt tggtgtggtg ctctctatcg aaccggaaac 540ctgaactcca ctctgaaccg ttacagttgg agggtaacct tcgttcagcg gccaactgtg 600tgacctcaaa attcctgaaa catcataatc ggcgtcaagc agagcccatc gtgttgtctc 660agttactatt gagaagcctg attcgggcaa acgcttctcg atccatgtga gtcatgcttg 720taccagccct gaactccatt gaataaaaaa aaagcaagaa aagagattgc ccctccgtcg 780ttttctgtat taaacatcca atcctcaacc ggcagcctta cattggctgc cacagatttg 840tgcctccata cagcatgctt cgtggtcttc gtgatgtcgt attattacaa tttgcaatcc 900ccttgttctt gctattggta tttcaaacat ggaatgggtg cttttcccgt ttcaattccc 960cgcaccctga acctcaagca ttgctagctt ctctaaaatg aataaaactg ttatacttgc 1020ttcctaaaag tttgcgcttc tggcctatgg attactaaca gcattttaga ttatcgctac 1080ggggtgtgat cacaggattt ggttctaaat cacatttcca gagaccattg agcaaaatgt 1140catctactca aaagagccat ttcaagctac tccagaagtt caaaccggag tactcgccta 1200gcgagtttgc tcagtatgag tcggagagaa caggcatgag ggtagtggtc attgaccaaa 1260aaggacccaa agtcacaggt tattttgttc tagccacaga gattctcgat gattcaggtg 1320ctcctcacac gttggagcac ttgtgcttta tgggctcgcg gaactataga tataagggct 1380tccttgacaa gctagcaaca cgtgtttatt cgagcaccaa tgcctggacg gccacagacc 1440acacggccta caccttggac acagcaggct gggaagggtt cgctcaaatc ttgcccgtgt 1500acctagagca tgttatagct ccaacactga cagatgaagg gtgctatacc gaagtgcatc 1560atattgatgg cgctggagac gacgctggag tcgtctactc ggagatgcag ggtgtgcaga 1620ataactctgc agagttaatc gatctaaccg ctcgtcgatt gacttacccg catggtgtag 1680gttttcgcta cgagacaggc ggtatgatgg agcagctccg cgtcctcacc gcggaccgta 1740tccgagcgtt ccatcgtgag atgtaccagc ccaagaactt atgcctaatc atcacaggcg 1800aagtagatca ccagaacatg ctggagacct tggacaagtt cgaagatact attctagatg 1860tcattcccag tcctgattca cctttcaaga ggccgtgggt agattccaag caggcgccgc 1920cattggagaa gtccattgtc cagactgtgg aatttccgga agaagatgaa tctttcgggg 1980agatagaaat tagattcctc ggtccggact gtaccgaccc tgttcaaagt gagtgttccg 2040ctgtcctcat ttcgaagata tacttactct gttatagccg gggctgtcaa tgttgcattg 2100ctgtatctgg ccggttcatc tgcttctcta ttggataaca tcctggttga gaaggagcag 2160ctcgccagtg ctgtctatta tgctaccgaa gatcatccca gcattgagat ccgcttcaca 2220ttaaccagtg tggagacaga gaaactcgcg aaggtagagc aacggttttt cgaagtgctc 2280aaggacgcta tggagaaaga tttagacatg aggtatatca aggagtgcat tgaccggcaa 2340agacggacct ggaagttctc taccgaaagc tccgcctctt cctttgcgga gtacgtgatc 2400tcggattttc ttttcggaaa gagagacgga tcgactatgc ttgatgttgc gaccttgcaa 2460gagtacgacg tgctggagaa gtggagtgaa gaacagtggc gcagttttat caaaacatgg 2520atttctgatg ccaaccatgt cactatcctt ggtgttccgt ccgttaagat gtctgacaca 2580ttaaagaagg aggaggaagc tagagtcgca gagcaaaaga agcgcttggg tgatgagggg 2640ctgaagaagt tggccgacaa gctggaaaaa gctaaagctg aaaatgacaa ggagatcccc 2700aaggagatgc tggagaggtt ccaaatccct ggaatagagt ctatccattt cgtggacact 2760actacagcca ggtctggtgc agccctcgat gccgggcgcc catcccacaa ggcgcaaaaa 2820ctggtggatg ctgatggctc tgatctgccc ttgttcatcc atttcgagca tatccccagt 2880agcttcgtgc agctctccct cctcatctcg gcacaggccg tacctgtgca gcttcgtcca 2940ctgctgtctg tgtatactga ggcattcttc aacctgcctg tcaaccggaa cggggaaacc 3000atcaactttg agcaggtggt tgtcgagttg gaaagggata ctgttggcta ctccatggaa 3060ggagctagaa gcctaggaaa ctcggagatg ttgcggatct cattccaggt ggagcttgag 3120aagtatcaca cggcgatcgc atggatccag gaactttcct ggaactcgat tttcgatgtc 3180gagcgactcc gagcgattac cagtcgactg ctctccgatg tgcccgattc caagcgtagt 3240ggcgacgaca tgctcgcggc tgttcatgtg atggtccact atgcagcaga gtctattgtt 3300cgggctcgga gcaccttggt gaaggcgcgt tatttgaaac ggatcaagaa gcaattagca 3360gaagagccga agtctgtcgt tgcgcggatg gaagaaatca gagatgcgct tttccgtttc 3420gagaacatgc gagtcttagt tatcgctgac ctggagaaac ttcaaaaccc tgtgtcagca 3480tggaaaccat ttgctgagcg tttgggtgca ggtgcccctc tacagcctat cacgactaga 3540agaccgttgc tcagtgaggc aggccagaag ttgggcggta agtcgtatgt ggttcctatg 3600ccgacgattg attcatcgtt cgcatatgct accgcacgtg gtttggattc ttatgatgat 3660ccaagacttc ctgccttaat ggttgcaatt gcatacatga acgcggttga gggtcccctc 3720tgggttgcag ttcgaggcaa gggtttggca tatggcacga actttgccta taacattgat 3780accggattcg tcaacttcga cgtttaccgc tcccccaacg cccataaagc cttcgactcc 3840agcaagcaga ttgttgagga tcacctctct ggtgcgatgc ccttcgatcc cttgatgctg 3900gagggttcca ttagcagcat tgtggtaagc tttgcgaatg aacagtcgac aattggtagc 3960gcagcctcag gcagtttcat ccgacaggtg attcggcgcc tgcctagcga ctacaaggag 4020cgggtgctca agcaggtgcg ggctactagc gttgatgacg tgaaaggcgc tctgaaggac 4080atcattctgc ctttgtttaa cccgtccacg gccaatatcg tggttacctg cgctacagtg 4140cttgaggagg tttgtcattc catgaagaaa ttatgatctt cttgtgtatc atttactaac 4200tgtcggttta gactatcaag gaaggtctcc aggcatcggg attcacgcct gcggtgcagc 4260cactcaaaga attcgaagat gactatgggc tgaaggtcgg cgatgacgag gacgaggagt 4320ccgacgatga cgacgatgag tatgaaaccg gatctgaaga tgaagatgac agtgatgaag 4380acatggagga tgacgaagat gatgagtgat gcaatctata cgacaacctc tagacatgac 4440aagatttatc tgagccagtt cctggataac acctaggtcg aaagaccagc tacccctggg 4500ggcccagata tgccgacccg tgtgatctgt attgttagag atgtctccaa ctagcagacg 4560cgcaatgatt tttgatgtta atgatatatc gtacaacata agtggttaac caccacaaat 4620ctgcacctaa atcttagttg tgattatcgg tacctaccaa acccgagtaa acgttgccag 4680aagtttatga aaaagctctc gttcttctta tttcattgaa tgttgtaata aaaagtgcta 4740gcagatgctt tcgctatcgg gcccactact atgattaacc tgaagcttag tctcttaggt 4800gacataacct gttctacaca ggctgccatt atatttgcaa cacacagctt ctatctctga 4860cctttgtgag aataatacaa ttactagaaa ccccaggaga tataaataca ctctactcct 4920accgaactaa cacccagatc gacaaattat aaaccaaacc acgtgacaat atgatatcta 4980tatatgaata tgtataaggt a 500133850DNAAspergillus niger 3gcgcggggtt cctgcatgtc tttcatggtt gggaggtata tgtacatgta atgccgttgg 60gttctggata cccacaataa agtgtttcta ctattacttt tgcattgtta gactttgaag 120gctgctctgt aagggtccat tccgttggag tcaaacaacc gtctgtccgc gggcatatgt 180ctcagtctga ggtgagaact gcaatataca ctccaagctt tctcaatctg atgcacagat 240tgcaaacatc tcccttgctg tgtggtaaag tctccctttc tcggtgaacc ttcttcgggg 300tcgcaactga ttccattgac cctcaccatc tgtcgaattg ttcccgaaag ctcgcgtcca 360aataggcttt acggacgcca cagctgctcg aggccatctc caagggggaa tgaacaatgg 420aatggtaagc cgctaagaaa ggggaactgt cggttctggt cgattggcag ggtcagggca 480gtgcttgggc tgttcctctg gccctccctt gcttcaagct ggccccgatt tggcagctcg 540tgaagctcac cagacattca gccagccaga tgactggcac ctttccgctg ggcataaatt 600ggccctggca gccatgtcat gccaatcttg gctccaggac cagtcattcc ttttcttgtt 660cctgtcaaac agatcaagtc ctcgaggatg ggagctcttc agtggctgtc catcacggct 720gctgcggcct ccgcagtgtc agccttgacc ccggagtaag tatctccaat catttggaac 780tggcccatat tgtgcatagc taaccagctt acctgcatag gcagatgatc ggtgccccac 840ggagaaccga agttatacca aacccctccg gtgtatgccc attgccaggt ccagccttac 900aaagaagcgt cgtctgctga cacgagaagg acaccggtct attctcgacc tcccaatggt 960cgtttgacac tcattctgag agcacctggt ggagcttgat cgacctccaa tcgggcaaga 1020ccaccactct caccgatgat agcgatatcg aggagatcat ctggcttggc tctgacaatt 1080ctacgctcct ctacatcaac agcaccaacg cgcaggttcc cggtggcgtg gagctgtgga 1140ttgcggactc ttctgacttt gcaaatgcgt tggttcaggc ctttaacgat gcctctgcag 1200actagtgcta atcctacttg gtgcagttac aaggcagcct ctctctccgc cggttttctc 1260ggcatcaaat caaccgtgac agattccggc gacgtgcatt tcatccttcg tggaaagtcc 1320tatcccaacg gaacggcata caatgatcag ctcgccgaga cctatcccag tacagcccgc 1380atctacgaca gcatctttgt gcggcactgg gacacttacc tgaccaccgc ctcccacgct 1440gtattctccg gtaccctgca aagctcgacc agcgacgacg gcaatgttca atatacctct 1500tcagggggat tgaccaacct ggttaaccca gtcaagggtg ccgaaagccc attccctcct 1560tttggaggca acgacgacta tgacctctcg cctgacggca aatgggttac cttcaagagc 1620aaagcgccag agctgcctct tgctaacaac acggctgcct atgtctatct cgtcccacac 1680gacggctctg cgactgcctt tgccgtcaac ggccctgata gtcctgcaac cccggaggga 1740gttgaaggag aatccaacaa tcccgtgttc tcccctgata gcgacaaaat agcgtacttc 1800caaatggcta ctaatacata cgagtcggac cgcaacgtgc tatacgtata ctccatcgcc 1860gatgacacca tcactcccct tgcaaaggac tgggaccgat cgcctagctc cgtgacatgg 1920gtcgatggag acaacctcgt cgtggcaagc caagatctag gacgaaccag acttttcgcc 1980atcccaggcg atgcagggga cgacttcaag cccacgaact tcaccgacgg cggctccgtg 2040tcggctcaat acgtcctatc caactctacc ctcctcgtca cgtccagcgc cttctggaca 2100agctggagcg tctacaccgc cagccctgac gagggcgtga tcaacacact ggcctcagcc 2160aacgagatcg accccgagct tagcggcctt agttcctccg actttgaaga gttctacttt 2220gacggcaact ggactaccgt aagtctatcc ctccttgccc ccaccaccac atcacaaaca 2280tactaaactc accgcagctc caaggatgga tcacctaccc ccaagacttc gactcatcca 2340agaaataccc cctcgccttc ctcatccacg gcggccccga agacgcctgg gcggatgaat 2400ggaacctgaa atggcactcc aaggtcttcg ccgaccaggg atacgtcgtc gtccagccaa 2460accccacagg aagcaccggg ttcggccagc agctcacaga cgctatccaa cttaactgga 2520gtacgccatt ccctatcccc aaactcccct cttaaacata cagctaacaa atgaaataac 2580agccggcgcc gcctacgacg acctaaccaa agcctggcaa tacgtgcacg atacctacga 2640cttcatcgac acggacaacg gcgtcgccgc gggtcccagc ttcggcgcgt tcatgatcac 2700ctggatccag ggcgatgact ttggacgcaa gttcaaggcg ctggttagcc atgatggtcc 2760gttcattggc gatgcgtggg tcgagacgga tgagttatgg tttgttgagc atgaggtgag 2820tggaccaagc caaacccccc ttttctcccc ttacaccatt acccctatac aaatatgatg 2880attctgaccg tgtatagttc aacggcacct tctggcaagc gcgcgacgca ttccacaaca 2940cggatccatc cggccccagc cgcgtcctcg catacagcac cccccagctc gtcatccaca 3000gtgacaagga ttatcgcata cctgtggcaa atgggattgg actgtttaat acgctgcagg 3060agaggggcgt gcccagtcgg tttttgaatt tcccggatga ggatcattgg tatgttcata 3120cccttttctt cccccttttt tctcccatga ttatgggtgt tgtggatgct gatgtagcta 3180tgtgtgtgtt tagggtcacc gggcaagaaa acagcctcgt ctggtatcag caggtgctgg 3240gatggattaa tcggtattct ggggtgggag ggtcgaatcc tgatgcgatt gctttggagg 3300atacggtgaa tccggtggtg gatttgaatc cttgatcatt ccctgttgct cgttactact 3360agtcagttat gatcatgttc tggctgggtc ccaggataga tggacggtta ttactggtcg 3420ttatattctg tttgcagtgg ttactagttg gtagatcagt tacgagatga tgtatgagac 3480gacagaaaga cttatgctta tgttgggagc tgcttcattt gtatatcaat ttattcttgt 3540agtgattgat aactaactac tgtctgactg tctgtcaacc gctatactaa cattatacca 3600accaaccaac caatcaaatc aatttctggt tctttcttct cttctgtttc ttcacctcgc 3660aactagacca attcatcaag gacagggcag gacaggatct ggtatctgaa cggaacaacc 3720gaaggaaaaa caaatcatac acaagctttt gtacaatcaa accataagaa tcagtacagc 3780tttctctttc agcctttcca aatgagagga aggacagaga aaatacaaag atgataccct 3840agaaacgaaa 385043139DNAAspergillus niger 4attgagtagg ctgcgctctt tgattctttg cgaggtacta aacccaaaca ggcaattgag 60atgttcggga gagaatatgc ggggatgcta tgcctgttgc agggatgatt atctccacac 120tagcgcgtta aaggtttagt agcctgagat ggattgccga tctccgaccg ggccctgcct 180cagccccagt acttgtggaa cgcgtcgaag atttacaaca ccatgccaga cctaactagg 240taataaagtt gcgatgatgg ggactgccgc aaggctgtca atttgggggc cgaactcagc 300ctcaacctgg aaaaattaac tccgattgtt ttgatttgat catgggagat tacagtctac 360gtgaaatgag cttataaaga acgttggagt accggctctc aacctgtctt gtacctgcaa 420gctttcctca attcccttct atctttctta aaatcctctc attagacatc atgacgaggc 480agacttctct cgttcccagg ctactaacgc tagcctcact agctgcactt tcacaagcag 540agctaggcaa gatccaatgg aaaggatctt gcaacttgac cacttatccg gcattgatct 600gtggaacact agacgtgcca tacgactaca cggagtcaaa ttccagcaag acactgactc 660tcgacatcgc caagtggcca gcgaccaaga aaccagtctc ggagcccatc atatttaact 720ttggaggacc tggtgtcaat tcgttcgagg gccttgggct ttatggagag gaatttcagg 780cgtaggttgc agttctgctt tgataccgca tcttatgctg actgacattg ttctctagta 840ttcttggagg tcacaatgat ttgatagctt ttaacaaccg gtttgtcgct cttctttctt 900gagctagaaa catctactaa cgttgtacct ttatatagag gcgttggaaa caccatcccg 960ttctcctgct acagcgatga cgccacccgt gaactcgtcg cccttcaagc tcctaacgac 1020ggcagagcgt ccagcacggc tttgggagaa atctgggccc agaacgcaaa catcgcacag 1080gcatgctatg ctacgaacaa tcaaactggt agtcttattg gaactagctt tgctgcaagg 1140gacatcatgc aggtcgctga tgcgctcagt ggaaaggata gtttggtcaa ctactggggt 1200aaatatcacg gctgaaccga gtttatactt ttgctgacaa tctacacttt aggattctca 1260tacggcacta caatcggtgc tgttctcgca gccatgttcc cggatcgaat ggggaatgtc 1320gcgcttgacg gagtggacaa ccccagagag gctctttatg gatagtgagt ggcccttgaa 1380gtttgcccga tctggtatga ttcagacagc taattccttc cgaaaagcaa cgcacaagcg 1440gttgtggacg tcgacaaagt tttcgaagga ttctgcacgg gctgcatggc cgcaccggac 1500ctctgcccta tcgccaagga gtacaccagc gccgccaact tggaagccgc aatttacctg 1560atgctggaaa acctcaagta caacccgatt gccattcccg aaaccggtgg aatcgtaact 1620tggagcgacg tcaagtcgac catttttgag gccatgtacc tgccaagctc ttggcccttg 1680acctctgagc ttctttacta cgtgcaaacc cgcaacacaa cgatccttgg caactctgaa 1740gtatacgaca ccatcaaatc ctacggtcaa tcggcttctt tgacttcggc ttccgatgag 1800gtcggcacgg ccattacatg ctccgacaag catcgatctg ccaccattaa agaggtcctc 1860ccgtacgtca aagccagaca ggctctgacc aagatcggaa gtgatggctc ggacggcgac 1920atgagatgcg cgcagtggaa tccgaagatg ttcgccaagg agcgctactc cggtgacttt 1980gaagtcaaga cagccaaccc ggtgttgatt ctgagcaaca cttacgatcc agcgactcct 2040cttcccgcag cgaagaacct gacagagacc tttgagggaa gtgtcttgct cgagcagaac 2100ggatacggtg tatgtttata cttccccttc tcatcatatc aaaagtgagc aagcagctaa 2160cctactgatg atagcatact accctgtcta tgccatctct ttgcactgcc aaggccgtcc 2220gggcttactt caccaatggc acattgcccg ctgacggaac gatctgccag gtggacgtgc 2280ctctgttcac gaacttgacc tacaaggatg tgtggccgaa gagtttccaa cggagcgttg 2340agtcgaggga tgatgcgact atcctcaagg ctttgatgtc ggtccgtgat aagatgtcgc 2400gacgcaggat gtggtaagcg catgctatag atggggatgt tgaaaaccca aagcgatgac 2460tggataatgt tcttcatata atttattctg tgccgattcc ggcatacgct cgtcatgtaa 2520tagagtttag ttaatgttgc aagggattgt atagtattta tttgtacacc aacagcgctt 2580catggagacc ggaacttccc tgagtacaga atttcccatc taggctttta tttaactttg 2640acaatactca gtagtttgga tgtcgatagc attgaggcaa gtaccggttg ttgttttggt 2700agtggagtga atcaggactg tcccacaaca atccgctgat ctgaatgttt gatgtttcga 2760tctgaggtat ctgagctgcg agcctccaaa tcggcaaccc catacttcag ggatattcca 2820gaacattact agccttggag gctttgaggt ttagctgcag ggcggtcaaa ctaattgatt 2880tctctcaatt gtcctaccgc tattgagtga tctttagtgg atgagtggaa cggagaattc 2940ccggtcggat aatgcctgca ttagtattgg ccaacagagt attccatcaa cgactcccgc 3000gctgacattt aatccatgca caccctgaat tacctcgagc ttattctcgg tcctacattt 3060gatcctctca tactttccct tatgtccttg cccacttgct ttacagattg aatccggatc 3120cttcagcact cggcagaca 313952940DNAAspergillus niger 5atagcagaac agaacatgta tcttgtcaac gaattgattg atttcagcac ggaaatgttc 60aaggcatgga acaattgctt ctgacccgga accgcggatt gcaaggatgg atatgtggat 120cagatggtgt gaagaagatc tgtctgttag catacttcat aagttccaag gaggagtaaa 180tgtggagtca taagagtaat atcgaatatc atagaatggg gttgtcttgc taacggtgaa 240tcggactccg tcggctctgc cagcgatcgg

caggtcacgc gtctgcgtaa cttggtactt 300atcttcccag tcacctaagc actgttactc cactcttctc tctttgacga taagaagata 360gcagagactc ttgataaaaa gggttgggag catgctttga atttcttcac tccgagagct 420ttctgtcccc atctggtctc ttgttgtccc cgatgtacta ctctctctgg gttgctgcct 480tggtggccgc gctgcccgtc tcccgggccc agtttgtggc tccgcccacg gatctcattc 540ccaccaaggg atatctcgac atccccgtcc gctacaaaca ggtccccacc ggcatttgtg 600agactgatcc cagtgtcaag agcttctccg gttacgtcga tgtcgctgag catgagcaca 660tcttcttctg gttcttcgag gcgcgcaacc aagatcccac cgaggctccc ttgaccgtct 720ggatcaatgg aggcatgtct gaccccggtc attatttcct tccaattgct aaccgttcgt 780aggtcctggt tcctcctcca tgatcggctt gttccaagag cacggcccat gcggcattga 840cgccaatggc tccgtctaca acaaccccta ctcctggaac aacgccagca acatgctcta 900catcgaccag cccgtgcaga ccggcttctc ctacagcatt ccggttcccg gctatgtgga 960ttcttccaca gacaatgtta ttgctctgcc ctcccccgcc tgccccgact atgcagcgga 1020tatgttctgt ggcacttact cctaccccaa cgtgagcctt acggctaatt ccaccgacaa 1080cgccgccccc aacttctacc gcgccctaca gggttttatg ggcgcatttc ctcagtactc 1140gcgcgaaacc ttccacttca ccacggagag ttatggcggc cactacgggc ccgtcttcaa 1200cgagtacatc gaggagcaga acgcccatct ccagccggga gccaagaaga tccaactggg 1260cagtgtgatg atcggcaatg gctggtatga cccgattatt caataccagg cctactacaa 1320ctttacggta cactacctgg tttctgatcc ttatccttac agcctggaca ctaatctatc 1380tacaggtata tccgggcaac acatacgact acctgccatt caacaagtcc atcagctcgc 1440tgatgtacaa caacctctat ggccccggaa actgcctcga ccagctctac gactgcgccg 1500cccgaggcat cgacgagatc tgcagcactg ccgacgattt ttgcgccaac gaggtcgaaa 1560acgtctacga catttactcc ggtcgggatg agtatgactt tcgtgaactc actccggacc 1620cgttccctta cgagttctac gttgactacc tgaacaaagc gtccgtgcag gccgccatcg 1680gcgcatacat caattacacg gagagcaaca acgctgttgg actcgccttt tcgtccaccg 1740gtgacgacgg gcgactcatg aacaccatcc aggatgtggg caagctgctc aaacagggtg 1800tcacggtggt catgtacgcc ggggatgccg actataactg caactggctg ggtggggaag 1860ccgtgtcgtt gcaggtcaag gccgccaact tcagtagtgc gggttacacc aacattgtca 1920cctcggatgg agtgacacac ggccaggtgc gccaggcggg gcaatttgcc tttgtgcgag 1980tgtatgagag tggacatgag gttcccttct atcaaccctt gcttgcgctg gagatgtttg 2040agcgcgtcat tggcggcaag gatgtggcga cgggaaagat tcccatctcg tcgagtttac 2100agacggtggg cacgcccaag agttactacc gggagggcaa cagcacgatt cagtgggagg 2160tgttggattc tctggcgacg tacaacacaa ccacgaatgc tccgaacccg gtgagccgga 2220ggctgaagcg gatgggacca gctttgcggt ttcagatgta gatctgaagt acctgcgatt 2280gtgcattgaa gtacattgtt cagtgcaatt accgatcatg gctagctgtg ccgcccaaag 2340ggggaagcta caatctaaac gccatatctt tcgatgcaga caccttacga gccatgaaat 2400gccattttat gatcaggcta tctactgccg gtgattttat gtagtgttgg aaattttctg 2460ttcaatcgca acccaaagga accaactggc tgtaaaagac acaacataac tcgccagagc 2520caaactgtgc gaagatatga gaagcaaagt ttaaacgctc ccaagccatg gtttccctgt 2580caagcctcat tcactctatt ggcttcagct gaaagaagag gataaacatt caggggtaga 2640accagacaaa atctggtctg gcggggatct ggtggggacc cgaatccaag ttgcgttagt 2700ttgaggcatg gatcgacacg cgacgaacat gcagtggagg gccgctatcg ctgttttgac 2760tcgacatcgg accaaaacca aggaaattcg tattcatcga tcgatagttc ttctcatctg 2820gcaaggcatg gatccgtctc cccacttcag ccggtacctc ccggcacaac aaaaggagca 2880tggcagcctg atttcctgcg ttccaactgt tcgtcggttg atctccctga tcaagtccag 294064550DNAAspergillus niger 6tgaaccatca ggtgggacca cagagcccac cgtccagctc aaggcagctc tctattcgaa 60gaaagaggta ctggatatat cgggtacttc tagctccagg tcgtgaagcg ttgcgagata 120cacaaatact gttggcgatc gaatgggacg aacatgtgaa tgttagcacc agaagtggat 180ggtagctacg aacgatggga ggcggaggtc cgagtgtacg atagagctgt ggagatagat 240tcgtatataa tagagatata tattcattgc attgcattgc tgtggtagaa aacttgtttt 300ggatcgcatg aattgctggc ctgaatgatc aggtcagaag acgccgcagc tccgccggac 360aagagccaat cagagggcgc caatcggggt gtccgcccgg ttcccttttc agtgtctgtc 420actgcagctc gcctgacttc agttcctttt ctccttcctc acggtcctcg tcattcgccc 480ctctctgttg cagtctctct tgttgggggg tcttgtgaat gtcttgcgtc tggctccaca 540tccacaaaag gagcctactg tctgtcgcta cgaacaattc tgttgcgagg gccgctgcct 600ctacctccgc cgcgccgccg ccgccgtcat cgccgccgcc tggttctaat acttattcgc 660ctctttatcg ccccatcacc aatcccatcg gatttacttt gtcgcctgcg aggtcactag 720tttctcgcaa tcctaaattt cctgcctatc ggcgctctag tcgacacttt tctttgtgcc 780cggccgctgc aacgcccggt gtcaccacga gcatctgccc tggtcaggcg cccgtccgct 840ctctcagctc gctcattata cactctacga gaccccgtgc tatacgtatc cgtaccgacc 900agatggattt gaatggagac gcaggcgcca agcgcaagcg cagctccatc accacacccg 960ccgaacggcc cgtaaagcac cttcgccccg aatcgagcgc attgacaccc ggggattcga 1020cgcctgccaa tgggactgta tacgatgtgg aggatgatga agatgcgagt cgtctgctgc 1080ctgtagggcc tgctcaggcc gactcaccgg aatggcaagc taccatagag gaggttgtga 1140aaagcgtagt gtctatccac ttctgtcaga cctgctcctt cgacacggag ctgtccatga 1200gtagtcaggc tactgggttt gtggtagatg cagagaatgg gtacatattg acaaaccgac 1260acgtggtttg cccgggacct ttctggggat actgcatctt tgataaccat gaggaagtat 1320gttgtacatt ccacatgtgg atcgccttat gacagtgatg ctgatttgaa ttggttacta 1380gtgcgacgtt cgtcctgtgt atcgggaccc tgttcacgac tttggaattt tgaaattcga 1440cccgaaggct attcgatata tgaaattgag ggaactgaaa ctgcagccgg atgcagctaa 1500agtgggatca gaaattcgcg ttgtgggtaa tgatgcagga gaaaaactga gtattctgtc 1560tggtgtcatt agtcggctgg atagaaacgc gcccgaatac ggcgatggct acagtgactt 1620caatacgaat tacatccagg ccgccgcagc agctagcggt ggaagttccg gcagtcctgt 1680agttaacatt gatggccatg cgattgctct gcaggccggt ggtcgtgcag acggtgcagc 1740gacggattac ttcctccctc tggaccgacc gctacgcgca ctggaatgca tccgtcgcgg 1800agagcctgtc acgcgtggaa cgattcagac gcagtggatc ttgaagccgt tcgacgagtg 1860tcgtcggttg ggcttgacgc ctgagtggga ggcgaccgtg cgtaaagcag cgcccacgga 1920aaccagcatg ctggtggccg agatcatcct gcctgaaggc ccggcggacg gaaagctcga 1980ggaaggagac gtgctcctgc aggtcaacgg ggtgcttctc acccaattca tccggttgga 2040tgacatcctg gattcgagtg ttgggcagac agtgcgtctg cttgtccaaa gaggcggtca 2100gaatgtggag attgagtgcc aggttggcga cctgcatgcc atcacgcccg accggttcgt 2160gacggtggct ggaggcacgt tccataacct gtcttaccag cagtcgcggc tgtatgccat 2220cgctactcgc ggtgtctacg tctgcgaggc tgccggctcc ttcaaactgg aaaacacact 2280gtcaggatgg atcatcgact cggtggacaa gcggcccact cgcaatctgg atgagttcgt 2340ggaggtgatg cgaacgattc ccgatcgttc gcgcgtggtc atctcgtatc ggcatattcg 2400cgatctccac acccgaggca ccagcatcgt ctatatcgat cgacactggc accccaagat 2460gcgactggct gtgcgcaacg acgacaccgg tctgtgggac ttttcggacc tcgcggaccc 2520tatcccagct cttcctccgg ttccgaggaa agccgatttc attcaactcg atggtgttag 2580ccagcctgct gcggccgaca ttgtgcgcag cttcgtacga gtatcctgta cgatgcccct 2640gaagctggac ggctaccccc aggccaagaa gactgggttc ggattggtcg tcgatgcaga 2700gaagggtttg gtggttgtgt cgcgagcgat cgtgccgtac gacctctgcg acatcaacgt 2760cacggtggcc gactccatca tcgtgaacgc taaagtagtt ttcctgcatc cgctccaaaa 2820ctacagcatc atccagtacg acccaagcct ggtgcaggcg ccggttcaga gtgccaaact 2880cgccaccgac tacatcaagc agggacagga cacgatcttt gtgggattca accagaactt 2940ccggattgtc gtggccaaga ccgccgtaac cgacatcacc actgtttcta ttccagccaa 3000cgcgtccgca ccgcgctacc gcgcgatcaa cctggacgcc atcactgtgg acaccggact 3060cagcgggcag tgttctaacg gtgtcctgat tggcgaggac ggagtggtgc aggcattgtg 3120gttgaactat cttggagaac gcacatctaa ttcgcataag gatgtggaat accatctagg 3180atttgcgact ccatctcttc ttcctgtcct gtcgaaggtg cagcagggag agatgccgga 3240attgcggatt ctgaacatgg agagctacgt ggtccagatg agtcaagctc gtatcatggg 3300cgtgtcggag gaatggatcg agaaggtgac gcaagctaac ccatcgcggc atcagctctt 3360catggtgcgc aaggtcgatt gcccaccgcc tgggttcaac tcagcggccg acacgttcga 3420ggagggtgat atcatcctga ccttggacgg acagctgatc acccgcgtct cggagttgga 3480tatcatgtac gagaaggata cgctggaagc cctgattgtt cgaaatggac aagaaatgcg 3540gatccaggtg ccgactgttc caacagagga cctagagact gaccgtgcgg tcgtgttctg 3600tggtgctgtg ttgcagaaac cacaccatgc ggtccgtcag cagatttcta agctacacag 3660cgaagtctac gtcagcgcaa gagtatgctc ctcacccctt aaccactgcc atcaagtaac 3720taaccaccct atcccttcaa cagagtcgcg gatccccctc ctaccaatac ggcttggccc 3780caaccaattt catcaccgcc gtaaacggcg ttccaacccc gaacctggac cgcttctccg 3840aagaagtgag caaaatcccc gacaacacat atttccgcct acgggcggtg acattcgaca 3900atgtgccgtg ggtagtgacc gtgaagaaga acgatcatta cgtatgccac aacccctccc 3960tctttacctc caccaaattc agagaatgtg gagactaaca caataatctc cagttcccca 4020tgtccgagta tatcaaagac cagtcccagc cttccggttg gcggaccgtg tctcacgaca 4080aggataaata taaagacggc attgcaccgg atgctgcgaa cttgaacccg gatgctatgg 4140acgaagggtt tgatggagtc agtgatattg agccggattt ggagtgattg aaggcggact 4200gtatagtatt ctgtgatgag catggctgtg ttagatgtgt atagcagaca tggcttggaa 4260tagtagaaaa agtgaaaaat gggaaaatga tagagattaa atcggttcgc atatacgaag 4320ttgtagatgg atgtattgtt tcggatgttt acgtagtacg tagtggctac tctatcgagg 4380tgtgatgata gcattagtct ttgatttgtt ttcgtcccat ctgcacatgt actccgtata 4440tgagaagtat gttgctcgac aacccaagtc tgaaagtatg aatgaacgaa tcgacaacac 4500acatgaagat aattttatcc aagcaaaaga agccccattt catcttattt 455072660DNAAspergillus niger 7gaatgcgctg aaaaaaatgc tgttgatagc ctaaggtagt cacccgacgg gcttgtgatt 60ggaggaaacc gcaatgacgc tggtcccgtg ccatgagctg actcagctgg ctgactcaac 120gcgtgacttt ctgcaaaggg aaggcaccgg catgtgattg gtcgccttcc gttcctgcta 180tcgaggcgtc atcgcctaca gcccatcgag tacacctcct cttctctcct ctctccttcc 240ttccttcctc tccatcctct tctgggtttc cattgatcac ccagtagctg gtattttctg 300agctacttgc tttttctatt ttgatacttt tgtgtccgta agttcacttt atgccctctg 360acccccccct tgataacccg tgctgataag ctccctgccc aggtaccgta ccttccagac 420cgcaaggtac ccatcctctg cctactcatc ccatcaccat ctcaattcat accggccccg 480tagggtttca gcaacaatga gagtccttcc agctgctatg ctggttggag cggccacggc 540ggccgttcct cccttccagc aggtccttgg aggtaacggt gccaagcacg gtgccgacca 600tgcggccgag gtccctgcgg atcacagtgc cgacgggttc tccaagccgc tgcacgcatt 660ccaggaggaa ctgaagtctc tctctgacga ggctcgtaag ctttgggatg aggtggccag 720cttcttcccg gagagcatgg atcagaaccc tctcttttcc ctccccaaga agcacaaccg 780ccgtcccgac tcgcactggg accacatcgt ccgcggctcc gacgttcaga gcgtctgggt 840cactggtgag aacggtgaga aggagcgcga ggtcgatggc aagctggaag cctatgatct 900cagggtcaag aagaccgatc ctggctctct tggcatcgac cccggcgtga agcagtacac 960cggttatctc gatgacaacg agaatgataa gcatttgttc tactgtaagc acaccttggt 1020tcaagatcac gctttttata tgctctggat atctaacgca acttagggtt cttcgagtct 1080cgcaatgacc ccgagaatga tcccgttgtt ctgtggctga acggtggccc tgggtgctct 1140tccctcaccg gtctcttcat ggagcttggc cctagcagca tcaacaagaa gatccagccg 1200gtctacaatg actacgcttg gaactccaac gcgtccgtga tcttccttga ccagcctgtc 1260aatgtcggtt actcctacag taactctgct gtcagcgaca cggtcgctgc tggcaaggac 1320gtctatgcct tgcttaccct cttcttcaaa caattccccg agtatgctaa gcaggacttc 1380cacattgccg gtgaatctta tgctggtcac tatatccccg tcttcgcttc ggagatcctg 1440tctcacaaga agcgcaacat caacctgcag tccgttctca ttggcaacgg tctcaccgac 1500ggatacaccc agtacgagta ctaccgtccc atggcctgcg gtgacggcgg ttacccagct 1560gtcttggacg agagctcctg ccagtccatg gacaacgctc ttcctcgctg ccagtctatg 1620attgagtctt gctacagttc cgagagcgct tgggtttgtg tcccggcctc catctactgt 1680aacaacgccc tccttgcccc ttaccagcgc actgggcaga acgtctatga tgtccgtggt 1740aagtgcgagg atagctctaa cctttgctac tcggctatgg gctacgtcag cgactacctg 1800aacaagcccg aagtcatcga ggctgttggc gctgaggtca acggctacga ctcgtgcaac 1860tttgacatca accgcaactt cctcttccac ggtgactgga tgaagcccta ccaccgcctc 1920gttccgggac tcctggagca gatccctgtc ttgatctatg ccggtgatgc tgatttcatt 1980tgcaactggc tgggcaacaa ggcctggact gaagccctgg agtggcccgg acaggctgaa 2040tatgcctccg ctgagctgga ggatctggtc attgtcgaca atgagcacac gggcaagaag 2100attggccagg ttaagtccca tggcaacttc accttcatgc gtctctatgg tggtggccac 2160atggtcccga tggaccagcc cgagtcgagt ctcgagttct tcaaccgctg gttgggaggt 2220gaatggttct aaagacgtgc taccaccgca tatagacttt ctggtcattt cggtgacact 2280gcagatatgt ttcttaacga tagtttgagc atgcttgtca atgcccacta gtcccgatcc 2340ttatatgttg catggtatct atgagttttg tcactatagt gcattataca tttgtacttc 2400gtatgagaat gaatcgatcg catttacacg catataaata gtacccaaac cgtctggaca 2460tgaataaggc ccggccagta gtttacatac agtgtagaaa actaggcgta cagacgtctc 2520agtacgtaat caatggttaa aaaaaccact cccatagaag ccaagccata agagcctact 2580catgtagttc gccactgaac gcacccgtat atcgtaaacc agcagaaaga gaaaaggaaa 2640attgaggaaa ggacgatttg 266081680DNAAspergillus niger 8aaaacgtgcg cactgcaccc actcgttccg gctggggtct agaaatctgg acggtcccag 60gcagatcggt gcctgggcaa aaccttgata aaaatagctt gttcgatctt gagttagaca 120gccaattgta tactcactag agacacttga tgattcagtc tgtgacgtac gtgcacctcc 180acactccgtc gatggattat gtgtccccgt gggcacgcgg agatcgggga catcagtcga 240gaaacttgcc taatctagtg acaagcagaa aagtcaaagt catccgcatg cgacttgcag 300atcatctaga gggatataat aaagtcgtgc gtttatgacc ttgcaggaaa cgacccgcct 360cctcctgcct ctttattatc gataccctct gccactagcg tcgtacatca cacttcacaa 420tccattctcc tctcattcat catgaagttc acaaattatc tcttgacgac tgcaacgctc 480gcaagcagtg tcctagcggc tcctgctccc cgcaccggtt tggaggacag actccgtgcc 540cggtcattgc agcgtcaatc acatcctctg gcacctattc cacttgacac atccaccaaa 600gagaattcca gactcctcga agccgacgag aataccaccc atgttacata cagcagtaac 660tgggcgggcg cagtgcgcga gcaaccacct ccgcaaggca cgtattctgc cgtgtcggca 720acctttcgtg taccagaacc cacggcgcaa ggggggagcg gaacgcaggc tgggtcggcc 780tgggtcggga tagatggcga cacatacagc aacgccattc tacagacagg agtcgacttc 840tacgtggaaa acgggcagac gtacaacgat gcctggtatg agtggtaccc agactatgca 900tatgacttcg acctagatgt aagcacaggg gacacgatcg tcgccaaggt ggaagccatc 960tcgccaagtc aaggtgtagc cactattgag aacatatcga cggggaagaa ggccacgcag 1020acgatcagag ccccagctgc gacagctacc cttgccggcc agaatgccga ctggatcgtg 1080gaggatttcc agtctggcga ctcaatggtc gatctggctg gctttggcga gatcagcttc 1140tggggcgtgc aagcacaagg aggagggtct acatggggtg tagatgatgc gactattgtc 1200gaactgaagc agggcaacga agtgttgaca gacgtggagg tgcaaagtga ttcggccttt 1260acggtgaaat atacgagctg atgtgatggt atatggtcgc atattctcat ccttcgacta 1320atctttctcc ttttggacgg tgacataatt tttctggttg attttgaaaa tgccttgatg 1380tatttcggta gtagttttaa ggttgatact tccagcatgc gggctcggct attgggagga 1440accaagaagg ctatatggcc ctcgggtatt cgccgcattc taaggtcgca tgccttctcg 1500gctttcctta tatatatcta ctttccattt ccccaacctc attcttgatg cgagaatcta 1560cccacacata cagttaatca tgtcccgtat ataccaacta agccgagcat ttcagcgcag 1620ccaagttggc gcgctccggc cgcgctctct actacccgct cggtcatccc gctgcggctt 168092590DNAAspergillus niger 9ttacatgctc tgtgtgttgg taaacacgct gtcacattct tcatgtcctc tggattgcac 60gataacttta ccgcgtctct ccaaccggat tgatgaaact atcaacaggg ccccgcatta 120ttggcataac cgacattttg aaaaagtatc gcgggcgaga agagagcctt tttcgacaac 180aaacgtcggt ctctttggtt tgcatcgaga gacatagata cagttgaccg cggcgcgaca 240ctttttagga gcgcagagga cggtttctgc ggcgatttga tccgcaggcg agcaaaggtc 300taagacacct ctgtttggaa ctgcgcaggt accagaactc gaaactaatg cgacattcga 360gcgacgatga tatatgtcaa ctatatcctg ggacttctgt ccctcttaca caccgctgta 420gccacagctc ctgattatgt cgtggtagac caactgaaca gcatccccga cggatggaca 480aaaggcgcag ctcccccgcc atttactccg atgaagttct ggttgtcgat gcatcacgag 540tacaaggcgg acttcgagca gaaagtcatc gatatctcga cacccggtca ccgggattat 600ggacggcata tgaaacgcaa cgatgtcatg gcctttatgc gcccatccga tcaggtctca 660aagatcatct tctcttggct tgagtcggag catgttccac caaatgccat cgaagatcgc 720ggggattggg tcgccttcac agtcccgttg gcccaagcac aatcaatgat gaagaccgat 780ttttacaact tccaccacct ggaaacaaac acaacccaaa ttaggaccct caagtactcc 840gttcccgagc aagtcgatgc tcatctgcaa atgatccagc caacgactcg cttcggccga 900cctaagacac aaaccagcct accgagcctc atgccagtgt cggttaacat tgatgaaata 960agcgaagact gcttgacagg cgtgacgccc atttgccttc gccagctcta tggtttacct 1020agcaccaagg caagccccga ctcgagaaac gtcctcggaa tttccggcta tctggaccag 1080tacgcgcgct acagtgacct cgacgagttt ctagccgtat actctccaaa cagcgtagac 1140gccgacttct ccgtagtatc gatcaacgga ggccaaaacc cacaaaactc acaagaggga 1200agcacagagg ccagtctcga catccaatac gccctctcca tggcatttga cgctaacgcg 1260actttctaca ctaccgccgg acgtgcgcca tccgtctcag actcgggtac ggtgagcacc 1320gacggctcga ccaacgagcc gtatctcgaa cagctccagt atctggtggg tcttccggac 1380gaggatcttc ctgcagtgct tagcacgtct tacggcgagg atgagcaaag tctgccggag 1440gaatacacag aagccacgtg caatttattt gcccaattag gtgcacgcgg ggtctcggtg 1500atcttcagca gcggagactc gggcgtcgga ggatcgtgtg tatctaacga cggaagccag 1560aggacccgct ttcagcctat cttcccggcg tcgtgcccgt ttgttacatc cgtgggtggg 1620actgagggcg tcgggccgga aaaggctgtg gacttttcga gtggagggtt ctccgagcgc 1680tttgctcgcc cgtcgtacca gaatgcgagt gtggaagcat accttgcccg cttaggagat 1740aaatgggatg gattgtataa tccagacgga cggggtattc ctgatgtgtc ggcccaggct 1800agcaactatg taatcaggga ccatgggcaa tggctacaaa ctgcgggaac aaggttagtg 1860gccctaccaa gtcaacaatt gaaaatcaaa cgagctgata atattacagt gctgccgccc 1920ctgtctttgc agcagtcatc tctcgactga acgctgcacg tctcgagcag ggtaaaccta 1980cactagggtt tctgaatcct tggctgtact cactcgacca gcaaggattt acggatattg 2040tagacggcgg atcagtgggt tgtgacgggt caaatggagg agctcttgtc ccgtatgcca 2100gttggaatgc caccaaggga tgggatccgg ttactgggct ggggacacct ctgtatcaga 2160ctctggagca gttggcgcag tctgcttagt actgcggcgg gatggcctat tttgtgtcgt 2220tgatgttttt gtcccctaaa tgtcaacgcc attaattctt ctcaagtgcg attagatttc 2280gtaaaacaga agctggacaa tatgcagaaa ttagagtaca aagctggaga cagaaggtcg 2340atctccagaa tttgctaatg gttgtggtac tcacgtcagg gtgctcgagc acaccagcta 2400actaccaact ttacccgtta attctaccgc agtagtaatc tagaaaatac tagataagct 2460gatcaagctt gaaacaaata agcttaccga ccgagaccca tacagcctcg cagtacaaca 2520acttactacg ggtgagacat cctcacccgt ccgtaagatc gaaaggatta ctatacacgg 2580agtaagcact 2590103080DNAAspergillus niger 10ggtacagtag tgggttttag tttggatgta tctggagaca tcgatgcttg ttcgccggcg 60ctaatttggg gccatcgctt agggaagaaa aagaaaggaa ggatttcatc tgccgcggca 120tttttggtca ggcattggca atactccaag cagcttgcca aagtgagaaa tgtgcttatg 180aataatattg agtaatagtt aatcaattgt cttacaggat aatatgggaa tagcattggc 240attgcgtggt tggcaggcag catgttgcaa attgcaacaa cgcgatcccg gcgatcgccg 300tcggactccg ggtgggaatc agggttggag acccattgct tatcaacaac agccgacgcc 360agtcgttctg gggtgcattt gcagaatctt tggacgaatc agccttttgt cagtatcggc 420cggtccgaat tgacccagct tgctagccgt tggagacatg caatgatgcc attgtctcgt 480ccgataagca agtgcggcca atccctcgtt ccttctggct gtctcagaaa agttataatg 540tccgtctcgc ctgcctagcg aacaattcga actctgtgtg tgttgtccct ctcaaggtct 600ccagcatgcg ttcttccggt ctctacacag cactcctgtg ctccctggcc gcctcgacca

660acgcgattgt ccatgaaaag ctcgccgcgg tcccctccgg ctggcatcat gtcgaagatg 720ctggctccga ccaccagata agcttgtcga tcgcgctggc acgcaagaac ctcgatcagc 780ttgaatccaa gctgaaagac ttgtcaacac ctggcgaatc gcaatacggc cagtggctgg 840accaggagga tgtcgacacg ctgttcccgg tggccagcga caaggctgtg attaactggc 900tgcgcagcgc caacatcacc catatttccc gccagggcag cttggtgaac tttgcgacca 960cggtcgataa ggtgaacaag cttctcaacg ccacctttgc ctactaccaa agcggctctt 1020cccagagatt gcgcacaaca gagtactcca tcccggatga tctggtcgac tcaatcgacc 1080tcatctcccc aacgaccttc ttcggcaagg aaaagaccac tgctggtctg aaccagcggg 1140cgcaaaagat tgacacccat gtggccaaac gctccaacag ctcgtcctgt gccgatgtca 1200tcacgctgtc ctgcctgaag gagatgtaca attttggcaa ctacactccc agcgcctcgt 1260cgggcagcaa gctgggcttc ggcagcttcc tgaacgaatc cgcctcgtat tctgaccttg 1320ccaagttcga gaagctgttt aacctgccct cccagagctt ttccgtggag ttggtcaacg 1380gcggtgtcaa tgatcagaat caatcgacgg cttccttgac cgaggcggac ctcgatgtgg 1440aattgctcgt cggagttgct catcccctcc cggtgactga gttcatcact tctggcgaac 1500cgtgagtatt gaattcctag acagagcttg aatcgaagct aattgtgtag tcctttcatt 1560cccgaccccg atgagccgag tgccgccgac aacgagaacg agccttacct ccagtactat 1620gagtaccttc tctccaagcc caactcggct ctgccccaag tgatttccaa ctcctatggt 1680gacgacgaac aggtacgacc ccacattccc ccttccctgt atgtagatac taaccggacc 1740agaccgttcc agagtactac gccaagcgag tctgcaacct gatcggactt gttggcctgc 1800gcggcatcag tgtcctcgag tcgtccggtg acgaaggtac acttacttcc cctgtcctat 1860tccttgcatc gaaaataccc taacagcagc acaggtatcg gatctggctg ccgaaccacc 1920gacggcacca accgaaccca attcaacccc atcttcccgg ccacctgtcc ctacgtgact 1980gccgtgggag gaacaatgtc ctatgccccc gaaatcgcct gggaagccag ttccggcgga 2040ttcagcaact acttcgagcg ggcgtggttc cagaaggaag ctgtgcagaa ctacctggcg 2100caccacatca ccaacgagac caagcagtac tactcgcaat tcgccaactt tagcggtcgc 2160ggatttcctg acgttgctgc ccatagcttt gagccttcgt gagtccattc ccagcatcat 2220gataatacga aatagggtct aatgacatct gcagatatga ggttatcttc tacggcgccc 2280gctacggctc cggcggtacc tcagccgcgt gtcccctttt ctctgcgcta gtgggcatgc 2340tgaacgatgc tcgtctgcgg gcgggcaagt ccacgctggg tttcttgaac cccctgctct 2400atagcaaggg gtacagagcg ttgactgatg tgacgggggg ccagtcgatc ggatgcaatg 2460gcattgatcc gcagaatgat gagactgttg ccggcgcggg cattatcccg tgggcgcact 2520ggaatgccac ggtcggatgg gatccggtga ctggattggg acttcctgac tttgagaagt 2580tgaggcagtt ggtgctgtcg ttgtagatgt atactatata tatggtatga gattatgtat 2640gtgatatgtg atattatgtg agagagaatg gtttagactg tgcgtcatat acatggacag 2700ttcattttct cattaaacga gcaccttcat acggtaagga cctcagaggt tcctcccatt 2760gttatgaccg cttcccttct ttctagagat acatgcttcc ccaccccgcc tcaacgcgac 2820cgtctacgga caccagtcag aagaccccaa caacccacta ttagtggcta gtaaggacga 2880catgcataat tactccgtga aacccccgaa attaagcccg acaggggcat agagaaaccg 2940atccaatcac ttaacttacc ccgcttctag cacggcatag ggctgagcga tgcgatggtg 3000caatggccac gccgttgccg attagccgta gggccagttg tgaatttccg ggatcaccct 3060acaacacatg cttcatgcgt 3080111890DNAAspergillus niger 11gaggatgata gtctgatggc cattccgctt gaggcaaagt gtgccccaat gtcacgcggt 60cagctagtct tctgcaggtc tgcagttgga caggggaact tgagtgctat tatcgccaag 120gtgaatgttc tctaccgctt tgataccaga gtgatcgtcc cttttgccgt cactcttggt 180gttgcgaagc agatgtcgtt cgtttgcata tgggagccga agatccacgc agggtgcttg 240aaaagacata ctgcgatcct cccgtttcca agaatgcttg tacacttgaa gtttttgtca 300agatcccccc gcctggccag tcccgagcta agcgaaatga gctttccctc aatgctgcag 360acaggagaca ccatcgcttt ggcgccttgg caccatcagc caccgtcggt cctatcatca 420tcgccctggt caatagggaa cgcgtcaatt gcgtatctgg gtagtgttat ctgctcgata 480ttgcaccggc agagcaggaa tcgggattgg cggatgtaga gaaaattcag cttcaaggag 540gggggaaggg agacgctgaa atggtataaa accacgtcca attccctacc agatagccct 600catccagcag catcaaaagc atcttccact cagactccaa gcagctccca gtccctcttc 660aattcattac cttccaaaca tcatcccatc aagatgaaga ctactgctct cttgaccgcc 720ggcctgctgg ccaccactgc tatggccgct cctctgacgg ccaagcgcca ggctgctcgg 780gccaagcgct ccacgaaccg ccagagcaac cctcccttca agcctggcac caacgaggtc 840ctcgccctta acggcaccaa gaatgtggag tacagctcca actgggccgg tgccgtcctc 900attggcactg gttacactgc cgtgaccgcc gagttcgtcg tgcccacccc ctccgtgccc 960tccggtggct cgagccgcga ggagtactgt gcctccgcct gggtgggcat tgacggtgac 1020acctgtgaca ctgctatcct ccagaccggt gtggactttt gtgtccaggg cagcgaggtg 1080agcttcgatg cctggtacga gtggtacccc gactacgcct acgacttcag cggcatctcc 1140atctcggccg gtgataccat caaggtcacc gtcgatgcca gcagcgacac caccggtact 1200gccacgattg agaacgtgag cactggtacc acggtcaccc acagcttcac gggcggtgtt 1260gatggtgatc tgtgtgagta caacgctgag tggatcgtcg aggacttcga ggaggatgac 1320tccctcgttc cctttgccga ctttggcacc gtgactttca ccagctgctc cgctaccaag 1380gatggttcct ctgttggccc tgaggatgct accatcatcg acatcgagca gaatgaggtg 1440ctgacctccg tttccgtctc cagtagcgag gtcgttgtca agtacgtcta agacgttgga 1500tgtatggggt tcgggattgt tgatgccccg atgggtgtgc tttcgacggc aatggtgaga 1560tgagtgatgg aaatgagagg ttggtctttt ggcccggggc tagttttctc ttggtactcc 1620tgaaaagcca atagttcaaa tgtctttatc ttgttagttt gatgttatag tttgccttga 1680gttgatttaa ttgaaccaac gttggatcat cgtatccctt agcgcaaata aaatattacg 1740tacgcctttt aaaatattat gtatgtctgt taaggttctg actgttcaga tttatgtcaa 1800acaacagcaa atcattggta atccaggact cggggatatg agcttcagac attcacccca 1860ttactgcatg actatgaccg tgtctttagc 1890123080DNAAspergillus niger 12ttgttgtgat tgctaagaga catcacattg ctcatatgag tttgattgcg actgttaata 60ttaatgtccg actgggagga aatgagtggc gttatccagg cagctgcatg caatactaca 120ttcccctcac gagggaaatc tggccatctc ggaaatcaat ggtgtcatcc gagttgattc 180ccctcaataa tggtcctgat aagccactat tgctgcagaa cgcctatctg tgccgttagt 240gcatgcatag tgtccccagt tctttttctg ccgattaatc tattgccaga cggactccgt 300cgcgcttccg aatgccggga accgcggcta agctttgctg tagctttgct gcaggaacat 360ctgcatcttt caaaatatct tcagaggagc cgatcgctga gtttctcaag agattagatg 420aatgttcgta cttggccgca atataagctt catggcggct tcaaccttcc atgagaaata 480agaataaggc tgccggggat ggcctcaccg tgtccctgca tgcaagggat gcataatgca 540ccgtgacctg ttccaccacg ccggagcccg cccgccctcc gacggcccaa acccactgca 600gaatggcttg attaagttcc ccttctataa ctaaccggtt gttcctcgtc gttgtctgct 660ctgctctcca cccagggtcg tttttgcttt tgcctcctta accatggtcg ccttttcccg 720catctcggca ggcttcgccc ttgccgcccc tgccctggcc agcgtcgtcc tggagaccgt 780caagtctgtt cccagcgact ggaagctcgt ggaggctgct gataccagct ccacaatttc 840tttgtccgtt gctctggcgc gtcagaacct ggaccagttg gaggagaagc tcctggccgt 900gtccacccct ggcaaggaca cctacggcca gttcttggat ctggacgaca tcaatgagca 960gtttcctctc gcagatgacg ctgctgttgt ggcttggctg aagaaggcag gcgtcaccca 1020gatccataag gagggtggtc tgctgaactt tgcgaccact gtgggcacag ccaaccagct 1080tctcaacacc accttctcgg tgtacaagag cggatctacc cagaagctgc gcacaacgca 1140atactctgtt ccggatgagc tgaccgggtc cattgatctc atctcgccga ctgttttctt 1200tggaaagtcc aacgctgcgc gctcggcggc cgtgcgtgct tcgcagacta ccaaggagac 1260cagcagaaag aagagcagta atgtgtgcga gtacatcact ccggattgcc tcaaagagca 1320gtatagcatt gactatacgc ccgaggcatc gtcgggaagt cgtgttgggt ttggcagttt 1380cttgaacgag tcggccttgt actcggattt ggatctgttc acccagtact ttgacattcc 1440ccagcagagt ttcactgttg agactatcaa cgggggaatc aacaaccagg agaatgatcc 1500ggatggtgaa gccgatctcg atgtccagaa catcgtgggc atctcgcatc ccttgccggt 1560gacggagtac attaccggag gatctccgtg agtgttccca aagatgcaat tgaattaaag 1620ctaatggttc agtccattca ttcccgacgt cgagactact accgacgaga acgagcctta 1680cctgcagtac tacgagtatc tgctggccaa gaccaacgac gagctgccac tggttatcag 1740caactcgtac ggcgatgacg aagatgtaag catccctgcc tcccacacaa atcgcctgct 1800gacagaatag accgttccca ttgcctacgc cacccgcgta tgcaacctca tcggcctgat 1860gggcacacgt ggtatctcca tcctcgagtc ttccggcgac tctggtacgt tgtaccccat 1920atatattgca tcaagtcccg actgacaaat acaggtgtgg gcggcgcatg catgtccaac 1980gacggcaccg acaagaccga attcaccccc atgttcccag gaacatgccc gtacatcacc 2040gcggtcggcg gcacccaaga cgtgcccgaa gtcgcctggg tggacagctc cggcggcttc 2100agcaactact tctcgcagcc gtcgtaccag tcggatcagg tggagaccta cctggacaag 2160tacatctctg cctcgacgaa gaagtactac gagcagtaca ccaacttcag cggtcgcgcg 2220ttccctgacg tgtctgcgtt tgcaggttct ccttagtatg tatccatccc agatgattgt 2280atggacatct gctaatgtcc gacagctacg aaacttatat tgatggtcag ctcggccttg 2340tggcgggtac ttctggcgct agccctgtgt ttgcggggat cgtcgcgctg ctgaacgatg 2400cccgtctgcg ggccaacaag acatccttgg gcttcctgaa cccttggctg tactcgagcg 2460gctacaagag cctgaatgac attaccagtg gcgaggcagt gggctgccaa ggcgatgtgg 2520agggcgctgg agtcattcct tgggcgagct ggaatgccac gacgggatgg gatccggcga 2580cagggctggg aacgcctaat tttgccaagc tgaaggaggc ggttcttgcg ttgtaagcag 2640gaggatactg agtggacgtg cggagtgaag gatatgtgca aggcgttaac ttataatagc 2700ctgtgtgtgg actatagaat catctacagc ccacaaccaa ttagcttctg catagtcacc 2760acccttaaac taaggataat caattgttta ccgctgtcag tctcaaatcc gtcatgtcat 2820ggaccctgtt cgatcaactt gaaacaagct taatctacca gcggcggtga tgaaaccgcc 2880agcggacact tgtttcagtt acccgcaagc ctgtatccag tatgcaagcc ctacttaaac 2940ccttcaccac cctgattatt ctactctctc tctctctcca accacaccat tcttttcttc 3000attgtgccgg tcacatccat tctttacttt cattctcctc ccttctcttc tcttctctac 3060ttccccaagt cactcattat 3080133598DNAAspergillus niger 13accggagcag aggaacaagc ggagaagctg aaacgtatga atgctgagta cgagcaaaag 60ttccctggct tgcggtttgt gtatgttctc tcagtatacc caacgacttg tgttggtctg 120acatatctcc ctggcatagt acttttgtaa acggtcgcaa ccgggatgtc atcatggagg 180agatgcgtga gaggattgac cggggcaatg ccgatcgtga ggtggaggag attatacagg 240tgagatggct gtctacccaa acacggagca gtgctgacag ttcgctcctt taaaggcaat 300gtgcgatatt gcaaaggatc gggcgcggaa actggagcag tccgctaaga tatagttcac 360atactgcaag catatattta aacaatgaat acccttcgat ttcagcaggc gctgcgacat 420ctccttgctg aatcgctgct ttacaagcca tatttcggtc catgcgattc atctatggag 480cactctgcct ctgtccggaa acaatggctg gtaatctgca tggaacttgg tgattccgtt 540agtataaagt gaccaactag tgccggcgaa ttatgggaag cctgccttgt cttacgacgg 600gacgatcttc cgtcgaacgc gtgctaccag cattttcata gtatgacggg tccgtatttg 660atttactatc gatggtaaaa cgcctcctct atggggtccc ctagcactcg gcaggccagc 720ttgtgagaca acccgggagg tcagccatta ttaggccaat gagagctggc aggttggaga 780ggttgtactt cgacaatgtt ggacagccat gcaacgtcgg acaatagctt tgatagggaa 840tatcctaagg gcgaaccagg agggataggg gtaggtatgg ctgtatcgat tagtagtccc 900tctttcaccc agaacaaact ctagtatata tagtagtaaa tgttccgcgg atggccaatg 960accccaaatc atctttcatc ccatccacgc atgagcaaac atgcatggtc tgcgcctagt 1020atgcagcata gggacattgc ctttggttat cctggcatat ccggcggctt cattgcatac 1080aacttcagca gccgtggact tggactccct tcgtctgacc tctaactccg aatacgtcaa 1140ttctgtccat gtagacacga atcgatcagt cgcagtgtcc gctgaagaac attataccga 1200tacagcagct cgactggttc agaacattgt tcctggagcg agctttcgtc tcatcgatga 1260ccactttgtc ggcgacaatg gagttgcaca tgtatacttc cgccaaacgc tccatggtat 1320tgacattgac aatgcggatt tcaatgttaa tgtctgctcc ccaattactc tgttcggaag 1380gaagcttact gttacagatt ggaaaagatg gactggtctt gtctttcgga cattcgttct 1440tcacaggcgc gttgccgagc agccatctgg acaataccaa cgttttgagt ccggaggctg 1500cacttagagg agcaagggac gctatacagc ttccactgac tattgacaat gtttctactg 1560aagctgcaga ggggcggaac gagtacatat tcagagaggc agtgggagcg gtatctgacc 1620ccaaagctaa gctagtctac cttgtcaagc cagaagggac tctggcgctc acctggagga 1680tagaaacaga catgtatgag cactggctac tgacatacat tgatgcagag actaccactg 1740tccacggcgt ggttgactat gtcgcagacg cgacatatca agtttagtga gtggctctcc 1800ccatcgaata acgaagctaa gacaacagtc cctggggcac aaacgatcca gcagaaggac 1860atcgcaccat tgtcaccgac ccctgggacc tatccgcatc cgcatacacc tggataagcg 1920atggacggga caactacacc acaaccagag gcaacaatgc catcgcacac tggaatccga 1980ccggcggtgg ctcctatctc tacaacctac gtccatccga ccccaacttg aatttccaat 2040ggccatactc cccaaacatg tccccacccc gatcatacat caacgcctcc atcgtccaac 2100tcttctacac agcaaacgcc taccacgacc tcctctatac actcggcttc accgaatccg 2160ctggcaactt ccaatggaat aacagcgccc acggcggccg agacaaagac tacgtgatcc 2220tcaacgcaca agacggctcc gggttcagca acgcaaactt tgcaacccca cccgatggta 2280tccccggccg tatgcgcatg tacatctgga tcgagtctac tccgtcgcgt gatggaagtt 2340ttgacgcggg cattgtaatt cacgaataca ctcacggtgg taagcatctc cccagaagat 2400ggaagtccta atctaacaaa ccagtatcca atcgtctcac cggcggctcc cacaacgccg 2460gatgcctcag cgccctcgaa tcgggtggca tgggcgaagg ctggggcgac tttatggcga 2520cggccatccg aatcaagccc aacgatacac gcacaacgtc ttacactatg ggtgcatggg 2580cagataatga taaatgtggt gtccgggact atccttattc tacctccttt actgagaacc 2640ctttgaacta tacgagcgtg aataccatga acggcgtgca cgccatcgga actgtctggg 2700caaccatgct atacgaggtc ttgtggaacc tcatcgacaa gtacgggaag aatgatgggt 2760cgaggccggt gtttagaaac ggggtgccta cagatggaaa gtacttgatg atgaagttgg 2820tggtggatgg gatggcactg taagtgatgc acagaatagc ttctttcacc tttgtaatgt 2880ccgtggtatc ctgactaatg gactgaaggc aaccatgtaa tccgaacttc gtgcaagcca 2940gggacgcgat ccttgacgca gacattgtgt tgactggcgg gaagaatcgc tgtgagatct 3000ggagggggtt tgcgaagaga ggattggggc aaggagcggc tcatagtagt ttaaattgga 3060tgcggagggg gagtacactt cttcctacgg gatgttagtc ttgcacaggt cgttcttggt 3120gagagatgag tggagatgcc tggtttatta gaataggact aattatctag cactaataca 3180atatcgacag atctaaacag taagtataaa tctataagtt atcacacgca taaaccccat 3240caccccctag tctacttcga aacaaacacc acaccaccaa catcctcatc ctcaccaaac 3300acccctcccc cgcataagaa cctaaacaac agccctcaac tccatactct gcgcccccct 3360cgccacacac aacaacaacc cacccacgag cagactcacc cccgcgtata tcgacagcgc 3420cagaaaccca tacttctgca ccagcgcccc ggaaataggt atcccagcca tagcactaca 3480ctcccagata agatatgatt agcaaaatcc acccttactc cccaagaaga tcaattcaaa 3540ataaatctaa tgtgcatacc tcaaagccgt agcccccata acaaccccca ccgccaac 3598142847DNAAspergillus niger 14cttttggctt gtgatcttga ttgctagaga tgtatatcct cacggatacc gccggagtgc 60gccatttctg gttaccttct ctttcccttt ttgtctcgat cgtgaggcgg aacgcaggat 120gaagacacgg cttctccatc gcggcccacc aaccaacaat gtccttggac gcccaactct 180ccatctactg gtcattggtc caatgcagag actccgtcga gctcaaatgg gccggccaac 240cccgagtcgt caggggcagc ggcagcgacg agctaaatta gaccactgat aagacgcgat 300agtccaaagt ctgaccgtca cattgtgcca ggcagataag ttgaatcgtg tgactggatg 360ttggctaacg tatggcgtct ccggaggccc gacggaccct gcgcgatcgg cggtggagcg 420caatctaagg acatccgcgc ctaagatatc tacccttcag cagttcagcc tagccctgca 480gacttgtcgg accagtgcta tcgtgatcgg cccccacggt cgaatgagct cttgtctctt 540tccgtcagac cctgccagtt aatctgctat ctactccgcg gtaacatcgt gcctgtctcc 600actaaggcag ggtccagggc tgtatgtctt actttgcacc gagtcggccg ccggttggct 660ctgtcttggc aattgcgaat atcctcacgg gcgacggacg acacggattt ggacggacat 720gcggagatct tcgtcggttt attcctggaa gggacatcat ctccttccat catgacggct 780gccatagcgg ggactctgag acatttttgc tctgaagagc atggtcgact tggatgatgg 840aggagttgat cgaggtcaat gaggagaggc ttgcaagtat aagaagagac tgctcgacca 900gcagaatgga tcttcttgtt catcaaccaa gagtccaagg cttctttgtc tggttctatc 960tcttctccga actctcttgc ttgacattct cgtggtcaaa atggtcgtct tcagcaaaac 1020cgctgccctc gttctgggtc tgtcctccgc cgtctctgcg gcgccggctc ctactcgcaa 1080gggcttcacc atcaaccaga ttgcccggcc tgccaacaag acccgcacca tcaacctgcc 1140aggcatgtac gcccgttccc tggccaagtt tggcggtacg gtgccccaga gcgtgaagga 1200ggctgccagc aagggtagtg ccgtgaccac gccccagaac aatgacgagg agtacctgac 1260tcccgtcact gtcggaaagt ccaccctcca tctggacttt gacaccggat ctgcagatct 1320gtaagcttcc ctgctcgggt gttcgggcaa atcgtgacta acctggacta gctgggtctt 1380ctcggacgag ctcccttcct cggagcagac cggtcacgat ctgtacacgc ctagctccag 1440cgcgaccaag ctgagcggct acacttggga catctcctac ggtgacggca gctcggccag 1500cggagacgtg taccgggata ctgtcactgt cggcggtgtc accaccaaca agcaggctgt 1560tgaagcagcc agcaagatca gctccgagtt cgttcagaac acggccaatg acggcctttt 1620gggactggcc tttagctcca tcaacactgg tgagtcaatc ctacatcagc cgggttgacc 1680tacctgctga ccgatacaca gtccagccca aggcgcagac caccttcttc gacaccgtca 1740agtcccagct ggactctccc cttttcgccg tgcagctgaa gcacgacgcc cccggtgttt 1800acgactttgg ctacatcgat gactccaagt acaccggttc tatcacctac acggatgccg 1860atagctccca gggttactgg ggcttcagca ccgacggcta cagtatcggt gacggcagct 1920ccagctccag cggcttcagc gccattgctg gtaagaaccg ccttcattta acacacaact 1980tgtccacctc tttactaact agtgtataga caccggtacc accctcatcc tcctcgatga 2040cgaaatcgtc tccgcctact acgagcaggt ttctggcgct caggagagcg aggaagccgg 2100tggctacgtt ttctcttgct cgaccaaccc ccctgacttc actgtcgtga ttggcgacta 2160caaggccgtt gttccgggca agtacatcaa ctacgctccc atctcgactg gcagctccac 2220ctgctttggc ggtatccaga gcaacagcgg tctgggactg tccatcctgg gtgatgtttt 2280cttgaagagc cagtacgtgg tcttcaactc tgagggccct aagctgggat tcgccgctca 2340ggcttagatt atccactgaa gtggagtcta tgatctgctg attgatccct cgacgatgaa 2400ctacatgtgg aaatgcatag cagacgaggg tgatggtgat gatgttgatt tgatgatgac 2460ccgtacatac ttgatgaagc tcggtacata tgcaaatgtg actgtatcta tgtgatgaat 2520atatgtatcc atctcatggc ttttggctat gagtgcagga taaacacctg aaccagtagt 2580agtactttcc cacctatatc tactgcggtg cctcgtccgg cccaacatca ccccagaggt 2640ggccgcagag gagtcttata agatagctac tatcagttac aacacctctc tgacagatgt 2700gaaggagtac aataaatcac cgaaacacaa attcaactaa agtcggtaag taataataat 2760ttaagaccca atccacgcaa tgttaaacta tctctggtgt tgaaagatct ctcccctggc 2820aacacctagt tgtgggagaa ctgtgtt 2847152899DNAAspergillus niger 15gcccaggtga agaccggaca ggaagcggat aggtacggga cattttctaa tctacccgcg 60atcgggacat ggctaaccaa gcatatagac tcgaattcta ccggtaaatc aagtatggga 120cgtgcatcag gctggatatc ggattacgca aggcgaacag ggggaccgtt agctgtatta 180tcaacatcta ggctatttca tattaggaca acgactgacg cattgggtat tccgctgggg 240tagtcttatc ggttggggcc aagtaccttg tagaactgta acccacgtta ataccgccac 300ttggctgggg cggtgattta gcatatgtaa gctccagttg gacggctacc cgagcttccc 360atgatctaca ggagtacgtg tctggctgtc tgctgcctac ttggtagaca ggtcagcgat 420aggtagatag gacctgtccg cagctgttgg ctagtttggt aaggcggttg cgctagtttg 480aagtaggcag gcaccgggaa cctaaggcgg tcttacatca tcacccgcgc tcggattcgc 540gtgatccgac catcacgata aggcctcagg tagcaaggag accttccaga cagctctgaa 600tgagactcaa aggtagatat aatgatggaa agataggata gctagatcag gcttattgta 660cctgatcgtt aagagcctag agaagatgta cctggaagac ctggcagcta caatcacctg 720gagcgataac ccgtgacgat ccccttgcca aatgacgcag ccgggctggc caaccattgg 780ctgcgacctg gcaggtcgct ccgcaaccag cgccgcccgg ctccaagtca cccgcatcac 840tcttccctac ccccagacct cctcttttcc cttgctatcc tccatctctt cttcatcgtt 900ctttgtctct atcatcattt tctattcata

cgtgcatcat tcagtcgttt ggcccagtcc 960atcatatccc gctgggtagc cgtttccgcc gtcgcccatc atgaagtcag cctccttgct 1020cacagcatcc gtgctgttgg gctgtgcctc cgccgaggtt cacaagctca agcttaacaa 1080ggtgcctctg gaagagcagc ttgtgagtgt ggtctttcac tgctttgttt tttttagcta 1140gttagcttca aagaagctcc agaaccattc aaagctgatt tcgtggtcta tagtacacgc 1200ataacatcga cgcccatgtc cgcgctctgg gccagaagta catgggtatc cgcccgtcca 1260tccacaaaga gctggtcgag gagaacccta tcaatgacat gagccgtcat gatgttctgg 1320tggacaactt cctgaacgca cagtgtatgg agataccgtc ttcttatggc tgcaactgct 1380gacccttcct gccatagact tctctgagat cgagctgggt actccccccc agaagttcaa 1440ggttgtcctg gacactggca gctcgaacct ttgggttcct tcgagcgaat gcagctctat 1500cgcctgctac ctccacaaca agtatgattc gtctgcctcc agtacgtatc acaagaatgg 1560cagtgaattc gccatcaagt acggctctgg cagccttagc ggattcattt ctcaggacac 1620cctgaagatt ggcgacctga aggtcaaggg acaggacttc gctgaggcga ccaatgagcc 1680tggccttgcc tttgccttcg gccggttcga tggcattctc ggcttgggtt atgacaccat 1740ctccgtgaac aagattgttc ctcccttcta caacatgctt gaccagggac tcctcgacga 1800gccggtcttt gccttctacc ttggagatac caacaaggag ggtgacgagt ccgtggcgac 1860cttcggtggt gtcgacaagg accactacac cggcgagctg atcaagattc ccctccgtcg 1920caaggcttac tgggaggttg agcttgacgc cattgctctt ggcgatgatg ttgctgagat 1980ggagaacacc ggtgtcattc tggacactgg tacctccctg attgctctgc ctgctgacct 2040ggctgagatg atgtaagtcg aattcttcgg attcctgggt tgaaaagaaa tgctgctaac 2100aaccttctag caatgctcag atcggtgcta agaagggctg gaccggccag tacaccgttg 2160actgcgacaa gcgctcgtcc ctgcccgatg ttactttcac ccttgccggc cacaacttca 2220ccatctcctc gtatgactac accttggagg tgcagggctc ttgcgtcagt gccttcatgg 2280gcatggactt ccctgagccg gttggtccct tggccatttt gggcgatgcg ttcctgcgca 2340agtggtacag cgtgtatgac ctgggcaaca gcgctgttgg tctggccaag gccaagtaaa 2400ttagttctgc gggttgatgt ggtatctatg atgcagctgk tgctgtcatt attgcttctt 2460gtagcttgat ctatgatttt tgcagacgaa cacacgtgat gttgtgaatg gttttcctca 2520tgtttgcagc ggttgccgga tagattctag ggatcttcaa tggaaagccg gtgatattat 2580ttgaccttta tttgggcact gagaatcttg actgtatgaa atatgatagt aacaccttaa 2640acatgaatgc aaatggcgta aaccgtgtga tgcagtcaca ataaccagca accgcggtac 2700cagccgaagt ctgggccggc gagtctcgcc ccgcacaggc caggcgccaa acccaagcag 2760cgctcttggc agccaagcct tcttcatcac gctctcacca cctcctccat ccaggctttc 2820tctctgctcg gtctttgttt catcatcctc ccacgcctgc ccttctattc aaccgctctt 2880cgatcttcat atccgatcg 2899162738DNAAspergillus niger 16gaggcatgag gcatttctga ggcccgctac tccgcattct gcagcatatc gtctctgcgt 60aggggaggtc gaaaccagct gtaggactcg gcttcggtgt atctgtaccg actgactaga 120aatcgctcaa tcgtgtagta tagctgtctc tttgttcctc acaacatgtc tacgatatgc 180tattaaaaaa agcagaagat ggagtcagag ccacccggtt agggccgggc cgcccgggag 240gagaacaaaa tacgggacag aatctcagtg atgggggaga agagagagtg gcgacctgac 300aattcacaca cgacacgaat aatagccgaa actaacaaga taaatcacat cacatcatga 360agaagacctg cgtaatgatg ataagcaatc ccaccaataa tacaatgcca ttgatagtgg 420ctgacctgaa gcaattcggg gaggagacgc caagctcgac gatcaccgga gcttgaaaga 480ccaacgagac aagatgacag gcccgtcgca ccacgccact aactgcccta acagaaatcg 540gcctgaatag tgcgacgagt gtcccggttc tgggcctcca cgataagata agtcatgggc 600ttatcgcgtc atcggcgccg atctcgcgat cagctgaaac caatcattca atcaatttgc 660atcacccgac tgggggcgag atttcagggc cagctgaaac ggtcggctgc cgagattgtc 720agtggatgat gaatgttatg ctggaagaga gggggagaat gacgtctcaa ttctgggtca 780cttactagtt gactagccac ctagtattta gctgctagct agggattcgg tttaaaagcc 840tggtggtttc tctcttcttc tcgtcatttt ctcttcatct catacccatt cttcaaaact 900cctccacttt gatcaattat cctccatcat ggctaccaaa atcaagctca tccccaatct 960caactacaag cgctcaggca ccaagtccta cgtgcacttg atgcgcaagt accgcttcca 1020tcccaccaag cctggtccct acactctcag cagctccatc caacagaccg gtcgtccgta 1080cactgaaaag cccatcgggg gtcgggccca tatccggcag ctggtgcgga agaagagcac 1140caccagcgat gaggttggcg aggttccggc cgaagatgtg cagaacgact ccatgtatct 1200ggcgaccgtg gggatcggaa ccccggcgca gaacctgaag ttggactttg acactggttc 1260agctgatctt tgggtacacc cccattatga aagacctaat atggaaacga gcgtcactga 1320cagatgtagg tctggtccaa caaactcccc tcaacccttc tatccgagaa caagacccat 1380gcgatcttcg actcgtccaa atcgagcacc ttcaagacct tggaaggtga atcctggcaa 1440atctcctacg gagatggatc ctccgcatca gggagtgtgg gcaccgacga cgtcaacatt 1500ggcggcgtag tcgtcaagaa ccaagccgtt gagctggcag agaagatgtc cagcacattc 1560gcccaaggcg aaggggacgg attgctcggt ctagcattca gcaacatcaa cacggtacag 1620ccaaagtccg tgaaaacgcc cgtcgagaac atgatcctgc aggatgacat tcccaagtcg 1680gctgagctgt tcacggccaa gctggatacc tggcgggaca ctgatgacga gtcgttttac 1740acctttggct tcattgacca ggatctggtg aagacggcag gtgaagaggt ctactacacc 1800cctgtcgata acagtcaagg cttctggcta ttcaactcga cctccgcgac ggtaaatgga 1860aagaccatta accggtcggg taacaccgcc attgctgata ccggtacgac gctggccttg 1920gtggacgatg acacgtgtga ggccatttat agtgcaattg acggcgccta ttatgatcag 1980gaagtacagg gctggatcta tccgaccgat acggcgcagg ataagctacc cactgtgtcg 2040tttgccgtgg gtgaaaagca gttcgtggtg cagaaggagg acctggcgtt ttcggaggcg 2100aagacgggct atgtctatgg aggaatccaa agtcgtggtg atatgaccat ggacatcttg 2160ggagacacat ttttgaagag tatttatgct gtaagtgcat tgctgttggc gttaaggggt 2220gatatcgaag ctcactaact ggattgcaga tctttgatgt cgggaacctg cgctttggag 2280ccgtccagcg cgaggagttg cgccagagcc tgaagtcgga gtagacgagt ggctgaatct 2340atcatggttt gatgatgtta tgtatttgca tgtcccgttt ttttggttaa atcctagtgg 2400cttttgagcc ccgaagtatg tacgcagtaa atagcagtgc aatatagtac tccgtacctt 2460gttatcagat gctctggttt gaagcacaaa ggaagccatc agtctcccaa tcagagcttc 2520cagcccgccc cgtccttcca tttccacaac ctcagcgcca tgaaacatgc catccctgct 2580cctaccataa ccgccgcaaa aagctgcccc ttccagaaaa cagcatgttc cagatccaac 2640aacgccccgg caataggatt tccaatgaga atgccaagcc ccgcgaacac gaaagacatg 2700cccatccacg tccccacaac agccatgtct ggacacaa 2738172349DNAAspergillus niger 17cgcgcactaa ccctccacgt attccaatat accaaatctg cccaaagcgc cagccagctt 60cctcaagcct tgcggtcaga taaggccctg tacctagcta gttgccgctg ctcccggcgc 120tgggccaagc cgtcggacgt ccgtcccccc tctttccccc tcctctcccc tctccactgg 180tggaacgatg tctggctgtt gccatcgttc tcagaagcaa cgccccctgg atcgggtggc 240tgtcgtacta ttgcatgttc gtccgcgcta ctaggaaagt ttttttccca cccggagtat 300ccgtgtttag tccgcgggct ggctgaccgg ctagctggcc gtgccagttg ggtaaggttc 360caagggagga ccttactagg tagaaacggg atccaacaat gaggggaaaa gggcggatat 420ggcttgccgg gggttcattg cggcctggac gaagaaaggg agatgatcac taatgcaaca 480caatcttggc ttgcaaggaa ttgcgctcca accagaatgt ctctgcgtag ggatgccaat 540tcgtgcgggc catgctggat ggatagtacg ctgctccact ctcgctcgac cttttgcagt 600ccacaatcgt ttccccgtat cgttgggcgg gggcgttttt ctgcagctat ggttgctgct 660gccccgacgg tgaacctttc tgcatccccg gttttagtcg attttagttg gcgggcctgg 720agattaaact ccgtcggacg aagaggagca gtggtgtcat cgtcggcgga ttgcatgcta 780tcggaagagc atggaagagg gaaaacatca acttcatttg caaaacgctc gagcataaat 840agaggcctgg attccgccgt tctggtgtct tttcttcttc atccagcatc gcaagtctct 900caagcatcgc ctggttcgtt cttctcactc ttccaccacc agccttgtca ataagttagc 960tcttcatctt ttcgaagaaa ccaattctcc aaacgtcaaa atgaagttct ctaccatcct 1020taccggctcc ctcttcgcca ctgccgctct ggctgctcct ctcactgaga agcgccgtgc 1080tcgcaaggag gcccgcgccg ctggcaagcg ccacagcaac cctccctaca tccctggttc 1140cgacaaggag atcctcaagc tgaacggcac ctccaacgag gattacagct ccaactgggc 1200tggtgccgtc ctgatcggcg acggctacac caaggtcact ggcgagttca ctgtccccag 1260tgtctctgct ggatctagca gctccagtgg ctacggcggt ggctacggct actacaagaa 1320caagagacaa tccgaggagt actgcgcctc cgcttgggtt ggtatcgacg gtgacacctg 1380cgagaccgct attctccaga ctggtgtcga cttctgctac gaggatggcc agacttccta 1440cgatgcctgg tacgagtggt accccgacta cgcctacgac ttcaacgaca tcaccatctc 1500cgagggtgac accatcaagg tcactgtcga ggccaccagc aagagcagcg gtagcgccac 1560cgttgagaac ctgaccactg gccagtccgt cacccacacc ttcagcggca acgtcgaggg 1620tgacctttgc gagaccaacg ccgagtggat cgtcgaggac ttcgagtctg gtgactctct 1680tgtggctttc gctgacttcg gctccgttac cttcaccaat gctgaggcta ccagcgacgg 1740ttccactgtc ggcccctctg acgctaccgt tatggacatt gagcaggatg gcaccgtcct 1800caccgagacc tccgtctctg gcgacagcgt cactgtcacc tacgtttaaa tgcatctcta 1860tgcatgagat atcggtcgct tcaatgtctt cgagacgaag acaaaccctg gggatgaatg 1920aaaaaatgag tgatgagcta tccggattga tctgatcttg ttgagttgtt aattccgttt 1980ctgttgatgt ttttgaatga ttatacctac ttttaagtag aagaaatgga tgagcgcgtg 2040catgctgaaa atgactgtcc ctgcttatat tgtagaagat cttccagaaa gctgtgctgc 2100cgatctgaag atctgaagat cactagtgag atctcgcagc tcggctgtgt aagtgcattt 2160gctctgtcga tcataacttt gtaaaagctt gtatgcatag cagacatctg tcgattattt 2220agatgcttcg atttgatcat ctttactaga atccccattc gagtagagct tcagagcgtc 2280gggtggaaat atcgggtcgt ggatggtatc ggagaagtct cacaacatga acgaaagatc 2340cgcggtata 2349181495DNAAspergillus niger 18tgattgtgca gacttcctca tcatcgaagg agacaacaat gaaaccccag ggagacacgg 60aagcaggaaa acagactgcg gccggcgaga aagacacgat gtgacgaagg cttatctcgt 120gacgccaaga caatgcgggg aaagctgccc ttccaagacc caactggcct gcctctttct 180cattacaacc tcatcgcctt gattgacttt ctggaccttg gtggcttgga ggccggtcgc 240atcgagcttg ctactcgcta cttgctttgt ttcgatgact ggctttcgtt gatcgcaaca 300ttctttcttg gtatttttgt agggatagct agttgcttat catgggagat tacggccccg 360gagtgtcgtc actcacggca cagctacctg gaaatccgcc tgtctctgaa acagatcagg 420atgagatctc agtacttgta acgggctttg gggtaagctt ccagtgtcca taccattctc 480ccaatatcgc aactcacatg ttctacagcc attcaagtct aatctagtga acgcctcata 540tctgatagcc tcgtccctac caccctcttt cacattctca cctgcatctt cagacggctc 600tgatgctgtt ccccgtcgag tttcgataaa tgtccatcct tcacccatac ccgttgcata 660ttcatcggtg cggacgaccc tccccgtcat tctcgatgac tatgccaaga cgcacggagg 720ccgacgccca gacatcgtca tacacattgg catagcagca atgaggaact actattccgt 780ggagacgcag gctcaccgtg atgggtatct gatgtccgac atcaaaggca gatccgggta 840cgaggatggc gagaagctgt ggagggagct cgacttgcca ctggtgctta gggctggccc 900ttcagaggga cacgcctcgg agaagaaaca tctcagcccc cgtccaccgg acgaagattt 960cctagcagca tggaagacat tttgccctcc agaaaccgat gcgcggatct ccactgatgc 1020cggacgttat ctctgcgagt tcatcctgta caccagcttg gcactggcat accaggcggg 1080tgaggatcgc aatgtcacct tcttccatgt tcccgcgtca tgcttggatg aggatataga 1140gacgggcaag gaggttgccg tcgcgctaat caaggctctt gtgactagct ggagtgagca 1200gcagcacagc gttccctagt tctgaatgac tttttcaatc ttctcggagt tgtgacattg 1260catgtcccag cagttttggt ttatcggtgg tcctatctga gtactatatt tttttggcaa 1320tattttgcat tagtgaatac atatgggcgc ctgatgggtt atgatcgcat cacacctggc 1380gccgcataga ttttgggcat aaggagtgtt ggtgtaagat caccatcaat ttattactgg 1440tgttggattt gtgtagggat agaaccaata tagattaaat tctcacgcca tacat 1495192501DNAAspergillus niger 19gcgtcttcgg caagcggaag ggaccccgca aaagctacgc attgccattg ttcaggaacc 60cactaaataa acacacggac atgtggtttt ggctgcccgt gcgccccgaa gccgcagccc 120gaacggaggc attaaccctg atgcgtccgt tgattgttat ggtcttgtcc aacataacgg 180ggaatttctg accgcacacg atgccaggca acccatttta tcacggctga gcatgttgat 240aggtgttgaa ttcattttcc gtaggcagac gtctcctaga gcaatttctg ctgtatggca 300gacattcgtg accgaaaccg tctcactcac ggtctaccat ggtagttatg cttcgtacat 360aagacaagaa aggaatgcct tcaatcatgg caagaaggga atttggtaat ttgggtgcta 420ctgccgtctt cctttgttgt gaaccttctc cattacacac agtgtccctt gaaggccccg 480tatgccttca tactccgcca caatagccgc catcggggct ttcctgcttt cgcagcccgt 540catgggctca aggcagggaa aggccccctt tggctggggt actcagtcac ttgctcactt 600tggtatcaac ccagaccttg ggttgcacaa ccagcagaac ctcaactccc tcatttcaca 660ttcagcgatg gccactgcgt tggagacgga atatgccacc gtatgaaaag caccagccct 720ggctcttagt cctgatcact gattgtagac tcagatccct attgaccata acaacgcatc 780ggctggcact tatcaaaatc ggttctgggt cagcgatgaa ttctatcagc ctggcaaccc 840gatatttgtg tacgataccg gggagtcgga tggcggatcg atagcccagt cctacctaac 900ctccactctc tccttcttca gagaattcct gatcgaattc aacgccatgg gaatcgcctg 960ggagcacaga tactatggaa actcgacccc ggctcccgta tcctatgaaa ctccacccga 1020ggcatggcaa tacctcacca ccaagcaggc gctcgcggac cttccgtact ttgctagtaa 1080ctttagccgc gagaagtatc ctgacatgga cctgacgccg cagggcacgc cgtggatcat 1140ggtgggcggc tcgtacgcag ggattcgtgc tgcattaact cgcaaggagt acccagagac 1200gatattcgca gccttttcct catcgtctcc ggtggaagca caggtcaata tgagcgcgta 1260ttacgaccaa gtctatcgtg gcatggttgc cagcggatgg accaactgct cggcagatat 1320ccacgctgct ctggaatata ttgacgatca actttcggat gaagatacag ctacctcggt 1380caaacaactt ttcttcggat ctggcgccga gaccaactcc aacggtgatt tcactgcagc 1440gctaactgcc atctacggct acttccaaag ttatggtatg gcgggaggta ttggaggtct 1500aggcgcattc tgcgagtatc tcgaaattga tcccaagacg aacgggacta caggaccgga 1560tggccttgcc cctacgtatg gcggccagta tgtcgccgaa cgatgggccg catggccaac 1620ctttctcgag ctggtcaatc tgaatatggg gaccaactgc gggcctcagg acgcgtctca 1680gccaattgac tgtgactttt ccaagccata cggcgatccc tcggccatca cttggacttg 1740gcaatactgc agcgaatggg ggttcttcca ggcgaacaac gatgggccgc actcgctggc 1800ctcgcgatat cagtcggtgg aataccagca agaagtatgt aaccggcagt tccccgatgc 1860agtggacaag ggactgctgc ctccgtcgcc gcgggcggat gatgtcaacc aagagtttgg 1920gggatggacg atccgcccgt ccaatgttta cttcagcgga ggagaattcg atccgtggcg 1980atcattgtcc attctgtcga cagaagattt cgcacctcaa ggggtggagt ttacgagcgc 2040gatcccagcc tgtggggtgc agaccaatga ggacaccgtc tttggatacg tcatgcagaa 2100ctcggaacat tgctttgact ttcaagcgac gccgaccgtg gggaagttat cacgcggcat 2160cttcacatcc gccttgttgc aatggctcga atgttttgga cagaactcaa gccaatccag 2220gtgatctggg gggccagggg gtgtgtgggt gtgtaggtgt gggtgtgttt ggttgtgctg 2280gagcctggag ccaggataaa gaagatagga caaggatgac tgagtggatc ctgggatgct 2340cctacttact tagaaaggta cagggcgcgt cacggcgaag gtagactcgt accccagatt 2400agatgatcaa cgagaagcct cggaggtttt ggatcaacgt tgggttttag cgtcacgtcc 2460aaagtcctgc atgcaggtgc cgcttttccc ttttgggaga t 2501202660DNAAspergillus niger 20agagtccgcc ttgacaatgt ctaagaaagc atgctgagcc ccctccccca gtgtttatag 60gtgagtagga atggagtata gtgcttgagt gctttcacgc tggtaaacgg acccgctggg 120cggctagact gccttgtttt cggtctagga accattcaag attcaacggc tacaagtcaa 180gtcagaccat ctatcaatag tgcgagatag cagagagtcg gaccggagtc tcacaggcat 240ccttggcggt cgaggagtga tgagttgtgc gaccagcgcg tgttccttat ttaagccgcg 300cgcgcacctc tgacgcaacg gtctcaaagg ggggtctcac ctcttgcatg ttcggctgca 360ttcaattcga cctctccgtg tctgtctagc atcaccccaa atcctatcgg aatagtcctc 420cggttaagtc aacattgcaa atcagtcctt tcatttttgc ccagctcagc gctcggcctt 480ctgtgaccct tggagcctga tcaattgccg aaaggtgttc gggcgggtca gccttggaca 540gctcatttgc agtgcagagg ttcatcagca tcagctgtac tacttgactt cctatcatca 600ttattgatta ttatattata tcctatcttc tccgccaatc ttccatcgcc ggtagttttt 660cgtagacaac atgaagctct caatagctct tgcactcggc gcaacggctt cgacgggggt 720gttggctgct gttgtaccgc agcaagaacc gctgataacc ccccaagatc ccccaactca 780tcatcatcag gagaagttct tgatcgagtt ggctccttat cagacgagat gggttaccga 840ggaagaaaag tgggacttaa aactggtata gcaacattcc ccattttatt actgtcacaa 900tagcacatct cactgatcgc tctgcgaatg ttccattagg atggcgtgaa cttcatcgat 960attactgaag aacgaaacac tgggttctac ccaacgttgc atgctggtag ctatgttcac 1020tatccgccga cgatgaagca tgcggagaag gtggttcccc ttctgcgggg tctctccaag 1080gacaacatgg agcaaaacct caacaaattt acctcatttc acactcgcta ctataggtcg 1140tccactggta ttgagtccgc aaagtggcta tacagtaggg tttcggatgt cattgagcag 1200tcgggtgcag cagagtacgg cgccactgtg gagcagttcg ctcactcatg gggccaattc 1260agtatcattg ctcggatccc aggccagact aacaaaactg ttgtcctggg cgcacatcag 1320gacagcatca atcttttcct cccctccatc ctagctgcac ctggtgccga tgatgacgga 1380agtggaaccg tgactatact cgaagctttg cgtggtctgc tgcagtcaga cgccattgtc 1440cggggcaacg cttccaacac aatcgaattc cactggtact cggcagagga aggtggtatg 1500cttggttcgc aagccatatt ctctcaatat aagagagata agcgagacat caaggcgatg 1560cttcaacagg atatgactgg ttatacccag ggagctctgg acgccggtcg tcaagaagcc 1620attgggatta tggttgacta cgttgatgag ggactgacac aattcctcaa agatgtcact 1680actgaggtaa ggtcactccc gctttccttc tttgtgagac atataactaa cgattgcggt 1740caaagtattg tggtattggc tacatcgaaa ccagatgtgg ctacgcctgt tcggaccaca 1800cgtccgcaag caaatatggc tatcccgcag ctatggcgac ggaatccgaa atggaaaaca 1860gcaacaagag gatccacacg actgatgaca gcatccggta tctaagcttc gatcatatgc 1920tggagcatgc gaggttgaca cttggcttcg cttacgagct ggcctttgct caattctagt 1980gtccttcatg attttacgtt gtaaccgggt ctagcagata attctggcta actagtgagg 2040cttatatgtg ttcaggtttc ctatgtcggt ttattgtggc attagacaag attacagagt 2100aaccaatact ccattttgta atggaataga tgtctgaggc ccaagtgttg gcaaggaacc 2160ttgcctatat accacagatt aatactattg gctttggtga ttcaagaata ggcctatggc 2220tggactttat atatgttgac attctatttt gtaccggcaa cagactctaa cactagcacc 2280taacaaataa aacacgtgtg actcttatgg gtggcatgat gatagtctgc agaatggccc 2340gataagataa acgaaggaga tcctactata cccgattgag tcacactagc ctgaaacaga 2400aagacggtca ctccgccggg gcgatcactt ccactggctt caatcttcga gtcattcctg 2460cggtctgttt tctccttgtt accactccct ttgcccttca gatcagatcc tgaacggaga 2520aagctcaccc ttcatactac ataatattct acataacttg cttggactga attggcgata 2580ttccgtcggt cgctcctatc tatcgcctac gtcaccagcg gtgcccctcc aaggaagacc 2640ccaccatcag accttggatc 2660212047DNAAspergillus niger 21ccgagctata caaatgcgca tacaaaaatg gacagagtta catttcaacg ataaacatga 60atgataagct tccagcaatg gcggccaagc gatatgcaaa ccgattttag tacgcattcg 120gtttatctgt tatctctctc ggagtaaact gtatgctctt cgccgaaacc acaaaagtaa 180gcggggaaac gtatactacc aatcaaacac cccgagatgg tgactccgaa cgcagcagac 240ctatttagat atatttaggc atgacaagta tcaatggatg acagaaacac cgagacctgg 300tacaatctaa gttgaggaga gatttgaatc agaaagcagc tcgcacattt catcatgaga 360actactacgt cttttgctag gcttgcattg gcagtggcct cagttggtat tgtctttgct 420agtccaacaa aaaataacga tgggaaactg gtatatggct caccagaatc cgtcggcatg 480atatccgccc ctttgcacca aatggtccaa aatgttagcg catatacaca tgctgccaac 540tatagcaagt tctcgtacga caaagtccat cccatcgagc cagggtctgt taccctggtg 600gctctcgacg gtgtcatcgt cagcgaattt gccttgggca agagaaatct ctacgccgat 660gtcaacggca ccaatttacc tcgatacctg caggaagaca ccaccctgga tacagtctac 720gatatggcaa gcctcacgaa gctgttcacc acggtagctg ctttacggga acttgacgct 780ggtcgaattg cgcttaatgt aactgttgca acttatatac cggactttgc gacgaatggg 840aaggagaata ttactatctt ggagctgttc acgcatacaa gcggtttcgc ttctgatcca 900tcgccaccac ttttctctgc ttattatacg acgtatgatg aacgcattaa agcaattttg 960acgcaaaaaa ttatcaatac ccccggcagc

acatacctct acttagatct caactttatg 1020tcgctgggcc tcgttatcga gaccgtaacg ggacgtgccc tggatgatct tatttatgac 1080ttcaccagac cgcttgaaat gacatctacc ttcttcaacc gcgggaatat cgaaggctct 1140acaccccagt cacccaacta cgaccgcaca gccgtacaag aatttcagat cgcagccctc 1200ggaccctcag aaccacagcg tccacaacca gtgcgcggca cagttcacga cgagaacgca 1260tggtccctag acggcgtatc aggtcatgca ggtctattct ccactgtgcg cgatacagcg 1320acattctgcc agatgatcct caacaacggc acatatgcag gccaacggat cctttctcga 1380acagcggtag acatgatttt cacaaacttc aatgccaggt ttccggggga tgctcgtagt 1440ttagggtttg agttggatca gtattctact gcgggaccga tggcgagttt gcaaactgcg 1500agtcacactg gatttactgg gactacgttg gtgatggata ggacgtataa cgccttttgg 1560ttgcatttta gtaaccgggt gcatccgtct agggcatggt ctagcaatac tattgtgaga 1620gaggctattg ggtattgggt tgggaagagc ttggggttgg atgttgcgtt tgctctgttg 1680taatggttga gcggaggacg taccagatgg gatcctggat tcattccttc gatacacttg 1740tatgtacacg aggaatgtat tcgaatgcaa atacctcata tattacagaa tccgcagtat 1800gaatccggat aattttgtta aggcaaatcc agaaatttct aaaggttcac taccataaac 1860acaaatattc accattcaat atggcatgtt atcatccatt ctcataaaag accctcgatc 1920cggaagaccg atcctgtcag ggaattagtc aaccctctcc aataaatgca gcatgaaaga 1980aatctaccat gaatcaaccc cgagccctaa ataatccgaa aagatccagt ctggtgacag 2040tgcaggg 2047222730DNAAspergillus niger 22tggccacgcc atcctcttat gctctctcta tccactctct ccctcagctt ctctcaacca 60cttccttacc catctttcac cctctcttcc cctttccccc tttcaaatct cttgaccttc 120aagtctggcg cgcgtctgga cagcggctct tgtgctagag gtcttaactc ctaccccgcc 180ttcctctggc cttgaccttc tctgttcctg aaccaggttc cctcccggtc ctctccgccg 240acgttatccc cgacattgtg ctgctcatta cctccgcccc caaggtaacg ggtaagcgaa 300aagtgcaagg cccagttggc taaatttcga tgactccttg agcgcgactc caagtccgct 360tgggaccgtt tcctccgctc cgtcttcggc aatatctact actactacta ttactattac 420taccccggtc agccgccgcc gccgtattac aagtacccat cgcctactga tggtctcctt 480atcattccgc ggggagacca cttccattcc ctccatggcg tcctggttgc tctcgacgct 540cctttttctg agcccgtcct tggtgtcagc caaatcggcc gcagactatt atgttcactc 600cttgcccggt gcccccgagg ggcccttgct gaagatgcat gccgggtaag cttcgctgtc 660ccggaacggt ccgcttagca cctatatact gacttattgc ctccacgcgc agccatattg 720aggtggatcc acagaacaat ggaaatcttt tcttctggca ctaccagaat cgccatattg 780ccaaccgcca gcggactgtg atctggttga acggtggtcc cggatgtagt tccatggacg 840gcgcgttgat ggaggtcggt ccgtatcgcc tgaaggacaa tgaaaccttg acctataatg 900agggttcctg ggacgaattc gccaatttgt tgttcgtcga tcagccagtc ggaaccgggt 960tcagttatgt caacacggac agctatcttc atgagctcga tgagatgtcg gctcagttca 1020ttgtctttct ggaagagtgg ttcagattat ttccggagta tgaacgcgat gatgtatgct 1080gcaatcacct atgctgccct agtcctgcac cttcacggat tctgttctaa catctgcgac 1140agatctacat tgccggcgag tcttacgccg gtcagcatat tccatacatc gccaaagcca 1200tccaggaacg gaacaagaac gttcaaggga agaccatcgc ttcgtggaat ctaaaaggcc 1260tattgattgg caatggttgg atttctccta atgaacagta catgtcctac ttgccctacg 1320catatgaaga aggccttatc aaggaaggca gccggaccgc gaaggaactc gaagttttac 1380agtcagtctg taagtccagg ctggaaactg gcaagaacaa ggtccacctc aacgactgcg 1440agaaggtcat gaatgctctg ttggataaga cggtcgaaga caacaaatgt ctcaacatgt 1500atgacatccg ccttcgtgac accaccgatg catgcggtat gaactggccc accgacctgg 1560aggacgtgaa gccctatctg cagcgggaag atgtggttaa agcgcttaac atcaatccgg 1620agaagaagtc tggctgggtg gagtgttcag gtgcagtgag cagcgctttc aatccgcaaa 1680agtccccgcc ctcggttcaa ctacttcccg gcttgctgga atcgggactt caaatcctcc 1740ttttcagcgg agacaaggac ctgatttgca accatgttgg aacggaacag ctcatcaata 1800acatgaagtg gaacggaggc acgggtttcg agacctcacc tggcgtctgg gctcctcgac 1860acgactggag tttcgaaggc gagccggcgg gtatctatca atatgccaga aacctgactt 1920acgtgctcat ctacaacgca agccatatgg ttccctacga ccttcctcgt cagagccggg 1980acatgctaga tcgcttcatg aatgtcgata tcgcgagcat cggaggcagc cccgccgact 2040cgcgcattga cggcgagaag ctgccccaga cgtcggtggg cggccatccc aacagcaccg 2100cggcggagga gcaggagaag gagaggatca aggagacgga atggaaagcc tacgccaagt 2160caggcgaagc cgttctcctc gtcgtcatta tcggtgtatt agtttggggc ttcttcatct 2220ggcgcagccg ccggcgtcac cagggatacc ggggcgtctg gcataaggac atgagcggaa 2280gctctgttct cgagcggttc cacaacaagc gcacgggagg cgcagacgtc gaagcggggg 2340atttcgacga ggcggagctc gatgaccttc attctccaga cctcgaaaga gaacactacg 2400ccgtgggcga ggacagcgac gaggatgata tttcacgaca gcattctcaa caggcctccc 2460gagccggggg cagtcataat ctatcctagt tcatctttgg ttgggtaaac ttgtgatggt 2520gtaggtgtat ggcttgcttg gggtctttgc cttttgtttt tgttttcttg gccacgaaag 2580gacgtgcctc cttatatgtg catttatcat tttatctagc tggctgcctg gcatcattta 2640acatttagac atgaacaaag tttatgaccg cttcctgata catagccagg cggaaattcc 2700tcccgtctat aagccaacag tctcatccac 2730232660DNAAspergillus niger 23actttattgc caagcgaatg acttcgactt tcttatttct gcaacgcgtt tggccagtta 60ataatttgct agactcaact gattgctcgg tgccatctta ccagggatcg gcaagccgaa 120aagtacgcta ttgcacccaa tctgtaaaga agacttctcc aaactccaaa gtagaacaga 180cccatcttta gctttaataa ctccaatcat gacgattgga actatcggaa aatataatct 240aagttcaatg gatctggtcc gtcgctagaa tatcggagta aatgagccca acccctggcc 300atcaggttcg acggaggaat tcttctggtt gggtacaaga ttgacacgat ccccttggcc 360gctgaacgtc actcttccgc tgtcaaagct tgttggctga cttcgatccc ggatgatgtt 420tctgatttca cctgcagtga cagttgcggc tgcacttctg ctgatcaacg gcgcaggagc 480aactcaatct gaacgaagtc gggctgccgc tcatttttcc aaacgtcatc cgacgtaccg 540tgctgcgacc agagcccagt cgagcaacac ttccgactac cgattcttca ataataggac 600caagcgtatg tattacaccg gccatgaact ctattcgtcg ctgacatgtg gtcatccctg 660gatagcccac ttggtggaaa gcttacccga tgtgcacttc gatgttgggg agatgtactc 720ggggtcgatc cctatcgatg acagcaacaa tggatctcga tccctgtttt atatcttcca 780acctaagata ggcgaacctt cagacgacct taccatttac ctcaatggag ggccaggctg 840ttcctccgaa cagggattct ttcaggaaaa tggcaggttc acatggcagc ctggtaccta 900tgcacccgtc atcaacgaat attcttgggt caatttgacg aacatgctat ggtacgcttc 960ttcctgagga ttaaattgga ggtatgcact ctgtacattt tatgagacta atgtgaataa 1020attcagggtt gaccaaccag tcggaaccgg attttccgtt ggaaatgtta cagccaccaa 1080cgaagaagag attgccgccg attttctcga cttctttgaa aagtttgaag atctatacgg 1140gataaagaac tttcgcattt tcatgaccgg tgagagctac gccggtcgct atgttcccta 1200tatctcgtcg gcaatgctag acaagaacga caccacgcgt ttcaatctga gcggtacgag 1260ccctgtctac tcataactac tacccctata agcttagttg actgaaactg actttttaac 1320gtccctctag gagcccttct ttatgacgcc tgcatcggcc aatgggacta catccaggcc 1380gaactccctg cctacccctt cgtcaagcag cacgcttcac tattcaactt caatcagtcc 1440tacatgaacg agcttgaaac cacctacgaa gaatgcggct acaaggccta cttcgatgag 1500tactttgcct ttccaccaag cggcatccaa cccccaaaat acatgaacta ctccgagtgc 1560gacatctata acatgatcta ctacgaagcc tataacccga acccatgctt caatccctac 1620cgcgtcattg atgagtgtcc acttctctgg gacgtcctgg gctggccgac agacttggca 1680tacgagcctg cgcccaccac atacttcaac cgtatcgatg tcaagaaggc cctgcacgcc 1740cccatggatg tggaatggga gctctgcagc tacgacctcg tcttcgctgg aggcgacgct 1800gacccgggtc cggagcagca aggggatgac tcacccaacc ccaccgaggg tgtcctcccg 1860cgtgttattg aggcgaccaa ccgcgtgctc attgccaacg gtgactggga ctacctgatt 1920atcaccaacg gcaccctcct cgccatccag aatatgacct ggaacggcca gctgggcttc 1980cagtccgcac ctgccacacc gatcgatatt cagatgcccg atctccagtg ggttgagatt 2040tttgaggccc aggagggata tggagggctg gatggccctc agggggttat gggtgtacaa 2100cattatgagc gcggtttgat gtgggcggag acatatcagt cggggcataa gcaggctcag 2160gatcagggcc gtgtctcgta tcgccatctg cagtggctgt tggggcaagt tgagattctt 2220tagtctcccg ccttagatat aattgatatc acactgtaat gttccctcca aaaagcttca 2280tttattgata gtttcagtga attttgttac ttccagtaac aactctatta tggcattccc 2340tggtttttaa tgctgcctcc ttttaccgta gctacggcta tgactacata taacggactg 2400atttttctat ctcaacttaa ctttgtattg ccccctggat cctgactaca gaaaataaat 2460aattcaaatt gatatttatt ggccttttat tggcagcata atatctttct catataagca 2520cgcgagaaac ttgttcctca tcatactata tttatcccca cagctgatgc cgtgattcgg 2580taatgaagat ggagattatg cggattgcgc acttcataat caaacatcgt ataagtgtgt 2640cagtaatata tatctataat 2660242800DNAAspergillus niger 24aatgccgaag cttgacctga tacgacttca aggtatcgtc accgacaatc gttatcatca 60cgctacaggc ccgcagtttc cgcttgaatt cccgcattag gaaatgagca tcgcattcct 120cttcccacga ggtctctttc cgagggcagc cgctgcaaca tcattgggat catgcttggt 180tctcctctcc catagctgtc cgcgagcttc tcattggtac ctcttcgcta cctcgttgca 240tcctattcgc gcatggcccc gccagagatg tttctgcaag gtcccatcac cttgccgcgt 300tgctattccc cgccctcgag ttcccgacaa gttactttgt gtcagtggct gagaagcctg 360gttctgagag tgtactcaga caatcatatg gttccctcca tgtgctacgt cgtcctagcg 420tcgctgcact acatcatcgt taggcagcat ggaactggca cccgcacata aagcccccga 480cacccccatc gataggctcg gtgttcgtgc acgcctgtcc actggcccct cccccaaagg 540cccttcatca gtatgctgtt tcgcagtctg ttgtcgacgg ctgtcctagc cgtctcgctg 600tgcacggata atgcttcagc tgctaaacat ggtcgatttg gccaaaaagc tcgcgacgcc 660atgaacatcg cgaagcgttc cgctaacgcc gtgaaacact cgttgaagat ccctgtcgag 720gactatcagt tcttgaacaa caagactaag cgtatgtatc tcagttcgat attgaacgat 780ggctgatttg cttccgtcgg acagcttacc gcgtggaaag cctgcctgat gttcacttcg 840atctgggcga gatgtattcc ggcttggtcc ctattgagaa gggcaacgtg tcacggtccc 900ttttctttgt cttccagccc actattggcg agcctgtgga tgagatcacc atctggctga 960atggtggccc tggttgcagt tcccttgagg cctttctcca ggagaatggt agattcgtgt 1020ggcagcctgg aacctaccag cctgttgaga acccatactc gtgggtgaat ctcaccaatg 1080ttctgtggta agtgtgatat tactggatcg ctagttgagt ttacatgggc ggtatcgacc 1140taacctattt tttgtagggt tgaccaacct gtgggaacgg gattctctct gggtgtccca 1200accgctacgt ccgaggagga gattgctgaa gactttgtga agttcttcaa gaactggcag 1260cagatctttg ggatcaaaaa cttcaagatc tatgttactg gagaaagtta tgcgggccgt 1320tatgttcctt acatatccgc tgctttccta gatcagaatg atacagaaca cttcaaccta 1380aaaggtgagt tatacttcac caaagtaatc tttaactagg gcttgtactg attgtactat 1440ctaggtgcac tggcatatga tccctgtatt ggtcagtttg actacgtgca ggaggaagca 1500cctgttgttc cctttgtcca gaagaacaat gccctcttca atttcaatgc aagctttttg 1560gcggaactag agagcatcca tgagcaatgt ggatacaagg atttcatcga ccagtatcta 1620gtcttcccag catccggtgt ccagccgcca aaggctatga actggagcga tcccacctgt 1680gatgtttatg acatcgttaa taacgccgtc ctggatccca acccgtgctt caacccctac 1740gaaatcaacg agatgtgccc cattctctgg gacgttcttg gattccccac cgaagtcgac 1800tatctccctg cgggcgccag catctacttt gaccgcgctg atgttaagcg tgccatgcac 1860gctcctaaca tcacctggtc cgagtgctcg gtggagagcg tctttgtcgg gggcgacggc 1920ggtcccgagc aggagggcga ctactcggcc aaccccatcg agcatgtctt gccccaggtc 1980atcgaaggca ccaaccgagt tctgatcggt aacggtgatt atgacatggt catccttacc 2040aacggcaccc ttctctcgat ccagaacatg acatggaatg gaaagcttgg attcgacacg 2100gcccccagca cccccatcaa catcgacatc cctgacctga tgtacaatga agtgttcatt 2160gagaacggct atgacccaca aggtggtcag ggtgtcatgg gcatccagca ctatgagcgt 2220ggtcttatgt gggctgagac cttccagagc ggacacatgc agccccaatt ccaacccaga 2280gtgtcatacc gtcaccttga gtggctgctt ggccggcggg ataccctgta aggcgggtag 2340gctaccacgg gggacgatgt cacgatgata gtcataagtt atgatctgta gatacgttgt 2400atgcgaatgt acatgaattg cttttactgg cagtctctaa agcaaaattc atagtagagt 2460actggcctac ttaccctcac ttcccctatc ttttcaacct gaagaccgga agaattgtaa 2520ctaacaagca taacgtagct gatttgaagc agagcataac acactctacc cctcggcact 2580tctacttatg acgctatttg actgctaact cgggtttaat cctgaagctg cagtccaatc 2640gtacattaaa ctcaatgtgc cttgcccagg aaacgatatt tgacttatat gatctgaaaa 2700tgaacaattg tccccgagag agagagagag agcgagcggt aaatacttag caagtcagtc 2760acgcagtatc ctccactaat gccgtaacac aggaaatgga 2800252165DNAAspergillus niger 25gaatcaggat ggaggcccga cggccatcaa ccgccgaaca tccggctgct cgaccgaatt 60cggagacatg gtcggagcta ggcgggaata gccgtccaaa gtcacgatag gtcgcttgta 120ctgtgtagaa gtcagaccct ttggatccag cgttcgttgt gaatggctcc acgcagcctt 180tgctttgacc aatttggggc tgagtcactt ggtcgatgat gactggctat accagtgcaa 240agtgtgagca ccatgcttac actattgcct tagcctggcc gttgaagctg acatgagagg 300aacaggcaga agagaaatgc tgccttgcct cttgggggcc aatttaacct ccccagactg 360cggcacatcc gtcttggact tgtgcttctt tgcaacttac gttataacga gtctgtgaac 420aggaaaacag acgcccggtc agtcaagatg aaaggtgcgg cgctaattcc tcttgcggcg 480ggcattcctt ttgcccatgg cctgtctctc cataaacgcg acgggcctgc cgtcgttcgt 540atgcccattg agcgcaggag cgcccagtcc ttgcagaaac gagattctac ggtcggtgtg 600actttgcaga actgggtatg ttaagctata cggccgtgaa gtatagatca tgctgacaat 660cgctaggatg cgacctatta cgcagtcaac ctgacgttag gaacacctgc gcaaaaggta 720tcattagctt tggacactgg cagcagcgac ctctgggtga acaccggcaa ctcaacttac 780tgctcaatcg acaatctatg caccccttat ggcttgtaca atgccagcga atcgtctact 840gtaaagaccg tgggcacaca cctcaacgat acatatgcgg acggcacaaa cctttacggt 900ccttatgtga ccgataagct cacgatcggc aacacaacaa tcgataatat gcagtttggg 960atcgccgagt caacgactag taaacgtggg tgaaccgttt gtccatgaat gatcgtcgct 1020gactaggtct actataggcg ggatcgccgg cgtcggttac aagatttcga cctaccaagc 1080cgagcatgac gacaaagtct acgccaacct ccctcaggcc ctcgtcgaca gcggtgccat 1140taagtctgct gcgtacagca tatggctaga tagtttggag gcgtcgactg gctccctcct 1200tttcggaggt gtcaatacag ccaagtacaa gggcgatctg cagactcttc cgatcattcc 1260tgtgtatggc aaatactact ccctcgccat cgcccttacg gagctcagcg ttgcgaccga 1320ctccaactcc agtagcttca ccgacagtct ccccctctct gtgtcactcg atactggcac 1380caccatgacg gcactgccca gcgacctggt caacaaggtc tacgatgcgc tcaacgcaac 1440ctacgacaag acatacgaca tggcctacat cgactgcgac actagagagg cggattacaa 1500tgtaacatac agtttctccg gggcaacgat caccgtgagc atgagtgagc tgattatccc 1560cgcaacggag ccggggtggc ccgacaacac gtgtgtcttg ggcctcgtgc ctagccagcc 1620gggcgtgaac ctgctcggtg atacattcct gcgcagtgcg tacgtcgtgt atgatctcga 1680gaacaacgaa atctctctcg ccaataccaa tttcaatcca ggcgacgatg atatcctcga 1740aatcggaacg ggaacgtctg ctgtgccagg agccacaccg gttccctctg ctgtctcttc 1800tgcaactgga aatggactga tctcgtctgg caccgcagtg cccacgctgt cgggtgtcac 1860aataactgct acagccacag caaccggctc aaccggcact ggctctagcg gtggttcgtc 1920ggctgaagcc acgagtactt cctcggaggg cgctgcggcg caagctacga gcaacccgat 1980gaacctgctc ccaggacttg cgggtatcgg cctacttctc gctctgtaac gcgattgtac 2040ctactcaaat agatatcacg acgagactct aatgtaataa tgtggtatac aataacccca 2100atatctacat ttccttaacc gtaaactgca tactctacac caaatccacc accaaaatac 2160atacc 2165262800DNAAspergillus niger 26gcccagccaa tcataagaaa cccggtcctg gcaaggtctt ggcggggatg gtgcaagcca 60gccaaacaac cggtttgttg gacgccctgc ggtacactga aatcttgggc tgttcgacaa 120aaacaaagca ggtaacacaa agatataata cggcggaatg ataggatatc cctgtcgatc 180agccggacag gatggcgcta gtgtcacctc cagcttcggc taccctcgca gcggacccaa 240tcagcgtccc tcccagcccc cgatacagta atggtatgca catcgcagtc ttaatcgcct 300gcagcggcag taatgatagt cctgccggtg aataataccc cataacaaac aaataaataa 360tactacttat ctctcctcgt ccctttcact ttccctttgc cgtcttcaat cccctcatct 420tggtctcttc ggcagccttt caccatgctg tcgtctctcc ttagccaggg agcagccgta 480tccctcgcgg tgttgtcgct gctcccttcg cctgtagccg cggagatctt cgaaaagcta 540tccggcgtcc ccaatggtga gttatagacc ccaattcttc attttgagcc acatactgac 600gtgattcctt cgaatactac caggctggag atacgccaac aatcctcaag gcaacgaggt 660cattcgcttg caaatcgccc ttcagcagca tgatgtcgct ggtttcgaac aagccgtgat 720ggatatgtcc acccccggac acgccgacta tggaaagcat ttccgcaccc acgatgagat 780gaagcgcatg ttgctcccca gcgagactgc cgtcgactca gtccgcgact ggctggaatc 840cgccggtgtc cacaatatcc aggtcgacgc cgactgggtc aagttccata ccaccgtaaa 900caaggccaat gccctgctgg atgccgactt caagtggtat gtcagcgacg ccaagcatat 960tcgtcgtctg cgcaccctgc aatactccat ccccgacgcc ctggtctcgc acatcaacat 1020gatccagccc accacccgct ttggccagat ccagcccaac cgtgccacca tgcgcagcaa 1080gcccaagcac gccgatgaga cattcctcac cgcagccacc ctggcccaga acacctccca 1140ctgcgactcc atcatcacac cgcactgtct gaagcagctg tacaacatcg gtgactacca 1200ggccgatccc aagtccggca gcaagatcgg ctttgccagc taccttgagg aatacgcccg 1260gtatgccgat ctcgagaggt tcgagcagca cctggctccc aatgccatcg gccagaactt 1320cagcgtcgtc caattcaacg gcggcctcaa cgatcagctt tcatcgagtg acagcggcga 1380agccaacctc gacctgcagt acatcctggg cgtcagcgct cccgtcccca tcaccgagta 1440cagcaccggc ggacgcggcg aactagtccc cgacctgagc tcccccgacc ccaacgacaa 1500cagcaacgag ccctaccttg acttccttca gggaatcctc aagcttaaca actccgacct 1560cccacaagtc atctctacct cctacggtga agacgaacag gtatgcacct cacctgaccc 1620attccatttt acatccctca cctctctcaa ccaaactaac aacaccaaca gactatcccc 1680gtcccctacg cccgcaccgt ctgcaacctc tacgcccaac tcggcagccg cggcgtctct 1740gtaatcttct ccagcggcga ctccggcgtc ggcgccgcct gcctcaccaa cgacggcacc 1800aaccgcacgc acttccctcc tcaattcccc gcctcctgcc cctgggtaac ctccgtcggc 1860gcaacctcca agacctcccc cgagcaagcc gtctccttct cctccggcgg cttctccgac 1920ctctggcccc gcccctccta ccaacacgcc gccgtgcaaa cctacctcac caagcacctg 1980ggcaacaagt tctcggggct tttcaacgcc tccggccgcg ccttccccga cgtctccgcg 2040cagggcgtca actacgctgt ttacgacaag ggcatgcttg gccagttcga cgggacgagt 2100tgctccgcgc cgacgttcag tggcgtcatc gcgttgttga acgatgcgag actgagggcc 2160gggttgcctg tgatggggtt cttgaatccg ttcctgtatg gtgtcggaag tgagaagggt 2220gcgttgaatg atattgtgaa cggcgggagt gtgggttgtg atgggaggaa tcggttcggg 2280ggcacgccta atggtagtcc tgttgtgccg tttgctagtt ggaatgccac gaccgggtgg 2340gatcctgtgt cggggttggg aacgccggat tttgcgaagt tgaaaggggt ggcgttgggt 2400gaggagggtg gtaattaagt gtgagatggg gggaaaggga ttttcttttc gatgtgaata 2460ttaggtgaat tgtgtggata attttcatac ataattaagt ctgcattggc agtgataacc 2520tggaagaaat gtctaatgag tgtgatttgt ttacttatgt atattgagta atggaatgta 2580gatgacttgt ctttgtactg tataacgaaa tgattatttg agtggagggt attaaagaac 2640tataaaatat atacaaaggt taacccatgc agtcgtaacc cataatgcaa agctctactc 2700tatctgtatc ggtagcagat aagtgtatgc aatctatctt tgttgatgat gcaatcaagc 2760gggcacacca ccagtgccaa acagctccat cttgatgcgg 2800272660DNAAspergillus niger 27ggagacagaa tacatggaat tgatgctcaa caacgacaag gagctcgcgt tccgtaatgc 60caagttcatc gcttagattg ggaggatcgg ccaggtctgt atataggccg cgatagaaca 120cgaaataaat gatttatgac tatttgcggg catgagccct cacgtagtgt gctatagacc 180gtagacttgg taaacattgc tatcgatccc ccccttcgta tattagtcat aattcttcct 240gatgtcaact ctcaaaacac agcattccac agcgttcata tgatgtcaat gtctcaatcc 300ctaacgtttt gctgaaacag gtacctcttg gttatttttc atatagtagg aaggtcgccc 360ttgcatgtgg tatgagacca ttggcggcat ctagcttgaa tggtactcaa tatgaccagt 420agtctccact tcagcagtgt gtttgtgata

gccaagacat cggcagtagt tcctgcagag 480cttctacacc tcttcatctt cacttcacca atccactctc tcactgctca cttctagttt 540cgcaacacta gagaatcatg tggctctttc tcgtgtgcag tatcctgctg ccacttggag 600tagtcaacgc acagtctcaa tacttcaaca acaaaaccaa aggtatacca catcgcgtca 660gtttgaatcc cactaacagc gctagaattc gtcgtcaatg gctctgctat tccttttgtc 720gatttcgaca ttggcgagtc ctatgcgggc tacctaccca acacgccttc tggaatctcg 780agtctatact tctggttctt tccatcttct gatcctgatg cgtctgatga ggtatgctta 840tcgccgtctc atatgcttcg cacggctaat aaacagatca ccgtctggct gaatggcggc 900ccaggatgca gctctctggc aggcatcatg ctcgagaacg gcccctttct atggcaacct 960ggtacctacc gacccgtgcg caacccttat gcctggaaca acctcacaaa tatggtgtac 1020attgatcagc ctgctggaac gggattctcg cttggcccgt ctacggtggt ctcagaattt 1080gatgtagcca gacagtttat ggacttctgg aggcggttca tgaaaacatt cgatctgcag 1140aatcgaaaga tatatctcac tggcgagagc tatgcgggcc agtacatccc atacatcgcg 1200tcgcagatgc ttgaccagga tgatgatgag tatttccggg ttgccggcat ccagatcaat 1260gatccctaca tcaatgagct gccagttttg caagatggta tgcctctgac acaggttatt 1320gcttactcct ctgacattga tgacttccag tgcctgcagt tgcgaccgtc aatcagcacc 1380gctccctctt tccctttaat gacaccttca tgagtcaaat caccaagctt tccgacgatt 1440gtggctacac ttcgtttctt gacgatgccc ttacctttcc accccgttct caattcccat 1500cagtgcccta taatgctagc tgcaacatct gggatatcat aaacaacgct tctctagctc 1560tcaacccatg cttcaaccgc taccatatcc ccgacgcctg ccccaccccc tggaacccag 1620tcggcggccc catcgttgga cttggtccga ccaactactt caaccgcagt gacgtccaga 1680aagccatcaa cgcgtaccca acggactatt tcgtctgcaa ggatggaatc ttcccgacgg 1740ccaacggact ggacacatcc cctccaagct ccctgggacc gctgccgcgc gtcatcgaac 1800agaccaacaa taccatcatt gcgcacggcc tgatggattt cgagctgctg gcgcagggaa 1860ccctgatcag tatccagaat atgacctgga atgggaagca ggggttcgag cgggagccgg 1920tggagccgtt gttcgtgccg tatggtggat catcgggagg aggcgtgctg ggaacggcac 1980atacagagcg tggattgaca ttttcgacag tatttagttc aggacatggt aggtccatat 2040ctcagtatgc gatgcagcgg gttgctaaca ggaatagaaa tcccggaata tgcaccgggg 2100gcggcatatc gccagctgga gtttttgctg gggagggttg cgaatctgtc ggtgggttga 2160ccggagacag caaagagaat gaagaaaaga aaaaaaaaaa aaaaaaacaa tatgaataat 2220tgcagacaat tattgagcag gtgcagataa cagagcagaa tggttgagct gtcagatcgg 2280ttgacttttc ggcaatgaga tttggggaag ctagctctga gattggtcct ccgccaaagc 2340tatcgcaatc atgatccaat caacactgca tactaccttg atcccctcgc tgtagacccg 2400tattgccgga caaacaattg actagatatg aactcttgat tataaaccaa tcaagacccc 2460cagtagcgca tattatcacc cccatacgtt catgatcggc agcctaatcc gaggtcggat 2520cgggaattcc ttcaaactct gaaaccgcgc tgggtccacc ccgcatcttc acagtaaaaa 2580tctaagattc ccctcaatcc ctgctccatc tactttcctc cctctcatac cacttttgct 2640ttttgtatag taaatatcca 2660281540DNAAspergillus niger 28taaacagaac taagcaaaag tccagatctt gtgtcccctt cgactaccaa tcggaacaat 60aggaattaac tattagcctg caactgtctg caccatcatg caacccctct cgttgtgatt 120gctcctgttt tacattcccc gagacatgct catctagttg caagccatct ctaacccacc 180tgcatgaagg gtgcagaaac acgaacagtg gcgtggtagc acacactctc tgcagtactc 240gatgccaata tttccaccag ctgaactaca atctccgcgt cagaattaat atataaccat 300caccaatacc ccttacatcc caactcagca actacagcaa tacttacacc tatcctccac 360aaccccacaa ctccacccca tcatgtccaa actctccgct gctatctcca aggtacttcc 420ccatatccac aacacccccc acaccatccc tcaaatctaa caacaataac aataacctct 480caccacccca gctctccctc tccaccatag ccaccactct gctcctcctt acccccccaa 540ccaccgccta cttctacaaa tatcccgccc tcttcgtcta caaagacacc aactgcaccg 600atatctcctt ctcacttgtc tacccctccc tgggtaactg caacggcgga tactacgact 660acgcgggctc attccagatg ttcaatatcg atgctgcgta tacctgtaat ggcagtgact 720cgacactgat gtttgagatg tataatagct ccggctcgga ttgtggagat gagagtgatt 780tgttgtttag acagccggtg acggaggagt gtactgttgc ggatgtggag agtccggggc 840cgttggagat gccggtttgg tttgagttgg ggtgtatgta attgattcgt tgagtcggta 900aggagggatg gacggggggt tatataggta gcttggtggg taagcactat tggggaattg 960tggtgggatg gctggtacta tgttgttcgg tgtggggatt cttgagggtg ggttagagac 1020taaagtgagt tgtctgaggc agtagtggat gacttctgct tctgtgatgc tggtatgtga 1080taaagttaat tacatatgca aatgtgcaat catagactga taggtggaaa cttgtctact 1140cgttgagata tatagttata ctggaaatgt tattcatcaa ggctgaatac aagtgtaacc 1200gtgcacagat tatctttgat actgtctatg ggctgtacga gcgtctctga ctcctacaat 1260gagttagcgg ctgcacatta ctatgaggac ctgtgaattc gacaccaaaa ataaccagcc 1320ctgcagccga ttacatctgc ctttccatct attttctgga gtcaagcagg tattccaaca 1380tactcttact tgcttaatac accaactttc atatatctac ccagaattac tcaatcgtga 1440tgtaggcact ggcaatcata gtaactatat ttcgtttcat tttatttgtt tgtacaattt 1500tttttttccg gtagtttaat cattccaatc aaagaattgt 1540292800DNAAspergillus niger 29acactttctt cgatgctatg tcccagccat ataaggttca attctccgac tcaagtgaca 60gaatcagcta tacacggttc actgcttctt atatagtaca tgaggattca ataaagccaa 120gttcagcaga gtcttggttc cagagcttga atactcggta gcattccagg gattgtgggg 180agacaatcca ggagcagcag ccatcatttg gtgcctgagg cacacagcac tgcctcgtct 240ccactcccaa tacttaccaa gtcacccacc attccttccc tctttcggcc tttctctttc 300tctctctcac ttctgctctc gtgcaccact tttcttccca ctcacgccat ccttctccat 360ccatttcctg ccaaactttt gtctgtcatt ttaggttttt tgaaggagat gactcggtga 420ctactcttca atcccggcgt actcaacatc cataatgcgt cacctcttat cactgctggt 480gcttctgatc gcatcggccg ccctggtctc cgccgtcccc gccggctcca ttatcactcc 540acaaccaccc gtcgagcccg ttcaccttct ctcttcccag ccctctgatc cccgaaggcc 600atggatccgc ctccgtgact ggatcatcga gtccatatgg ggcatcgaaa aacccgcatc 660tcgtcgattc ccactcaacg attccccgcg caatcgctct cctccctccc ggattctggc 720gcgctacggt agtgacgtcg tacttcgttt cagcctgcgc aatcacgatg aggccgaggc 780attggcccag gctgcagaca ttctattcct ggacgtatgg gcgtctactc cagcattcgt 840agatatccga ctggccgagg aagtcgtaag tggttcatcc ttccgtccat atctgcccgg 900ttgactgatg cctgatccac tgtgaccctc gcaacagatt ccctcattat tgggcttgct 960accaaattcc ctccagaccg catatactcc cctaatagac aacctggcag agagaatcta 1020tacgacctat ccatctaaaa agccgatagg acttgaagga caatctggat ttgcgtcctc 1080gagtcgacct gcgccaaagt tcggtgacct ttttttccac gagtatcagc ctttgtccgt 1140cattatcccc tggatgcggc tgctggcttc catgtttcca tcccatgtgc gcatgattag 1200cgttggagta tcttacgagg gtcgcgaaat tcccgccctc cgactgagcg caggcagctc 1260caccgcggcg tcaggccctc gtaaaacaat catcgttacg ggtggtagcc atgcccgcga 1320atggattggc acctcaaccg tgaaccatgt aatgtacacg ctcattacca agtatggcaa 1380atccaaggcc gttacccgcc ttctacagga cttcgactgg atcatgatcc ccacgatcaa 1440tcccgacggc tatgtttata cctgggagac ggaccgacta tggcgcaaga atcgacagcg 1500gaccagccta cgcttctgtc ccggaatcga tcttgaccgc gcctggggct tcgaatggga 1560cggcggtcgg acccgcgcta acccttgttc agaaaactat gctggagacg agcccttcga 1620gggaatggaa gcacaacaat tagcacagtg ggcgctcaac gagacacaaa acaacaatgc 1680cgacatcgtg agcttccttg accttcactc ttactctcaa acaattctct accccttctc 1740ctactcctgc tcctcgatcc ctccaacgct cgagagcctg gaagagctag gccttggcct 1800agccaaggcc attcggtacg cgactcacga aatctacgat gtcacttctg cctgcgaagg 1860catcgtcacg gccagtgcgg cagataacaa ccccgggcgg ttcttcccca ttggtggcaa 1920ctccggtggc agtgcgttgg actggtttta ccaccaagtg cacgcgactt attcatacca 1980gatcaagctt cgtgatcgcg gaagctacgg gttcctcctt ccgtctgaac acatcatccc 2040caccggcaag gagatctaca atgttgttct gaaattggga tccttcctca tcggaggcga 2100ctcatttgac gtcgattggg aatcagaact cttcgatctg tcaaaggacg aatccgatct 2160ggatagccgc tattcaaaat ccaatgaccg ctccccggcg tatctacaca acgccaacgg 2220ccccctgccc aacattgacg aagacgaaga taaggaatgg gtaatggtgg aggaagaaga 2280ctacacagac gatgacgacg acgatgatga tgatgatgaa gaagaggaag aggaagagga 2340agatacatat tgggccaccg aacacacata cgaatttcgg cgacgacgct gatgatggac 2400aaactaatca accctattta tatgacaccc tcgcccatat actctccttc tgatgacgat 2460caataatgac taatgacggg tttgcgggag tgattgacgt gtttatcatg ctctgcttct 2520cgattctttt tattatttta gatactgttc ccttcaggtg cctatagcct atagagctta 2580ggggtattct ctacataatt aaatacagag taattcaatg aatcgtccta tcaaataatg 2640gacccgagta actaactggt gtttcattcc ttccgtactg tacttaatct gtaaggaatt 2700gaaagctaag cctcataagc tacttcaccc cactctttac ccaggtgcag tgtatcatga 2760tcatcgtcat acattcattc gttaggtatc tttccgatgc 2800302380DNAAspergillus niger 30cccgcctgta caaggctcat tgagcgacct ttatttctat gaaggcttct tgcagtgtag 60agccgctgtt tagaactcgg aaataggcgt gcatagtatg gacccaatca acagagttaa 120tctatttact ctaacgccta gcaagcaatc agtgcccaga ggaagctaac ggatggctgg 180ccaagctgcg ccagaaacga aatgagtccg taataccatc cctgcatgct tatctgtatt 240ctgtgcatgc atgatgcttt cctcatgggg cattacccag tagtccgaag acgcaatgtg 300accatctgac tgagttttaa atatactgtc caagtgcctt ctgacccggt ccccgcttga 360tggcaatcaa caaaaggtga atgtgactga aaggcgcggt ccagacaaca ggacttagac 420tttgttgtga gactataaaa ggatctaact attgcactac tgaaatcaag tattctagtc 480taccattgac atttctcccc tttcggtggc tactcgctca acatggcttt cctcaaacgc 540attctcccgc tgctggccct catcttacct gcagttttca gtgccacaga acaggtccct 600catccgacca tccagaccat cccggggaag tacattgtta ctttcaagtc cggcattgac 660aatgcgaaga ttgagtctca tgccgcatgg gtaacggagc tccacaggcg cagcttagaa 720ggccgcagta caaccgaaga tgaccttccc gccgggatcg aaagaacgta cagaattgcc 780aattttgctg ggtacgcggg gtctttcgat gagaaaacta tcgaggagat ccgcaaacat 840gaccatgttt gtgtccacgt atcctagacc gtatggtttc gactaattgc tgtacaggta 900gcttatgtgg aacaagatca ggtctggtat ctcgatacgc tagttaccga aaggcgagct 960ccttggggac tggggagcat ttctcaccgt ggtgggtcta gcaccgacta catctatgat 1020gacagcgctg gggagggtac atacgcttat gtagtggaca ccggcatctt ggctacgcat 1080aatgagtttg gtggtcgtgc tagcctggca tataatgctg cagggggtga gcacgttgat 1140gatgttggac atggtacaca tgtagcaggg accatcgggg gcaaaacata cggggtttcg 1200aaaaacgctc acctactgtc cgtgaaggtg tttgtaggtg aatccagctc gacatcggtc 1260attctggatg gcttcaattg ggccgccaat gatattgtga gcaagaaccg gaccagtaag 1320gcggcgataa atatgagtct tggtatgtgc gccctctctg gggatctaat cccgctaacc 1380gtgatgcagg tggaggctac tcctatgcgt ttaacaatgc agttgagaat gcttttgacg 1440agggtgtgct ctcttgtgtt gccgctggaa atgagaatgt aagctctgct gaactgtcca 1500ccattgagct aaatttagac taatgttttg cagagagatg cagcacggac tagcccggct 1560tctgcacccg acgccattac tgttgccgct atcaacagaa gcaatgcccg tgcgtcattc 1620tcaaactacg gctctgtggt tgacattttt gccccgggag agcaagtact ttctgcatgg 1680accggctcga actcggccac caacacgatc tccggcacgt ccatggctac accccatgtg 1740acaggtttga tcctctattt gatgggcttg cgggaccttg ctaccccagc ggctgcaacg 1800accgagctca agaggttggc tacgcggaat gctgtcacca atgtggcggg tagccccaat 1860cttctggcct acaatggaaa cagcggcgtg tcaaaagggg gtagcgatga tggagatgag 1920gactaggtgc gtaacatgag tgaatatggc ttagaatagt ggggatcgga gagtagacta 1980gtttatatgc gaaataaagt gtgtatcagc accctggcct gttcatgtaa gtcggcattt 2040tcacttttgc cgacaccgca aatatgctgt gcttgaggct gttgcctccc cagccagcct 2100tcccgagact gaaactcaca catccattgg atgtataaag ttctgcacat gcgaaatgcc 2160gctgccgttt acctcccgac gtggtaccgg accgaaggca gacacagatc atggaccgct 2220ataccgcaca gacaacttgt gctccttact gaaagtacca ttccacaggt cattgcagca 2280tgatgagtga tgatgtactt ctccccatca agaaccactg gcggtggttg gaatgaatct 2340agatcaaaga gatcaaccgc ttccccggac agatcaggcc 2380312441DNAAspergillus niger 31aaacgacgtt ttaggtcaat actgaagtcg ttgaaaacgc ttgattcttc gctatctagg 60cgcgctcgga ggagcagttg aagttacgga gttcgggtca cgtgacctcg actactagta 120atctactgag attacgttcc aacataattt catcaggaag aatgcaaagg ccccagagaa 180ggagaatttc acgatcggtg aaaacgacca agcagcatca catttgaatg aaactacatt 240gctccgtgtt tattccgttt ctctctcttc tctctatcta ttgcttctct ttggctagac 300ttcaccaact aattaatgct tacacgatga tagctgcatc cattgaatca aactgacccc 360gcaaagctga ctgaaccaac ccctccggtg ctgttgctac tgccagtttg aattcaatat 420cctataaccc accctgctca atgatcaccc ttttgtcggc cctgttcggc agcgtagtat 480atgccgctac gcagaccgtg ttagggccag agggggctga tccctttacg gtgtttcgca 540gcccacactc accggcattt tcaattcgca tccaggagca gaatgactcg atctgtgatg 600ctcgttcacc ccaattcact ggttggctcg acattggccc gaagcatctt ttcttttggt 660attttgaaag ccagaatgac cccttccatg atcccctaac gctatggatg actgggggcc 720caggagactc gagtatgatt ggacttttcg aagaagttgg cccttgccgg attaatgagt 780ttgggaatgg aacagatcac aacccctggg cctggaccaa gaattcatca cttctttttg 840ttgaccagcc agtcgatgtc gggttttcct atatcgatga gggctatgag ctgcctcatg 900actcacgtga agccgcggtg gacatgcatc ggttcttgcg attattcata tccgagattt 960ttcctcacaa acagttcctt cccgttcacc tttccggtga atcttacgca gtaagataga 1020agccgccccc agaaaaagct tgctcagtgt tctaacaatt accttgtgat acactgtgta 1080gggccggtac attccttatc tggcgaccca aatcttggaa caaaatgaac tgtataaaga 1140tagccccagg ataccgctga aatcgtgctt ggtgggtaac ggattcatgt cacccaagga 1200tgcaacgttc gggtattggg aaacactgtg tactactaac tcaggagtcc catctcctat 1260cttcaatgaa actaggtgcg atattatggc ggcgaatatg ccgcactgta tggatctata 1320tgacatatgc attcaacact cagaccccgc gatatgtcat gcggcccagt ccgtctgtta 1380cgatagtgtt gtagggtagt atgataacga ggccggcgct gatggccgta acagatttga 1440tagtgagttg ttatcatcag aggctcatgg ccaaattatt gctaaggatg acgacagtca 1500ctgcaccttg tgagatcgac gaaatgtgct atatcgaagc ggctctaatt gagagatatt 1560tgaattcgcc atctgtttgg gaggccctgt cgccaccgca acaggttacc gaatacaaat 1620tcgtcgctac ttctgttatt gatgcatttg ctcaatcagc ggacggcatg gtgtcgagct 1680cgaagcagat cgctttctta ctcgcaaata atgttgactt cttagcgtat caaggcaacc 1740ttgatctcgc ctgtaatacg gctggcaacc tacgttgggc gaactcgctt tcttggaaag 1800gccagacaga atttaccgca aagcccttac ttccgtgggt ctcgatcaac tctgggagcc 1860aggaacctgt ggggagtgcg aaggaaattc aggtttcggt cggtgaaggg acggacgaaa 1920cgtcacgctt tgcctttgtg actgtggaca acgctggaca cctggtaagt caaagtaaaa 1980ttaggagaga ggggtttaat gatccagttg gctaacgagt agtgttggta ctatggtagt 2040tgccccaaga tcggccggat gtagcgcttg acatgatgat tcgctggatt actggggcat 2100cctttgttta acaaggaaca gttgcgggac tcaaagattt caaactgacc tactccttac 2160cttttatgaa atgggcccgc tgcctaggtc aaacaagggt gctcgggcaa acaataccag 2220ttttggacta ggggtccgtc tgctttcatc agcccttcgt agcttggact tttgtccatg 2280tccctgctgc ctcggtccat cacacgcccg ctccccccat ttcctttcct tcccttctct 2340tttcgttcta ttatgcttga gtgcccgatc ttccctgcat gctatgccta tttcagtgta 2400cgcagtttgg gtttttgtcc gaggaagaca atcatccatg c 2441323500DNAAspergillus niger 32gtttgttgtg gttgttgttt ggggtcccat ttgcaatccc tgaaccggac cctgtcaatc 60cctcccaagt ccctcgttat cttccgcctt ttccaccccc tccacacttt atttttccat 120ccatcatctt ccagtgcctc aatccaaatc actgtcgttg aatatagatt cgcatctgtt 180ttccgtacgt gtatttgttt actttcggga gggagattct cgccgttcat tccagatttc 240cgcccgtccg ccaaggcggc tgcgcctcca gccaagccaa aacctccttg gatcgccagg 300tggaaagaat ccctttcact cccccgtcga gtgagtctgt ctcactgctc cctccggtcg 360ttgcgcgcgc tctctctttc ctctccacac ctccagtata cttcctctgc gggtgtgtga 420gagactgcga cgatccggag aagaataaaa ccctccagtg cagcttaatc tccggagtga 480tccgtcatac atgaccggct cccgagccaa gatctcgact gggtccatcc agtgaaaggg 540aactcaatcg tttgcacttt tcgtcgctgc ctgatgctgt ggaccgaagg gctctgttga 600accctgactc tccggatctc tcggtgttgt tttgatgcca gcacgctcgt tccacactca 660cctttaacct ctcccatcgg ctgtcttcac tcgctgacag caatgcggtt tctcacttat 720tccctgccct tcattgcaag tgctatctcg ctctttgggg tcaatgtaca aggttagctc 780ggcgacatcc ggcgcataga tttgttctaa ctggatcaaa tacagctcga tcacaagctc 840caagtgccat ccgtcatgtg tcgacgcttg accagcccac catcaagaca ccctcacagc 900gggtcgatca ccttgaccac tttgacatca ccttcaatat tcatgacaag caccagcgga 960taaagctgga gctggagccc aaccatgaca tcctggcgga agacgcatcc gtacagtatc 1020tcgacgcgga cgggaacgtg cgacggcacg agcccattgc tccacatgag cataaggtct 1080tcaaggggag gagtctactc gggcgaggaa aaggcatgtg ggatccggtc ggatgggcgc 1140ggatctactt gaagcaggat ggctcagagc cactatttga gggagtcttc agtatcgacg 1200gcgacaacca tcacgttcag ctgaaatcgg catacatgga gaagaaacgc cccgtggatg 1260tcgaccttcc cgactcagcg actgactata tgatcttcta ccgggattcg gatatggtgc 1320gtctacatac ggaactcaag cggtcgtcgc tcggatcgac ctcgtgtcaa gccgatcagc 1380tcggcttcaa cactaacccc aaccaccctg tgctacaacc gtatggccag gcagagaccg 1440atacgtgggg agcaatttca ttgaactcct tgtttggact caacaagcgc caatccgata 1500tcggaagtgt gtctggcaat gcgggcggag tcaatctggc gtcgaccatt ggtgatactt 1560cgggctgtcc gagtacgaag caagtagctt tgattggtgt tgcaacggac tgcgccttta 1620ccggctcatt caacaacgag actgccgcca aggaatgggt catcagtact gtcaacagcg 1680cgtccaatgt ctacgaaaag tccttcaaca ttacgattgg gctgcggaat ctgactatca 1740ccgacagctc atgccccgac aacccgcccg cggccacggc atggaacatg ccctgctcca 1800gcggcaatct cacctcccga ctggatctgt tttccaagtg gcgcggtgag caatcggatg 1860acaatgctta ttggaccctg atgagcgatt gcgcgacggg caacgaggtc ggactgtcat 1920ggcttggcca actctgcaat agcgatgctt cttcggatgg ctcgagcacg gtcagtggaa 1980ctaacgtcgt cgttcggtct tccggctcgg attggcagat ctttgctcat gaatctggcc 2040acacctttgg cgctgtccac gactgtgact cccagacctg cgcggaggat ctcgaagcct 2100cgtcccagtg ctgtccgttg acctcgagca cctgcaacgc caacgggaaa tacatcatga 2160atcctacaac tggaacagac atcactgcgt tctcgcaatg cactatcgga aatatatgcg 2220cagccctggg ccgcaacagc gttaagtcca gttgtctctc cgccaaccgc gacgtcacca 2280cctacactgg cagccagtgc ggcaacggaa ttgtcgagtc cggcgaagac tgcgattgtg 2340gcggggaaga tggttgcggc gacaacaact gctgcgacgc gaagacatgc aagttcaagt 2400cgggagctgt gtgtgatgac tccaacgaca gctgctgttc aagctgccaa ttctcctcag 2460ctgggacggt atgtcgtgcc agtcgcggcg actgcgacgt ggcagagacc tgcagcggca 2520actccagtac ttgtcctacc gactcgttca agaaggacgg cacgagctgc ggcagcagtg 2580gctcgggact tgcctgcgct agtggccaat gcaccagccg cgactaccag tgccgcagtg 2640tgatgggcag tctcctccac agcaacgaca cctacgcctg ttcctccttc agttcctcct 2700gcgaactggt ctgcacctcc ccgaagatcg gcacgtgcta cagcgtcaac caaaacttcc 2760tcgacggcac tccctgcggt agtggcggct actgcagcaa cggcgactgc aagggccaaa 2820acgtcgaatc ctggatcaag aaccacaaag gtatcgtcat tggtgtcgcc tgcgccgtag 2880gcgccctgat ccttttggcc ctgatgacct gcatcgtaaa ccgctgtcgc cgggctcgcg 2940cgccaaaacc cgtcccgcgt ccagtgcctt acgggccgtg gcccggcgct aggcctcccc 3000cgccgccgcc catgaaccag tggccggcgc gaggctatca aggcttaggg aatgagccgc 3060cgcccccgta tccaggtgta cctggtcagc cagtaccgca acatatgcct ccccaggggc 3120ggtacgcttg attgacgaga cttcttctgt gcttctttcc atgcgatata gtatgcatta 3180cgattcttgc agcactagca ttacaaatgt gacgattact tcattgatcc tttattgacc 3240ttacattctt gtcttggagt ggaggcgtgt tctagagttt tggtttgatg ctgaattgtt 3300cttttctata cgggggtctg ggcgtttcgt gaattgcagt acttacaatc caggggtgca 3360atccccaggg ggttggttcg cgtcttcttt ccctttcttt gcccatatta gacggggccg

3420tgggatgtat ggtcggggtc tgatgtatgt attcctgccg tgtataatga acttttccgt 3480cataatatat tgcttcttgt 3500332520DNAAspergillus niger 33ttgatgcata atgctttcct tcagaggtaa tacttcgagg acggctatga agcgtatgcc 60acatacgatt ggtatttgac gatatttgtc atgctataca tgaaatttac atattgtata 120tagtgtcatg ggtttgaata aagacatatc gatgtatctt aatagcaggt caattgatga 180cgctcttgtt gctccgacga aaagcgactg catcgggccg atgcgggtcc agggtcgtcc 240ttatcaacgc cccgtcagca ctaacagttg acatgtttct ccaggtcggc tagaaccgcc 300ttttcgcgag aaacgcgtgc tatcgcgagt gcagggcaat tgttgcctag cagtagctaa 360agcctgagtt ccgtgatctt cacttctact tcttcttctt ccctgctccc aacccattac 420tctgcacccc acgcccaaat gcgtttccta agcagtgcag ccctattcgg cctggcgtat 480gcctccaccc aggcggtcct ccagccagag gaaccatccg acttccgtac attccacagc 540ccatattccc cgcaccactc gatccgcatc cgccagcaga atgaatcaat ctgcgctgcc 600cattccgccc aatacaccgg ctggctcgac atcggccgta aacatctctt cttctggtac 660tttgagagcc agaatgaccc tgccaatgat cccctcactc tctggatgac aggagggcca 720ggggggtcca gcatgatcgg tctgtttgaa gaagtcgggc catgtctgat caatgagtac 780ggcaatggca cttactacaa tccgtggggc tggtcccgga actcctccct actatttgtc 840gatcagccag tcgatgtggg attttcgtac gtcgatgaag gagaggacct gccgggcgat 900tcgcatcaag ctgcaattga catgcatcgg ttcttgcagt tgtttgtctc ggaggttttc 960ccgcaattgc agactcttcc cgttcatctt tctggtgaat cgtatgctgt atgtatcttc 1020tctaggtcac ctgagctaag actaacttcc acagggtcac tatgtccctt acctcggcag 1080tcagatcgtc caacagaaca agctctatcc cactgagccc caggtccttc tgcactcatg 1140tctcgtaggc aacggctact attctcctcg cgacactacc tacggctact gggaaaccct 1200ctgcaccact aaccctggag tccccgagcc cgtcttcaac cgaaccagat gcgacatcat 1260ggcggccaat atgccgcgat gcatggaagt atccgacgta tgtgttcgga accccgatcc 1320agctatctgc catgctgcgt cggaggtatg ctacgagggc gtgatcggat ggtatgatga 1380cgagtctggt gaaggtggtc ggaataggtt tgatagtgag ctttgcccca tccagttgtc 1440ccctgtcagc aaatctctgc aatttactga tatgaaacag taaccgctcc ctgcgccctt 1500gacggcatat gctacatcga ggccgctcgc atcgagcagt acctgaacac acccgcagtt 1560tgggctgctc tatcaccacc caaagaaatc aaagaataca aggttacttc cgacaatgtg 1620tcgcgcgcat tcgatctcac ttcagacacg atgacgccag cgtctgagca agtcgcgttc 1680ctgcttgcga atcaggtaca tttcctggcg tatcagggca atctcgatct ggcgtgtaat 1740acggcgggta atctgcgctg ggcgcattct ctgccatgga gaggtcaggt cgagttcgcg 1800tcgaaggcgc tgcggccatg gagttgggta gatgtggtat ctggaaaagg tggagtggct 1860ggaacgacga aggaggtgag agtgaaggtt agtgagagta cggataagga gtcgaggttt 1920gcgctagtta cggttgatgg ggcgggacat tttgtgagta tccctttcgc cttgtgggat 1980ccaagtatgc ggattactaa tggtctatta caacttttac agcttcctca agatagacct 2040gatatcgcgt tggatatgat ggtgcgctgg atatccgggg catcgtttac tgagtgaagc 2100atgaatgtcg cagacgatgg gataccggca tatttcacag gtttggtgta atatatgtct 2160tgtagctgtc ttcagcagta tttacaatat gctgctgcct tctctgattt gggtataatt 2220atagtttaac acaatcaact gcatcggcag agatggatgg gcttgatttc gcacccgcag 2280cagcgatgaa tttccgtcta accgagcgaa cggtagcgga cactaacact gattgtattt 2340acaaccctgt ttctttcctc ttgatttgag acagaagtat gtaagctagg cgtagtagaa 2400tacatttgtc atctacttct actgagttgc ataacgtaag cgactattgg ccgctacctt 2460gccccagtta gttagttagt agtagtgggt gccgaagtca gcacacattt ttcagccctc 2520341721DNAAspergillus niger 34attgatacga ggcgtttgta ggtggcgttc ctgaagagga tctgataccc actggttttc 60ccagtgggcc tatgttttcg tgatagtttc ggcatttcta tccatctagg aaaattttga 120tggcacctgc tagtcgatgt gcccttcctg atggagcgat ctcaaagtgt caaatttctc 180ggcgaaacgc gtctacccct tctttgggat aattccctgg tatgcagcat tcctgacacg 240agggattgtt tgggattccc cagattccac gtagcggttg gcaatgatgc ttatgatttt 300ataattctca tcttgtcctt tgtcctcggt gcagtagaga atcttcactg cccgatacca 360atatgacatt gttactcaac ttccacgcgc tctttacagt cattcttgtt gccaatcttt 420caaccagatg cagcgcactg ctctctggac gtgacttttg ctccacgcca gcgcccggtg 480agtcactccg agcggagcat aggaggctgt atgatgtaca ggcccaacgt gacagcaccg 540ccgaggagag ccgggaggtg gtgccttgga ttgaaatcga gacatggttt catattgtaa 600gcagcaatga agcagcaaac acagtatcag acgacatgat caccagccag gtccgtcacc 660attcaacttt tgacccatgc ctgcgcaatg tcgtgttttg gactaacaag tcctagcttt 720cctatcttca gaaggcatat gaaagtgcga ctatcaccta tcggttggag ggcataactc 780gtcacataaa tgactcgtgg gcgcgaaatg atgatgaact ggggatgaag aatgccctac 840gaaggggcaa ttatggcaca ttaaatgtct atttccaaac agatctccag gcgtcatccg 900acgagaattc tcgggactat ccaaatgacg gtaaccgacg aacagatgtg tcagatcaat 960catcatcaac tgtcctaggc ttctgtacgt tgcctgaccc gagtgtgaat tccagcagcc 1020ctcgttccag ctacatcaag gatggttgta acgtgttagc ggatatcatg ccgggtggta 1080gtttagcgca gtacaacaaa ggcggcacag cggttcatga ggttggccat tggaatgggc 1140tgctgcatac gttcgaaggt gaatcgtgct cccctgataa tgaaggagat tacattgatg 1200acaccccgga gcaatctgag cctacgagcg gatgtcccgc cgagaaagat tcatgccccg 1260atcttcctgg ccttgatgct attcataatt ttatggacta ttcatctgat gactgttatg 1320agagttttac tccagatcaa gcggagagaa tgaggagtat gtggtccgct atgcgggaag 1380ggaagtgacg gacggactcc aagggtatat aatttgcaca tataccagct atagatagac 1440aactatggta gcacgaatat tgatgtcaac atcttggtct ttcaattccg tgggaattga 1500ctatcacaat tcatgaacct tttgtagaat ttgtgtattg gagagcgatt gatgcaaact 1560agacactcgt tcgaaattca cagctagctg tcatgtggaa tgcgaaatca gatcatcgct 1620tgcgcttttt tccacgatct tcatcgtcca ggccactttc cctgtccttt ttctttgcct 1680ttgattcgag ttcgtcccag tcttcaccac tctcttcgtc g 1721353550DNAAspergillus niger 35cctatcctct gctccgcccg gtggagagga tctattgacg ctatggttct tgagcaatgg 60cgacaagacc caccagtgga gataagagga ccgaaactat ggcttgttca aggtctgctt 120cgataaaccc ctcatcacga taaaccaagt tgggcttact aacaaggcca atccttcaac 180aatctcatcg cacaacgacc caaaatccag caaggcacga tccaacatac cctgtaatga 240caggaaacaa attatcactc ctctgggtgc tgatgcagac caactcagta ttccgcgtgg 300attgtccgac tccgaagaca agctttggtg tctggtgctg atcgtccgtc gtggagccac 360cactagtgga ttgaattacc cacacaccca ctacttatac tctttacgct gtctatcatc 420ttcgtgctga tcagggggtt attttcttgc gctatttggt ttcccactat gcttctgttt 480tgcagggctg gtcataacaa tttggtagtt tgggttgggt ggcttgttat ggtcgatgtc 540ggggaggggt tcaccgttga acaatatgct tgtcgttagg taggttgaac tgatgcttgt 600gttttgtttc caggcgccct ggacagcctt tggctatcag caatagctca atagctggtg 660ttttgctcgg acgcgggtct tggtcgggtt gacccagtgt gatctacgct agacgctttc 720ctgattggcg atggatgtca cgcctcttat cagggtttgg tgatcatatt tagcctacat 780aggcaggttc ccttccgctg ggtatggaag tgcaaacgcc agcgtatgga gagtgaagtg 840atgctagtca atgggatcag cagcgttctt gtcaactagc atatattccg acgtttccca 900ccgttcctga tgatggcttg catgccacgc ttgctctgtc gctgcgatca acatgcatgt 960ctcacttttc ctactcagtg ttacggcagc gtttgccagc ccaacacccc ataactatgt 1020tgttcatgag cggcgcgatg cattgcccag tgtctgggta gaagaaagcc ggctggacaa 1080aggtgcccta ctgcctatgc ggatagggct tactcagtcc aacctggatc gtggccatga 1140tttattgatg gaggtgtatg tgttccgact cctcaccaga accaagctga ttgtccaggt 1200ctcatccaca atcgtctcgc tacggaaagc atctctccag cgaggaggtg cacgacctat 1260ttgccccgtc gaatgaggcc gtcgagaccg tccgaacctg gattgaatcc gccggaattg 1320ctccaagccg catctcgcaa tcatacaaca agcagtggct acagttcgat gcccatgcaa 1380gcgaggttga gcagcttctg cagacggaat actacatcta cacccatgcc gacacgggaa 1440gttcccatgt gacatgccac gagtgagtcc attttctaca tgccatgaca ccgctaacca 1500gttaggtacc atgtgcccga aaccatccaa tcgcacatcg actacataac accaggagta 1560aagatgctgg aagtgcgcgg cacgccctcc aaaaagagag atgcagagaa gcgctctctt 1620ggcagtctgc ccccaatctt agcaccacta ccaatcaata tcacgaagat tttcgacgac 1680ccgctagcac actgcgatct ggcggtaacc ccagactgca ttcgaggtac gttcatccat 1740cccaattcaa gatttcacgc taaccgtcta gccatgtaca acatcaccaa aggaacaaca 1800gccacaaagg gcaacgagct cggcatcttc gaggacctag gagacatcta cagccaagat 1860gacctcaacc ttttcttcgc caactttgcc aggttcgatt actctccacc ctcccttaga 1920cacaactaac accaccaagc gacatcccac agggaaccca tccaaccctc gactccatcg 1980acggcgccac cgccccaaca gacgtcacca acgccggccc cgaatccgac ctggacttcc 2040aaatcgccta cccaatcatc tggccccaga acaccatcct ctaccaaacc gacgacccca 2100actacgaaga caactacaac ttcaaaggac tcctcaacaa cttcctctac gccatcgacg 2160gctcctattg caacgaaacc tcctctctag accctcaata cccagatccc tccccaggcg 2220gctactcctc ccccaagcaa tgcggcgtct acacccccac aaacgtaatc tccatctcct 2280acggcagccc cgaagccgac ctccccatcg cctaccaacg ccgccaatgc cacgagttca 2340tgaaactcgg ccttcagggc atcagcgtgg tcgtcgcatc gggcgactcc ggcgtcgcct 2400ccagcacggg cacctgcttt ggcgatgcag acaacgtctt cgtcccagat ttcccagcca 2460catgtcccta tctcaccgca gtaggaggca catacctccc cctaggcgca gacgcagcca 2520aggaccagga aatagcagtc acccgcttcc cctccggcgg cggcttcagc aatatctacg 2580cccgaccatc ctaccagaac cactccgtgg agacctattt ctccactacc agcgacgacc 2640tcacctaccc ttactactcc ggagtaaact acacagactt ctccaacaca gatggggtat 2700acaaccgcat cggacgagga taccccgatg tttcagctat cgcagacaat atcatcatct 2760acaaccaggg cgaagcgaca ctggtgggtg gtacgtctgc cgcggcgccg gcgttcgcgg 2820ccatgttgac gcgcattaac gaggagaggc tggcgaaggg gaagtccacg gtggggtttg 2880tgaacccggt gctgtatgaa catcctgagg cgtttaggga tgtgactgtt gggtcgaatc 2940ccgggtgtgg gactgatggg ttcccggttg ctggggggtg ggatccggtg acggggttgg 3000ggacgccgcg gtttgaggat ttgatggata tatttgtggg tgatgattga tggctgagac 3060aagatgtggg aaggtgtaat gaagatgatc ctatttaatc cggtaatcta ccacacattc 3120atattactag tttatagcct agtcagatat ataacattgt actactacta tagaggcgtg 3180tgatgcaaat gctaaaatat tgatatacta ttaagcaact acattatgat ctaaacttta 3240cagttcatag tacagaaagg ctttgatcag tcctagttca ataaaaggta tagactactc 3300actacatatt aaacaccaca actcgggatg cttggggtat agtgatctga gagtcgcggg 3360aatgcccaaa tgctctgttc gatcatatct tggttgatgt catgttggac gcattatatc 3420aaaagtcatc tagcgctttt ctgaaagttc tattatgaga attttgcttg tttatagcta 3480gcgggtggat gattaatttt gtatgagtga ttctatagac gttgatcatt tccatgattt 3540agaaactgag 3550362280DNAAspergillus niger 36ctgcctctca gcgaaaaccc caaaaccaaa catttctaga tcagacaatc aattgcggac 60tgagttccct gaatggtgga agatgccata ctgttagcgg ggactatttt tagcatgtca 120tgacttggtc ggcgtccgta catagaaggt tagcggatgt cttgatgatc acacaaaaaa 180gggataggat gaaactggat gtctcactgg ctatctcatt tgcccaacag catcagtcgt 240tccggcccgc tagttccacc acatgtcact tgtctcggat tattctcgaa ggtctggtat 300ttcaatgttc cacctggtcg ctctacataa atagaccttt acgccgtttt gttttcttct 360tcgttctacg tcgtttattt atccaaaatg gcttccaaga ccctcctact cattccggca 420ctggccacag ccgctctggg aagtgtattg gacctagata tcaaggttca aaatggctat 480gtatgtcaat gagaagctca gctccctgag aaatatctac taactcggcg aagaggacta 540tcgaggtaga ccttggaacc ccaggtggcc cgtttgattt gatgtacgac accggatcat 600caacactctg ggtgcttgat agcaattgta cagatgattg tccaaatgtt agcgggttag 660ttgattcatc ccaccattcc ttaagcctac actaatcacg agcgccaggt actcccgaca 720cggctacaac ctcacctcta ctggtgtcaa cttaggtgtc aacgacagca ttgcttacag 780cggaggcact gtcagcggct tcactgccac ggatattctc acggttcccg acaccaacgt 840ctcatatcgc cagagctttg ccgtcattac cgacagtacc tgggcggcct tagcagccga 900tgggttcatc ggcctggcat cgtctaccat cgcattcaag aatactacga cagccgtcga 960acagatgatg caggatggac ttttggatga acctcgattc gccatatatg caggttcagg 1020ggaatcgacc gtgaccaacc ctaatccgga gaataatggc gtgttcacct ttggtggcag 1080ccatgaggaa acctatgcgg acggggaact gcaatggatg aagatgctct ccccctttga 1140aatatacaaa acaaatctcc ttggaattca gggacacaac aactccgatg gccaggccct 1200gtcaagcgac gtcctgaact ggtacggcca ggttattttc gataccggta ggcattttct 1260accacactgt tttctttagc ttgctagact aatctattca acgtcgcagg tgcttcatcg 1320ataagcattc ccaacgacca gattgaggcg atgtatgccc taacgccttt ctcatacgct 1380gacatctcat ctggataccg acctctgtgc tccgatttca atgatacatg gtcgatctct 1440tttacaatgg gcttctatgg cgagggtgtc accttcaatt tgaccggtga tcagctggcc 1500gtgcctggct atcaggacga cgaccactgc ttccctccct tcaatccatg ggacagctac 1560aacacgatta ttggtcagca ttggttgagc aatttctatg ctgtattcga cttcggatca 1620ttcgacccgg agacatacga tatacgtgtt gggctggctc ctttgaagaa ggaatacctg 1680ccgagcgctt gacctaagaa cttctattcg tgtctttgag catttagttc aaacctcttg 1740ctcggacgtc aatgtttaag catgcgtaaa actatctact agaagttaat gttcatcgag 1800agttcatcgt ttaaataagc agcttatctt cattctttac agccactata cgcgacatga 1860caattgtttt atgggtcggt gcgataaagt ggccatctaa aggcaatagc aattaaaata 1920agccaggaga tggaacatga aagaatctta ctctttgtca tggcctcatg caactttggt 1980gcgggctgtc ggtgaccctg tggggcacat ctccggggag tggaggccgt taagcttcgg 2040acaacattat ttcttcagct caaccatgaa aaggttcggg gacctgcatg catcccccaa 2100gcccgcaagt ccgcgtcatc aacaaatatt gcgaagaaat ggtacgcttt agagccatgc 2160gggctatatt ttcggttcta tagattgtta gatataatta ttgcttgtcg aacccagatg 2220cagcattgat ctgttataat cctcatattc cgcgagtcac ttgattccgt gatcaagatt 2280372287DNAAspergillus niger 37tagttgaagg aggcttttgg ctttcttcct ctttatcttt cttctgttgt cagtgattct 60gatcgcagaa gatgtgcaca agatgaagac cgccccgagt catctatgga tactgaagag 120atggaagaga tctgacaacc aaggagtttg tattatccag ttccagtttc atgttttgcc 180tccgtctgat agttccacca aagatactgc cattttgtat ccgtagttag acggagacaa 240attgacaacg acagccttgg gggccaagtt cagacatact tccagccgca cgcatggatg 300tataccttgt tgctacgtga gcgtacgcca gcttatcgac ctattttagg acctgctccc 360acgtggagat tctgcagcaa acgcaggaaa caaggaccag aaattcgtca tcatcgtttc 420tccttagcaa tcggctagga tgtttccctg ctctcgtatt tggtctctgc tcgttgcagc 480cgccaccgct agtgctgtac ccaccagtct ggccaccacg cacctgcaat cggttgactt 540gcttctgact cgcagttctt acgggtttct tactgacata gcccttggaa ctccgggtca 600gagcctgccg tatctggttg actggacctg gaccggccac tatgtggtga ccaccttgtg 660ctacaacgat cccaccgcca cctacgattg tctcaacgtc gatcagaaaa ttttcaacca 720gactttgtca tccactttta tcaaccaaac tgaccagtat ggctatcttt actgggatcc 780caaccacttc tactttacgg agcccgcagc agccgatgtg gcgacggaca tgctgcgcat 840cggtcccacc gcggtgaaca ccaccatcca agcagccaat ttcgtcttca acgagactat 900tagcgcattc cctttctcgg gagtatatgg actctcacct gtttttcagg gtgacaatcg 960tgagttgttt ccccaccgtc ataaaactaa ttcatgttaa cacgaatcat aggatccgtg 1020caagcgtcct tctaccaagg atggaggagc ggcgcctggc actctccaat tgtctctttt 1080atctactgcc acgacaatgc caccaaagcg gtatgcagtg gttacgacgg ccttcagaca 1140ctaggcggat acaacacctc tcacgtccag ggagatatca cctggtacga catcattgtc 1200acggaggcga tcaacacgct ggactttgtc tatgcgccag ccgtgattaa ttattgggcg 1260ttgaacctca cgcgcttctc tatcggagac gaagagcaag agctcaacaa gaccactact 1320ctggatggaa agcaagccgc cgttgccgcg ttcgaccacg cttcgtatgg tcgcggtgcc 1380ccagtgtctg tgtacggtta ccagcgtcta gtcgagctgg tcggggcaaa agccgtcacg 1440ctttccgatc ctccaaataa cggtgagcag ggattctatc agttcgattg ccggaactcg 1500agtttactgc caccgctgcg gtatgagttt gccgggtcag agcgggcgtg ggagattgtg 1560cccgagaact atgtggaggt gctggcgaac ggaaccaata agtgcacctt taatgtacgc 1620accctgggag atggagcgat ggtaatggga aattttggcg agacatttgc cattgataag 1680tatgtcatgt ttgactttga gaagttgcag gtggggattg cagacttcgc gtggtaatgg 1740tataaggatg tgtgtttgaa catgtgcatt atctcgagtt tgactgaata gacggagaat 1800ccaagaccgt agatcatgat gctatctgct tgattatttt caatgtctct agtatgggga 1860aagtaataca tgtgataata tctccaaagt agtaattaaa agagaaaact aatcaccact 1920agtaattaat actgcaaata gcgctgttcc acattgagac aaccatataa taataagtta 1980gtggatatac ggaatattag aggtcatctt aataccatac tagtggatac aaccatccgt 2040acatacggaa taggaaggag gagcgagatg gtcatcattt gacactgagc atactgtgtt 2100ggcccagtca agctgttgta tgggggagct cctagtgtgc ccaaggctcc agcatcttca 2160ccttccgcaa cgactttact tagtttacat taggtgagcc tttctgttac atagttgatt 2220gaaagcctct ccccaattgt cttagcatga tagaggttac tcggagaacg tactaatcag 2280gaggcca 2287381950DNAAspergillus niger 38gatctttcta gagcattgtc ttgattgtgt cattctgtca ttgactccgg ctatgaaata 60ttattctcaa tctgcctaaa accaaattct actctatcac tacacatttg tatcacctga 120tctggctgag ataggagagt ccggcatctc atcgtctgca tcagacaatt gcgataaatt 180cattgcttgc acctgttatt gattcttcca agttatgcat ctcccacagc gtctcgttac 240agcagcgtgt ctttgcgcca gtgccacggc tttcatccca tacaccatca aactcgatac 300gtcggacgac atctcagccc gtgattcatt agctcgtcgt ttcctgccag taccaaaacc 360aagcgatgct ctagcagacg attccacctc atctgccagc gatgagtccc tgtcactgaa 420catcaaaagg attcccgttc gtcgtgacaa tgatttcaag attgtggtag cggaaactcc 480ctcttggtct aacaccgccg ctctcgatca agatggtagc gacatttcat acatctctgt 540cgtcaacatt gggtctgatg agaaatctat gtacatgttg ctcgacacag gcggctctga 600tacctgggtt ttcggttcca actgcacgtc cacaccctgc acgatgcaca ataccttcgg 660ttcggacgat tcttcgaccc ttgaaatgac atcggaagag tggagtgtgg gctatggaac 720tgggtctgtc agcggcttgc taggaaaaga caagctcacg attgcaaatg tcactgtacg 780catgactttc ggacttgctt ccaacgcatc ggataacttc gagtcgtacc caatggacgg 840cattctcggt ctcggtcgaa ccaacgatag ttcctacgac aacccaacat tcatggatgc 900cgttgcagaa agtaacgttt tcaagtcgaa tatcgttggc ttcgcccttt cacgtagccc 960cgccaaggat ggcacggtca gctttggcac tactgacaag gacaagtaca ccggcgatat 1020cacctacacc gataccgtcg gatcggacag ctattggcgc attcccgtgg acgatgtcta 1080tgttggcggc acttcatgcg atttctccaa caaatcagcc atcatcgata ccggaacttc 1140ttatgctatg ctgccttcaa gcgactcgaa gacgctgcac agtctcattc ccggcgccaa 1200atcttcgggg agctaccaca ttattccgtg caacacaact actaagctac aagtggcatt 1260ctctggtgtg aattacacca tctcgccgaa ggactacgtg ggagcaactt caggttctgg 1320atgcgtttcg aacattatca gctacgactt atttggtgat gacatctggc tcctgggtga 1380cacgtttctc aaaaatgtgt atgctgtgtt tgactacgat gagttacggg tcggatttgc 1440agagcgttcc tcgaacacca cctctgcgtc gaactctacg agctctggaa caagcagcac 1500ctcgggatcc actacaacgg gcagctcaac gactacgacg agctctgcta gctctagtag 1560ttcatctgat gctgaatcag gaagtagcat gaccattccc gctcctcagt atttcttctc 1620tgctctggcg attgcttcct tcatgctttg gctctagtta accgcatctt actcgacgcc 1680tgaacctcgg gaaacatatg cattatttac acatgctgct gatttgtatt tgcatatatt 1740cttcgagcct ggacggcgtg cgggtcatat taccttacat tcgaagtcct tctctaatca 1800atcaacattt attcttactc caccagttct ggctcgcaat taaccctgtc taagaaaaag 1860ttggtataga acatggcatc cactacctgg aacattcaaa gaaccttgtc cgggatcagt 1920gtgtatgact tcgggtacga ttctgacatg 1950392660DNAAspergillus niger 39accttctggg gtggattatc tgaagagatg aactgccccg cccaagtgca agaagatgat 60gcctgacagt tgatgcctga gggatgcttg tatcaggtga tcccggctat ggtggtctaa 120cccagttggg ctgaattgac cacatttagt tagtgtcagc cttaaacaga tgaggctttt 180cgcatgattc atttccaagg aacccaagga aatggtcaaa cagcaaagga ataatgaccc 240aacagttata cctagctatg cagcataaaa

gagaaaaaaa acttgaactg atacgagcca 300tcatgtaacc tccgtctctg gctcaattct ccatccaatc acaattcttc caagcaaact 360tgggattcgc cgggttctcg gcaaccctaa cctctaccag taaaggttga tccttccccc 420acccgatttc gcatggcttg gacccctgaa atatagttcc tctacgtgcc tgaatatgga 480gcacgttatt cgtctttcag ggtcttgggg ccttggcctt ggggctgcca agcgggcggc 540ggagtgtgcc ccgtggtgcc ctgttttgag cttggatgcg attactatca tcacttaata 600agagcaagac cctgcgtcga tattgacggt caatacactg acctcagaga accgtcgatg 660tgcctgattt cgctccatca aaatgacgtc ttctaccttg cgccttgccg tcgcgttggc 720tttgtcaact tgcagcagtg ccctatcgag ccagcgagat gattcacttg tggttccatt 780tccttttggc aatcttgagg atgtccatat tgccaagcgg gatagctcca agacagtaga 840agctcctcta gtgatatatg tcagtcagct ctcccactct ccatctatgt catcaactcg 900acaaccctaa caatcaacag ggcgacagct actggatgaa cgcctcaatt ggaacccctg 960cgcagtcact aagtttccta ctagatctta cgcgctcaag ggtcgagccc gcatacaccc 1020tcgatgagaa ttacgaatgt tctgacgatg aactctgctc cgaattcggc ttctacaaac 1080ccaccgattc atccacttat cagcatctca cctacacaca gagacacgat gcaggtgtcg 1140actactccta ccttgatacc ataactcttg gagatcacgc aaccgacaat gtcccactgg 1200acatgtatct tttgtcctac atttcctgtc agttccccct ctctccctta ccaccctatt 1260tatccatcat ctgaccattg tctaaccacc acatagacag ctccctcggt ctctcctccg 1320tcaacaccag cttcccctac atcctggtcg atcgcggcct caccacctcc ccatccttca 1380gcctaatcgg cgacaacgga aacaccacca cccccagcat catctttgga ggcatcaaca 1440cctccaaatt caacgggccc ctgcaagcct tctccttcgc agaccacagc atcaccaaca 1500atccattcgt caccgtcgaa gctgactccc tccaactaac caccaacacc aacgataatt 1560ccacctaccc tattccctcc tccaccccca tgatgctcag aaccgaagaa ctaatcacct 1620acctccccaa ctcgaccgtc caatccctct acaccgacct taacataacc atggacggcg 1680tgatctccac ttcaagattc tacggggtcc ttccctgcgc ccgccaggaa accgaatctc 1740acacaatctc tctagccatc ggcaacatga ccttctctgt gtcctgggat gagctcttcg 1800tcccgtggac gcgtgacgga ctatgcaagt tcggcattca ggcccaggat tcagattaca 1860aaactcgtgc ggagctgggt gttccctttc tgagacggat gtatgtcgct gtggattata 1920ataatcagtt tgtgggcgtt gcgacgctga aggatgatga tgatcagaat ggaggtgaag 1980atgagattgt ggagattggc actgggacgg cgttgcctag tgctgtcggg gattggccgg 2040ctagtgttac ggcgtatacg cctgctgctt ctacagggac ggcggctgcg acgttgacat 2100tcacgacggc gacgtctagc gggggaggtg tggtgccgac gggtctatca gagttgggta 2160gggcgttttt ggtgccgggg gtgctgggga tggctgtttt gcaggctgtt taggttagag 2220attgtggtac gattattctg taggttaaag atgtatattg tctgttattg tacttgatag 2280cttgatatgt ataatgaaag tagtatagtt tgaatttttg ttatacacca cgtgaaccca 2340ctggaccgtt gtctactgct cgcagtgagt gatatagtgt agacccgtat tactagtcat 2400gtaggaccct accttgatac cataacactc ggagaccacg caaccgacaa cgtcccactg 2460gacatgtacc ttttgtccta catttcctgt cagccccttt ttgaatgtac ctacatccct 2520ctaaactcta gtactatcac gaacagcaaa tgacattcaa tctattctat gcatattacc 2580cttctaacaa tacccagatt ctatcaaatc acgtgaacat acagccctcc caagtcacct 2640gacaaagcgg acaacaatgc 2660402501DNAAspergillus niger 40tgattcccaa atcgcaccag atgaagttga atcagtggta cagtttagcg ggtggctgtc 60atgacagaca gaccctcaaa ttgaagcaat ggcagataga tatggtctcc agtccaccga 120ttgaatgcag ttggagaagt caatcccccc ttggaaagcc cccaacgttg cgctttctga 180ccacctgaaa tctgacaatc agcaatcctt cagctcttct cagcgtctct tggggccgat 240ccccatcgga tgaacacgcc tcatccctca ttaggcatgg ctgagctgca tgtcagcgga 300gtcccaacac ccaaaccaat cctttagcgc gcaccgggcc tgcgaagcca tcaccatcgc 360ccgccttgca gcaatgtgct ccccggtcgc attcctttcg tttcataatc tcacctccgg 420ccagcccata tccttcatct cgcagctttt ccctactcct tcttttcttt tgctttcttc 480ccccatcgca ggctgtttga atgcctgctg aagtatccat ggtatgatgc gaccgatact 540tctcccccta ctgggggtat ttctgcagac ctcctcggca tccaatccct atgtaatgag 600ctggtcttcc caagcctacg gtccagatgg cccgtggcag gccgtatcca tcgacgtggg 660cagcaaccag cagacggtcg atctttaccc cggagccaac tatgctagca cgatcctgat 720gagcactctc tgcacgaaca aaaccctgtc atccacctgc tacgctgccg aagcaggcac 780gttcaaccaa aacacctcca ccactgccta caccaccgcc agctcgtggg aaacaactta 840ctgggccgtc gagggtggaa gccaagaggc tgtgctcggc gatgaggtca ccttagggtc 900gtttgtcgtc cccaatgtga gcttcgaagc catctaccag acctaccaga cctatcccaa 960tggcatcgcc tatcctgtct cggtcggcag tctggccctg gggggtccgt acttgtcgga 1020taccgtctcc aattcgacgg tcctgaacat gatcgcagga tggctttact cgtccaacga 1080cattccgtcc tactcgtacg gcatgcatat cgggtcggta gaccccaaaa tcccaggctc 1140cctgatcttg gggggctacg ataagagccg agtgatcgga gacgtgagtg cgcagggagt 1200agtgtcttcg agtggtcttt tggaacttga attaaaggat attgggctgg gtgttgcggc 1260gggttcctct cccttcagct tcaacaacga aagtggcttg tttctccaaa gcagtggttc 1320ggttcaggcc aagaccgtcc agattgatcc aaccaagccc tacatgtacc ttccccaggc 1380gacatgcgat gccatcacct ccaccatgcc gatctccttc aattccagct tggggctata 1440cttctgggac accacgagcg atgattatct gaatatcacg tcttccgccg catacctctc 1500ctttgtgttc aacatgaatg gggtcaacaa caagaacatt accatcaaga ttcccttttc 1560ccagctcaat cttacgctgc aagaaccgct ggtcgatcaa aacgtcacct acttcccgtg 1620cttcctcact acctccaccc cggtgctcgg tcgagccttt ctccagtccg cattcgttgg 1680ggtgaactgg ttcaacggga acaactcggg cacatggttt ctggcacagg cccccggccc 1740gggttacgcc agtgaagaca tcacccggat cgcagtgagt gacacgtcgc tttctgcctc 1800taacggtacc tgggaagaga cctgggctac gtactggggc atcaaaacat ccgacaactc 1860gagcagctcc aagagtggcc tgtcttccgg tgccaaaatt ggaattggcg tcggggtggg 1920tgtcggtgga gcagtgttga tcgcagcagg tatagccatt gcattctgtc ttcgccgtcg 1980ccgcggggcg agtcaagagg cggctggaga gcaacggagg tcgatgttta ggggctttgc 2040ggagctaccg ggaggtgctc acagtgaacc ggcgaaggag ttggatacga agatgcataa 2100gccgccgcag gaaatgatgg cttcgcagga ggtagagcga tacgagctgg ggtgatggct 2160aattctaaat tttaatatgc gaagggatcc ctacaggata ctacaggata ccatatacgt 2220gcgaatataa tagctagttg ttccaatatt atgtatcaag cttatactgt ggattaacca 2280acgacttgtc tccgatacat agggtagtac gtagtcatgg atccggggtg tattgtcatt 2340cagcatgacg cattgctcaa gccaaaagta agctgggcca gtgtatcacc catgaaagca 2400accctctctc acctctgtac tgatgacttg gtggaaattt ggatcctcgg aaattgtgat 2460taacacgtgg atctagaccc gaccaggcgg gagcttggca t 2501413570DNAAspergillus niger 41gaaaaggatt gtccccatgc ataataggcg ttccaccacc tgcatatcca tacatgcagc 60ccgagttatg cgatgtgatc gggcctggaa taacatgatc tccgatctaa cgggggccca 120aaaggggcag ccaagatctg ctaggcccaa ccaggctagc ggcgggccat ctgaggcggt 180gatccatttt gggcgaggaa aaggcaaaaa gtggatcggc gaaaggcaag ttggagtgtc 240gggagtttgg tctcccgccc cagggccgcg tattagtcta gctctctttc tattcactcg 300ggccaactcg tcaactctct ccctcgcttt cattcagatt tcattatttc tcttacggtc 360ttgccattct tgccactttc ggtccttatt attgcttttg atccccagtt cccttttccc 420aactgggtgg cgctcctaca gaccgacaca tacctggcgg actttccttg cttctggctg 480tacaccggga cccgcctcat acccagtacg tgttggtcca tggcaagcct cctacttggc 540ctgattacat cgtcctgaga gagagagttc accaaaactc tcccccaaac gatgcgtctt 600acaggtggtg tcgctgcggc tctgggcctc tgcgctgctg cctccgcttc tctccatccc 660catcgttcct acgagaccca tgattacttc gctctacacc ttgatgaatc cacctcgccg 720gccgacgtcg cccaacgact aggtgctcgc cacgaaggcc ccgtcggaga attaccctca 780catcatacct tctcgatacc ccgtgaaaac agtgacgatg tccatgcgct gctggatcaa 840ttgcgcgatc gtcggaggtt acgccgccgc tccggagatg acgccgctgt ccttccctcc 900ttggtcgggc gagacgaagg tctaggtggc attctttggt ccgagaagct ggctccccag 960agaaagctcc ataaaagagt gccgccgaca ggatatgctg ccagatcgcc cgtcaacact 1020cagaatgacc cccaagcgct tgcggcgcag aaacgcattg cctcggaatt gggcatcgcg 1080gaccccatct tcggcgaaca atggcatttg tataatactg ttcagttggg ccatgatctt 1140aacgtgacgg gtatctggct ggagggcgtt acagggcagg gtgtcacgac ggctattgtc 1200gatgacggtt tggacatgta cagcaacgat cttaggccga actattttgc ggcgggttct 1260tatgactata acgacaaagt accagagccg aggccgcgct tgagcgatga ccgccacggt 1320actagatgcg cgggtgaaat cggtgcggcg aagaacgacg tgtgcggggt tggtgttgcg 1380tatgatagtc gcatcgctgg tattcggatt ctctccgcac ccattgatga cactgatgag 1440gctgcggcta ttaactacgc ctatcaggag aacgatatct actcgtgttc ctggggtccc 1500tatgacgatg gcgccacaat ggaagccccg ggcaccctga tcaagcgggc catggtcaat 1560ggtatccaaa atggtcgtgg tggaaaaggc tcggtttttg tgtttgcggc tggtaacggt 1620gccattcatg acgataactg taactttgac ggttacacca acagtatcta cagcatcacg 1680gtgggtgcca ttgatcggga gggtaaccat cctccgtatt cggaatcctg ctcggcgcaa 1740ctggtggttg cctacagcag cggcgccagt gatgcaattc ataccacgga cgtcggcaca 1800gacaagtgct cgactaccca tggtggaact tcggcggccg gcccgctcgc tgcgggaacc 1860gtggcgctgg ccctcagtgt gcggccggaa ctcacctggc gtgacgttca gtatttgatg 1920attgaggcgg cagtgcctgt tcatgaagat gatggaagct ggcaggacac taagaacggg 1980aagaagttca gccatgactg gggatatggt aaggtcgaca catatacgct ggtgaaacgg 2040gcagagacct gggatctggt gaagcctcaa gcctggctcc attccccctg gcagcgggtt 2100gagcatgaga tcccacaggg cgagcagggc ttggctagtt cgtacgaggt gacggaggat 2160atgttgaagg gagccaacct ggaacggctg gagcatgtca cggtcaccat gaatgttaac 2220cacacccgcc gaggcgatct cagcgtggag ttacggagcc ctgacggtcg ggtcagtcac 2280ctcagtacgc cccggcggcc agataatcaa gaggtgggct atgttgactg gaccttcatg 2340agcgttgctc actggtaagt aaactttttc tcggttgtcg gttcttctgc taatacatat 2400ctaggggcga gtccgggatt ggcaaatgga ctgtgattgt caaggacacc aatgtcaacg 2460agcatactgg gcaattcatc gattggcgac tcaacttgtg gggcgaggcg attgacggag 2520ccgagcagcc tctccacccc atgcctactg aacacgatga cgaccacagc tatgaggaag 2580gaaacgtggc taccacgagc atcagcgccg ttcccacgaa aaccgagctg cctgacaagc 2640ccactggtgg cgttgatcgc ccggtgaacg ttaagcctac aacatccgcg atgccgaccg 2700gtagtcttac agagcccatc gatgatgaag aactccagaa gacccctagt acagaggcaa 2760gctcaacacc aagtccttct ccgaccaccg cgtcagatag tatcctgcct tccttcttcc 2820ccacgttcgg tgcgtcgaag cggacgcaag tttggatcta cgctgcgatc ggctccatca 2880ttgtgttctg cattggcctg ggcgtctact tccatgtgca gcgccgcaaa cgtattcgcg 2940acgacagccg ggatgactac gatttcgaga tgatcgagga cgaggatgag ctacaggcaa 3000tgaacggacg gtcgaaccgt tcacgtcgcc ggggtggcga gctgtacaat gcttttgcgg 3060gcgagagcga tgaggaaccg ttattcagtg atgaggatga tgaaccgtat cgggatcggg 3120ggatcagcgg cgaacaagaa cgggagggcg cagatggaga gcattctcgg agatgaagtg 3180cagtagatga gggttgattt tatttcggac agtgtttctt acttgttgga tgacctgcgt 3240tgaacaatat tcctgctgtg tatgctgcat agagaaagcg tgtatatacc atgtatgtgt 3300gcatcatctt tgatcgggtt attattcttc atctgccatg gtttgtgatc tccggaatag 3360taccaaagga acactaaatt aagggtcttg gcgatgacgc ttcccgtcgc tgcttttgac 3420ttcctccgca tctcgtctct cctgctgttg accgcccgcc aaccaacctc catctcctca 3480ctcctcccac cttaatcttg ctgtcctgct tctagagccc cccagtttaa tttaaaaacc 3540ggcttttcct agctccacgt attgtacctc 3570421236DNAAspergillus niger 42aggtcccgga cagatgacaa ggctctaaga ctgtatgtct cattcagggt ctagccgtgc 60ccgctcttat tggcccggac gcttcacgcc gcgattactg cgcccccgca tgtctctctc 120tccgctcgct atcgatgcgg tgtttgcccg ccattgatgg gaggaatgtc tcacttcggg 180cttgtgcttc gcagatccat acccctcaat gacctagtat agcaaacagg cgtgatgtca 240atgattgtgt ttctattcag agcatcaggc ctcccatgtc tatacctcag ttatggagcc 300ttggccgcct tgggtaggca aggcctcccg ggtattctca ttgccatttc accgctactg 360cagcttcaag tgaagagaaa gaggggaaag aaagaatata agtagcttga caatctcctg 420cacgtcctcc tcttcagctc acatcaaaca tctattcttc actcctcaag agtaaaccac 480tactaccaaa cacaatctca tctatagctc acgagtacca gcatcactca tctaccacaa 540tgaagacctt ctctaccgtc acctctctcc tcgctctctt ctcctcggct ctggccgcac 600ccgttgacag cgctgaagcc gccggcacca ccgtctctgt ctcatacgac actgcctacg 660atgtctctgg agcttccttg accaccgtct cctgctcgga cggtgccaac ggcctgatca 720ataagggcta ctccaacttc ggctcccttc cgggcttccc caagattgga ggcgccccta 780ccattgcagg ctggaactct cccaactgcg gcaagtgcta cgccctgacg tacaacggcc 840agacagtcaa cattctggcc attgattccg cacctggtgg cttcaacatc gctctggagg 900ccatgaacac cctcaccaac aaccaggccc agcagctggg tcgtatcgaa gctacctata 960ctgaggtgga tgtcagtctt tgcgcataaa cgccaaacat tcagcaaatg cttgggggat 1020gaattcggcc atggcaggga atggttatag ttggatatga tttcgggatt tacgattgat 1080acgcttattt gggatacttt cctttatctt acctattgtt aatagcataa tacggagcat 1140cacatacgta catacacata catcaatata gtgatatatg aacttgaata cagagctttt 1200tgaaaatgaa atgagagatt ctaaggtcgt atctac 1236431750DNAAspergillus niger 43gtgaaagata tcggatagcc gtagaccctg aaagattatt tgagcctaag ggctcttgca 60gtgacgctag caacagcgaa cccactggga tccaaaacac tagatgaagc tattgtaagc 120cggaaccctt ccggcgcccc acccagctcc tgcaggggcg aaaacatgac tctctaactt 180aggagaaatc acagccaagg cccaagttca ctgagagacc gaaatggcgt gaatttaaat 240gttgcctttc gcgcacttta ctattccctt gttcctatca gcagtcactg cttggcctcc 300tttctagtga gcagttccat tcactttagg ccccacggct tcgttacaag agcagtatgg 360ctcaaatatt ctggctttca ctcttcctgc ttgtctcttg ggtcagagcc gagtccaacc 420gcaccgaggt ggacctgatt ttcccaagaa atgatacctt tgcgccaatg cctttgatgc 480cggttgtatt cgccgttcaa gccccttccg tcgcccataa agttaataca tacatcgagt 540acggctatta cccagtaggc cgtccaaatg aaacagttat tggccagacc gaccatgtgt 600ccgactcaac aaacgaaacc acttatttca gtgtctctgg tatcggcaga acgttcaata 660ccactggcag ctgggagctg ttttggaggc tgagatggac caattgttca atctcagaag 720actcgagata ctacaaccaa tcctacccct ggatatcctc cccatacatc gacggtagcc 780tcaacatcga caaggtctat gagggctttc actacacagc atacaatgtc attgtcgaca 840gggttacctt cagcactcgc gaagatgcta gccaacccaa cctcacgacc ctcaccaata 900gcgagaactg cgataaagtc tcgtctcttg ctctattgtc gattgtggac tccctaagga 960ttccacccca gttaccccaa gaagatattg ataccgtgtc aatgtgccca caactcgccg 1020atgccaggct aaattcaact tcaacttcaa gcccctgcag cgttagcatt agtcccgagg 1080ttgagtctaa tatcctggcc aagatcgcag acaatgaatg caataacgca cttcaccccg 1140ctgtgagttg caccactgaa gaaaccaagg aaggcagcgc gagcagccat gaccacggcc 1200atgctgtatg gcttgtcatt acgctagctt ttgccttcct tttctaaagg atccaatgct 1260agatgtgctc gactcaggct ttgagacagg tagacaggaa aacaggcttt attgtcacgt 1320cgccagtagg ggaccatcaa ccacacatat gtccctacga gaccatagct atcaggaaca 1380atgtacgggc tggaactcca ctcactctta ggttgtaaat cccatttctc aatacatagt 1440ttgtgagcaa accacgcttt tcttgaatca ttgcatcctc tttagcttca attccttacc 1500cacaaacacg agaggagcgg acccgccatt ccacatagtg tcttggcagg gtcgcctctc 1560caactacaat gcccaacttc agaggcccag actatctctg ccaagtgcca aggctggact 1620caaattacgg aactctcgga tgcttgtgcc atggcttatt gcttgaaggg tttggaggtt 1680tcggtggtta gcgcccggat aggcagtaga acacctccaa atgaggaatg cggccgaagg 1740taggtggggc 1750442030DNAAspergillus niger 44tggatgccga gcaaattaat taactgcgct tacatggctg tcctaacaaa tcccttggca 60ctcttagcag tggtgcctgg atgggacgaa gccctgggca tagcttgttc atcggtaggc 120cgaaactctc ttttacgtac cgtacggcca atatcagtgt gaacccgcaa tttagatact 180attaacttac aagtaccctc acgttatgta gccgaatgtt taaaagcgat ggaccggttt 240aaagtctccg ttgtgcgatg gctgttatta acttggatta acttgcaatt tgcatcaagt 300aagacgtgct tctttttgga tctttttaca cacattactt acggcggatg ctctcgacac 360tccggatttc accagggtgg tgttagtcca ccatcggact ccgatgcatc ttaacatggg 420tggtcgagat gtcgccattc tcagcaggca ctttgctgtg acatcctcac aaagtgttaa 480tggcgttgtc tctgggatgg tatgaggaag aatgatgcca tccgtgaaga gtgtcgactt 540gatagatact caacaaaaag tcatcctata agtattgggt tggatctgct gttcttatca 600tttcgtctcc atcccactgc aatcttcttc aagacttcaa agtccatagt tccaacacac 660agtcacctct tcacccagct tcactaccaa ccaattcttc aagaagaagt tcactgctgc 720aattgctact gccattttcg caagcgttgc cgtcgcagct ccccagcgtg gcctcgaggc 780ccgcctcaag gcccgcggca gcagcaaggg atcccgaccc ctccaggcag ttgctagacc 840tgcatcaacc aagaaccaga ccaacgttga gtacagctcc aactggtccg gtgccgtgct 900ggtggagcct ccctctgctg cagcgaccta cactgcggtg accggcacct tcactgtccc 960tgagcccacc ggcaactctg gaggcagtca ggctgcatct gcctgggttg gtatcgacgg 1020tgatacctat ggaaacgcca ttcttcagac cggtgttgac ttcaccgtga ccgacggaga 1080ggcctcgttc gatgcctggt atgagtggta cccggattac gcctacgact tcagcggcat 1140cgacatctcg gcaggcgatg agattgttgc cattgtggag tcctacacct cgactaccgg 1200tattgccatt attgagaaca agagcaccgg ccagaaggtg tccaaggagc tgtcgtccag 1260ctccagcctc ggtggacaga acgctgagtg gattgtggaa ggtaatatga aacatacatt 1320cctcattcaa cattaccaaa cgctaacgcg atcttagact tcgaggaaaa tggttcgctc 1380gtcaacctgg tggactttgg caccgtcacc ttcactggtg ctgttgccaa ggcggcgggt 1440ggtgagagtg ttggacttac cgatgcgacc atcatcgaga ttgaggagaa tggccaggtt 1500gtcactgacg ttaccatcga cagcgactct gaggtgacca tcacctacga gtaaatttgc 1560acacgaggcc tgtcactgtg actgacggtg ttgagtgtct caatacaaag cgggttgatt 1620ggtatgcagg gatgtgatga tgtgatcagg tcagcgcttg atttcaatcg acgaggcagt 1680ggagaacgaa gatgtagata gttttgattt ctagtactac tttgcggggc ccctgttgaa 1740tttgagtcat tcttttgatt gatcctccgg aatcatatat caagtaatgg tgcagcgtag 1800ggagtactcc ataaggcaga tgaagtacag gtcttaaaac ggtatgatcc agtaagacaa 1860agcggatctt gtattccaaa caatcacgtc ggtaacatgg actactactt tcatctataa 1920tgtttgtatg ccagttgtgc tgcagattat taatttgtat aggcattgta caggtgcgct 1980acattgttca gcaagtaaac gtgattttga agtccccaag aacacaaagc 2030453080DNAAspergillus niger 45cttcggctgc gtcatgattc atgcgtcaaa tcagtggact cttagtaggt ggatgtacag 60cacttatttg atacttcgag tgtccgccaa catccggccg tctatattct ataccaatcc 120acattatgcc caacgaaact gtatgctgtg atttaagcag aagtgagcaa agcactgtgt 180cagctgatct aatatactat atgctccgat taaacccaag cagtctgcta ccagggagac 240taccaggcag aaagtatctg gctgcatttg tcccagtctg cacaggactc gctatgttat 300ggagcagaag tattgtgcat ggattccatc tgtcccacta gcatgactat ctcaatatcc 360accgggtaca tgatttagcc ggtatcactc ccccgtccct gtagcaaagg cccgcgcaag 420aggtgtttcc agaaagggct ccacgcttag caccgttcag caaattctgc atcagccgcg 480gggaaactgc ggtttgttgc caggtcgagg tgcttaaata ccaccgtctt ctcgctcgtc 540agtgctctgc tcaggcgtcg ctcagtcaag ttcagttcaa gactcaggat atccgggcag 600tcctccgcaa ctatgcgctg ctccctcatc tcccttctag gcctggcggc catcccggcc 660cttggaggct gtcccttcgc acacactgcg aacatgggca ttgataacat ggtgaaagca 720cacgctcaca tgtcccgacc gttgattgcc tccaagagca gcccctcaac tgttcctacc 780tcctctagca ccccttctgt cgggcagaaa ggcgtgttca tgatgaaccg cattgctcct 840ggcacatccg agctctacat tgccaacaca gatggcagta atgaacgccc actcctctcc 900aaccccgtct acgagtacca tgcctccttc tccccggatg tagaatggat caccttcacc 960agcgagcgca atggtgacgg taactctgac atctaccgcg tacggaccaa cggctccgat 1020ctccaggaat tggttgccac gcctgcagtg gaagactccg ttgttatctc tcccaacggc 1080cgcctggcag cctacgtctc caccgccaac aacatgaagg caaacatctg gatccttgat 1140cttcagaccg gcgcgcagtg gaacctcaca aatacaccca ccactgccgc caactcctcc 1200ctcatggaga gctatctccg tcctgcctgg

tctcctgatg gcgaatggat cgccttctct 1260tcggaccgca acacccaatg ggacggacac ggcgtaccga ccttcctcgg ccgcacgggc 1320tgggagacga cgcaagaact ctctctctac gccatccgtc ccaatggctc tgacttccgt 1380cagatcatct ccaagccata ctactctctt ggatctccga aatggtcagc agacggtaaa 1440cgcatcgtct actacgaaat gacccgggaa gacacctaca acgcccatcg tccagaaacc 1500attaccacag ccaactcgac gatcatgtcc gtagacttcg agacaggcac cgatgtgcgc 1560gtggaagtcg ccggctccgg tgtcaagcaa ttccctcagt acctggacaa gaacggcacc 1620atcgcctaca ccctcaaagg cggcaccagc gagggcttct acacgaccgc gggactctac 1680gtcaacacga cctcggcgac cctcaggtcc ccggcgtggt ctcccgacgg caagcaagta 1740gtctacgaaa agagcacctg gagcatccgc tcggggtaca agcagctcta cagctgggac 1800agtgactggg actaccgctt cacggacgtc ttccctcagg tctcgcacca ggagcgcgtc 1860gccatcacac agaagcagct gggcaattcg tccatcgtga cgttgaacac aaccggaggc 1920gacttgcaac tcgtctacga ccccagcacg gcggactttg tcagcgatga cgaaaccaca 1980ggactgagcg cttaccagcc cagctggtca ccctgcggcg agtggctcgt cttcggcgtc 2040ggattctggt tcgagacgag agaagcctca ggcggatgga tcgtgcgggc caccgccaac 2100gggagctact cggaggttct cgtgaacagc agctactcca tcaccgagga tggagccctg 2160aacagcgggt tcccgagttt ctcgccggat ggcaagaaag tggtgtatcg ggtttgggga 2220gccgacactg caacctacgg caacgccagc gagatcgggc tgcgggtgct ggacctcgag 2280acgcgaaaga caaccgtcct aaccacagaa tgggacaatc tgccccagtt ctctcccgat 2340ggagagctca tcctattcac acgcaaaacc agcacgtaca attacgatgt gtgcacgatc 2400cggccggatg ggacagatct ccgcgtgttg acgagcagcg gtgctaatga tgcgcatgcg 2460gtctggtcgc aggatggacg gattatgtgg tctaccggca tgtatgggtt ccggtttgag 2520tgtgcgctgt atggtgatac gttccagccg tatgggcagg ttatgattat ggatgcggat 2580gggggaaata agaagttgat gaccaactcg atgtgggaag attcgatgcc gttgttcttg 2640ccgagggagg tactttagtt ggtggcggga ggatgctctg atttttagag gatatgtgac 2700gtttgatgta tgataagaat tacacaagta gttttgatca taacgcgttg aagaggatga 2760aaaaaaaccc ccgttgttcg acttgatctt ggcgatccgg tgtagggttg ttggacgagc 2820aggatgtact gcttaattca agcaagtttg ctactccgat tcagtatgga ggggcaatta 2880atgatgacga tattctgcac tttctactct acctactact tatctgtata tgaatgagaa 2940aaaaatagta tgcaacgaat atagatcgta ttgacagaac ctgtcagaga gaatgacctc 3000gatagtcgac tccatagcat ttgatctttt actaacagcg aaagattccg gactaactat 3060ccatatatag tactcctaca 3080463290DNAAspergillus niger 46ttccaacttc ccatgaagtg atgtagtagt ctgctaataa tacctcaaga tagaatatag 60tatttactac ttatcgtcag ctttgtcgaa aattcaaagg tttgtggaag gccacctcat 120ccgcacctgt tgcctacagg gatagcatcc tgcgaggtgc ttatccgctt atcagcaaag 180gtggcagggg gggtaaggct atcccgggtt aggaaggccc gcggcacgat gcgatccttc 240cagactagga agctacctaa tagggacagt aagggaccaa tctcaggact aaaccgtgca 300gcctactgaa tctcaccact cggacctgat atttgccttc ggcttgcagg ggtatatcat 360ctcaatatcc tctagtggac ggaaactagc aactagtact ttgagctgac tcggccacta 420taaatatgcg gtcttatgct cctcaacgac aggcaactgc tctgactacc aaaatctgag 480taggactagc accgttgcga gctcctcttc acgataccga atcttttata agcaagtggt 540ccaatatcca ggtctaacgt atccatacaa tgcctccgga tgcaaaatcg cctggctacc 600agcctggtat ggcagtatta ccatctaggc cacatcctgc caagggaaaa gccattcgat 660tcctcctttc ccttgcattg gtcgcgtttg ctattgttca attatgtggt aatttccaca 720aaaataggag cgttgaacaa cagcttcaga gtcaaacact tgatgatgag tcctttaaat 780gggaagatgt gtgtaaatct atcacgttgg gatgtaacgt tctaacgcac tctattaggt 840tactcctacc aagcaactcg tataccatcc atgctttggt gatcacgaat gcgctcgctt 900gtcgcttcca atgaattgga accgaactga tggtgaaggg tcaaaaattg ccttggcggt 960tatcaaactt cctgccaagg tacctgtcac agatgcgcga tatggtggtg ccattcttct 1020gaatccaggt atgtagagcc atattgctac tcttcagcgg ctgtgctgag tttcaaatag 1080gtggtcctgg tggatccgga gtgagcatgg tctttagata cgggaaagct atccagacca 1140tcgtcgactc cccagaatca ccaagtgcag attcagcgag cggaaagtat ttcgatgttg 1200ttagctttga tccaagaggg gtcaacaaca caacacctaa tttttcctgc ttccctgacc 1260ccgcgacgag gaaagcgtgg ttactgcagt cagaggcaga gggtctactt gggagttctg 1320aaggagtctt cgatactcga tgggcaaggt acgaagcttt tggtatgagc tgcaatcaac 1380aaggagtcac agcgtcaaag gatggagaat ggataggaaa attcatgaat acggcccccg 1440tggtggcgga tatggttgaa ctcgtagagc gccatggaga gtggcgtgaa cgggaaacag 1500agcggctact ttcgacagct ccgaacactt tcccagttgg aacaaacgtt gacgccgaga 1560ggataaggct gcacaaccgt tggaaaaaag gggaggagaa gctgctatac tggggctttt 1620cctatgggac aatcctgggt tccacgtttg cggctatgca gcctcatcgc ataaaccgtg 1680ctgtcataga cggagtctgc aacgctgatg attattacgc cggcaactgg cttaccaatt 1740tacaagattc ggatgcagca ttcaataaat ttttcgagta ctgctacaca gctggcccat 1800cagcgtgtcc gtttgcgctc ggcggagatc ccgaagatct caagtctcgt tatgagcaga 1860ttttgaccaa tcttacatcg agccctattg ctgtgtctcc ttctggaaat aggggcccag 1920agataataac ctatagtgat gtgaagtcat tggtcgtgca agctctctat gtgcctttga 1980aattattcga tttggtggct aggctattag ctgagctcga gcaaggtaac ggctcttcat 2040tcgctgactt gaagtatgaa gccaaacaat ggccagtacc gcctccatgc gattcctcgt 2100ccacacaata caaagtacct ggcgagagtg atcaggaggc cgggaggaat atcctatgta 2160cagatggtcc aggcctcgac ggaactgcca aggaggattt ccggagctac tggaatatgc 2220tccggggaca aagtaaggcg gttggagatt tctgggccga ggttcgcatg tcgtgtgtca 2280aactggagac gcgacctgag tggcgctatg atggtaggtc cgaccaacac catattatac 2340acacaatata agctgacagg tatgcgtatc caagggccct tcgcaggcaa tacatcgcac 2400ccattgctgt ttatcgggaa tacttatgat ccagtaacgc cgctacggaa gtaagctttg 2460ttcacctgat cgtagcagac tttgaagtac agactgacgc ataggcagtg ctcatacgat 2520ggcgcgtgga tttcctgagt caatcgttct agagcagaac tctgtcggag tgagtacctt 2580atctgttccc caacccatat gcaagatgac taactgttca atgtcgcagc attgcacact 2640gagtggccca tccttgtgta cagcgaaagc gatacgccag tatttccaga ccggagagtt 2700acctgacccc ggaactgttt gccaggtaga ggagcttccc tttcgtcttg ccggatatga 2760gagaagtcag gtcatgtcgc caggtgacac agaattgatg tccgccttgc attcgctgag 2820cgagttccgc catctgctag gcgcgtgaaa aaggttaaat aagtgtcgcc agcgagcgct 2880gcagttatta atcctttaca tcataggagc tggctagaat gttaacgatg cagtttgccc 2940ctgtatctcg accaagagca tgaataacac attatatcag caaatgttat tgagcaaatc 3000aattattcac ctgcactcaa ttcaatttaa gatctgttgc ctagactacc agaattatta 3060aggcgacctt atcgaagcat ttgcagacca acccctgtcc atcgtcaggg gcaagacaga 3120catttcttct agaacccgga tgatgtataa tcgcggtggg gaagatcatc ctaaaccatt 3180gccccagact cgcctacctt aggtaatcca tacaaatgcc ggggaaatca ctgaggtgtt 3240gttcatcacg gcgttgaatc ggcttctgcg gtattaccac cataactgta 3290473080DNAAspergillus niger 47gaaaatcccg accgttaggc tacctaatct gctgtcttta cccccgttag cccacttacc 60cagctttagt ctctcgaagg aaaagaaaac aaagtaatcg ggagcctata atattcggcc 120agaagtgggg caatcacttc aaccgttcat ctgttattga gttatcaagt ctgtcaagtt 180cgtcggagct ggataaggta gtcgccatcc ccatttccgc tgtgcaatgc cgcagcgccg 240aagtgtctgc agctagctct attttgttca gctacgtatc tgtctcttaa ccaaatggat 300gtcgccattc gcccactaac aacgccattc cccacggccg acggactccg gcgcaagggc 360ctgataagcg ttagctccga ctccgagtta gtcatgcggc ttattacgcg cccttctccc 420ctcacgatgt tgatgctttt tctggtatct ctggcataac tggcaaagat caggctgtgg 480tcataagagt atcattgcct tcagcttctt cgccatgttg agtagtctgc tgcttggggg 540tcttctgggt ctagcgaccg ctcaatttcc tcccgagccg gaaggcatca ctgtgctcaa 600gtccaagttg catgagaatg tgactatttc tttcaaagag gtgtgtgcag agtatctaga 660aatagctttt atgctcgatg ccgtgctgat tgtcagcctg gaatttgcga aactacgccg 720ggtgtccgat cttattcggg ctatgtacac cttccccccg gtttcctttc cgacgggaca 780ggagaagtgc aggattatcc tatcaacacg taagccaatc tcgaaacatt ggaggatgag 840caattactga gcctcaacca gcttcttttg gtttttcgaa gcccgcaaag atcccagcaa 900tgcgcctctg gccatctggc tcaatggcgg tccgggtggc tcgtcgctca tggggctcct 960tgaagaatta ggtccttgtt ccattgcatc agactccaag accacagtcc tcaatccttg 1020gagttggaac aatgaagtca atcttctatt ccttgaccag ccaactcaag tcggcttctc 1080atacgatgtc ccaacaaatg gcactttggt tcggactgcg gacggcgaag aagagatagt 1140ttccggtgat ttctccattg atgttcccca gtccaacttc acccatcatg ttggtacctt 1200tgcaagccag aagcttgcac agacagctaa tgggactgca ttcgcggctc acgctctatg 1260gcatttcgcg caaacctggt ttttcgagtt cccacactac aagccaaacg atgatcgtgt 1320cagtctctgg gctgaaagtt acggaggcca ttatggtcca ggcatctttc ggttcttcca 1380acagcagaat gacaaaatcg cagaggggac tgcagaagac ggtgcacagt atttgcatct 1440cgacacgctt ggcattgtga acggcttgat ggatatggtg atccaagaag aggcttacat 1500tacttggcca tacaataacg taaggctcgc cccttcttca ttcaactcgc gtaatgccta 1560attcagttca gacctacggc ctcgaaatct tcgataaacc cctctacgaa gaactgatgt 1620ataactggac gcatccagga ggctttcgcg atcaggccct cgcctgcgaa gcggctttga 1680aagaacgcga ttccggcttg cctcactcag ggaagaatat ctctgaaatt tgcggaggcc 1740ttgcactaga atggggagat ggccccatca cctactacca caccttcaat cgcgggtggt 1800acgacatcgc ccatcctaag aacgacccat tccctgccaa gcacatgctc ggatatttga 1860cgcaggagtc cgtccttgcc gctcttgggg taccagtcaa tttcacatcg tcttcgagtg 1920ccgtggctac acagttcata aaaacctttg atatcgtcca cggcggcttc ctggatgcaa 1980ttggctacct cctcgacagt ggtgtaaaag tacacatgat gtacggagat cgtgattacg 2040cctgcaattg ggtcgggggc gaaaaagcca gccttgcagt tccgtattcc cgtatcaccg 2100aatttgccga cacgggatac tccccactcc ttacgcccga cgggatcagc ggcatgaccc 2160gccagctggg caactacagc ttcactcgcg tcttccaagc cgggcatgag gtcccctcct 2220accagcctgt cgcggcgtat gagatcttca tgcgggcgac attcaacaaa gatatcccta 2280ctggcctctt ggctgttgat gacgaattcc agtcggttgg acctaaggat acgtggcata 2340tcaagaatat ccctcctatt atgccaaagc cgcagtgcta tgttctaagt cccggcacgt 2400gtaccccgga ggtttgggag accgttttga acggatccgc gacggtaaag gattggtatg 2460tcgtggatga tagcgcgggt gttgaggacc acgaggggtt cagcattctt ggaggggatg 2520agttgtagta gcttagaagt ctaccggaaa gccttgctag ctcttaaaat acgacacaaa 2580tagttgagcg acatagtcta ctctctcact tacgaacacg tgatgaatct ctccagcaat 2640aaagtggacc aatcaattgg aggaaaatat atccacgatg gtcggacggg ccaacgaaaa 2700gggccaacta gcgcccctct gaggatgatg gtctagtctg caggatatga gattgttcac 2760atcttatggg tcttcaactg cacaaattag gcggaggtcg cctcaccgaa agagacgtaa 2820gctgcttttt ggtggattca ttattagccg ttatgccatt tactaaaaca ccgcagttcc 2880agatcgcgta gatggcctca aagtgttcgc cagatttgat tgagggctac ttcgcccaag 2940cctatggcct gtagatgcca atttcttcaa tacaaagata ggcgaaacat gttgaaaatc 3000catcatattc aattaaattt caaaacatag cgagacatta agtattacat atatttcaat 3060gaatagagac ttcttgcaca 3080482520DNAAspergillus niger 48tctcgcctgc ctcgaccttc ctgctatggc aattctttcc ccaagctgag cggttccatc 60cgcttcccga ccgccaaact tatcaacccg agcgatacgg agaggggaaa ggctatcacg 120gcaatgattg cgcaactctg cgataagata accccatgtt ttgacgtagc ctcggccctg 180tcttctcctc attattatcc tccgattccc ccagggttcc tgtcttctgc agaaagtgct 240ctcggaatcg aagatgacca ggtttcaatt gcttcccctt gtcgcagggc tgcttgcccc 300ttcaattgca gcccttagca tcccttcccc gcagcagatc ctcgattctc tcactttcgg 360agagcacacc gacggctttt gtccgctggc acccaaggtt gaggttcctg acgatggttt 420ctttccagct ctcaagttcg tagaagatgc ctcgttcaag tcgcgccaag tcaatcgtct 480ctccagggcg gttcaagttc cgaccgcaat cgacgactac atgaaggatc cctacgacga 540aaagttcgcc ccattcctcg acttccagaa gctcctgcag accctctttc ccctcacgta 600cgtccccagt ccccgtcttc atggctccat ctaacgcaat ccagccactc ctacgcccgc 660gtagatcaca tcaaccgatt tggtctcgtc ttcaccctca atggcacaga tgactcgctc 720aagcccctgc tattcaccgc gcaccaggac gtcgtgccca tcaacgaccc tgccgactgg 780acctatcccc ccttcgatgg ccactacgac ggcgaatggc tctggggccg cggtgccagc 840gactgcaaga acgtcctgat cggtctcatg tccgttgttg aagacctact ctcccaaaag 900tgggagccaa cccgcacagt cgtcctggcc ttcggattcg acgaagaatc ccacggcttc 960ctcggcgccg gatccatcgc caaattcctt gagaagaaat acggaccgga cagcttcgaa 1020tttatcctcg acgaaggcgg catgggcctc gaagttctag acgacaacaa caacggcgtc 1080gtctacgctc tccccggcgt tggcgaaaag ggcagcatcg acgttgtgct cactctggcc 1140gtaccaggcg gccacagctc cgtgccccct ccacacacgg gaatcggcat catcgccgag 1200atcatctatg agctagaacg ccaggacctc ttcgtccccg tcctagacac tcaccacccg 1260acccgcaaga tgctcgaatg ccaagtccgc cactccccct cgcaagtcga accgtggctc 1320gcctccgccc tccaatcaag cgactacatc tccctagcag agaaactggc ctcctcgcgc 1380ggcgacaagt tccgcttcat cctccaaacc tcccaagcag cggacatcat caacggcggc 1440gtcaaatcca acgctctccc cgagaaaatc aacgccctcg tcaactaccg catcgctctg 1500caccaaaccc cagacgatat caagaaccgc gctgtggaga tcatctctcc catcgtcaag 1560aaatataacc tctccctcac ggccttcccg gaaagcgaca ccgttgaccc ctccctcaac 1620aaccacctca cccttactac cctcagcggc gccctcagtc ccgccccggt cagcccaacg 1680gacatcgaca ccgacgccgt ctgggcccgt ttctcgggcg tcactcgctc ggtcttcgaa 1740tctgtcccta gtctcgaggg cagaaaggtc gtcgtgagcg gcgacatcat gaccgggaat 1800acggatacga gattctactg ggctttgtcg aggaatattt acaggtggag tccgtcgagg 1860gcgggtaaag cgctgaatat tcatactgtt gatgagagga tcgatattga tattcatctt 1920gaggcgatga tgctgtatta cggtatgcat ctctcctttt atggatactc ctatcagact 1980aacttgtatc tctagatctt attcgctctt tcgatggacg gaccgattca tctgtcattt 2040ctgctgcgtc ggcagctgct gatgatgaac ttgctcacga cgtgctgtga gtctgtagga 2100actctcctac tctttagggt ggctcaggat gaatgatggt tatgaatcat gtggtctact 2160gcgccaaaag ttcatgtctt tcctggagtt caacgagaac cagatctata tttccacgaa 2220tagctccagt atatagccaa atgcaaccac gtatttgtct atcgatctga cagtctaatt 2280ctttacctta tactaggggt aagaaagggt aagaaaataa aataatattt gcagcggcct 2340atgaagataa ttatgtactc gacgttgccc aatgcactgt agcccctctc cctgtaacag 2400gagtagccat aaaagcaaaa cgaaagtggt aagaagacgg gggcaatatc cctgctttag 2460caatatacaa caatagtaac aatcgagagc tcaatatgaa tgtataacga gtgacctgca 2520492730DNAAspergillus niger 49tttagttgtg atctcaatcg caaatggaca ggagatgata ttcatgtcat aatcagagtg 60ccatgtcagc gaccatgtct tgccaagagt catcatttcc ggtaaaaccg acggaggtaa 120aaccccggtc attcactagt tcgagggagg gaatagtctc gcaggtctct tcttctttct 180tcctcggggt ggcggatgga tcacttcttc atttgatggt tgcctgccaa cgacccactt 240gactaggttt cccccttgat gggattcgtt ggttttacca gacagagcct cttcacagcc 300cagcgcgtgt tccgcaaaag caacagccca agggtctgaa ggctgacatt ggagcgggtc 360tgacgcagga tggcttgctg ttaaaaaaac tcaggaacag gccaagacga agcgaccgcg 420caaggctgag cagttctccg atttccccgt gcccctcctg cgcctcccat gggcgacttt 480tgatcccaga tccatcgttt ctgcaccgac catataagaa gctccgcacc cccaaactcc 540cctggcaagt tcctgccccc aaattacgtg agacagggaa ccatcacagc aacaccatga 600agagcaccac tcttctttcc ttggcctggg ctgcccagtc cgcctattcc ctctctatcc 660acgagcgcga tgaacccgct actcttcagt tcaactttga acgtcgtcag atcgccgacc 720ggtcccgtcg gaagcgatcg acggcctcgg ccgacctcgt taacctggta tgttcccatc 780ccgagtctca aatcagggga attatgacgg tcgctaatgc aggtttctag gctacgaatc 840ttggctacac gatgaacctc acactcggca ctcccggcca ggaagtcagt gtgacgttgg 900acaccggcag cagcgatctc tgggtcaatg gggccaactc gtccgtctgc ccctgtaccg 960attacggctc ttacaactca agcgcttctt ccacctacac cttcgtgaac gatgagtttt 1020atatccagta tgtcgacggc agtgaagcca caggcgacta tgtcaacgat actctaaagt 1080tctccaatgt gactttgacg aactttcaat ttgccgtcgc atatgacggc gactccgagg 1140gtaagtcttc gctattccct cactttcatt ttacactttg ctaacggttt taccatgcag 1200agggggtcct cggtatcgga tacgccagca atgaagccag ccaggccacc gtcggtggtg 1260gtgaatacac caacttcccc gaagccctcg tcgatcaagg cgcgatcaac tggccggcct 1320acagtctatg gctcgatgac ctcgacgaag gaaaaggcac cattctgttc ggcggagtca 1380acaccgccaa gtactacggc agcctgcaga ccctgcctat cgtctccatc gaagacatgt 1440acgtcgagtt cgcggtcaac ctgacggccg tgcaccttga gaagaacggc aactccgtct 1500cggtcaacaa cagcgccacg caattcccca tccccgccgt gctggacagc ggcacggccc 1560tgacctacat cccgacctcc gccgcagcca gcatctacga ggccgtcggt gcccaatacc 1620tgagcgagta cgggtacgga gtgatcgagt gcgacgtcaa ggacgaagac ttcaccttcc 1680tgttcgactt tggatccttc aacatgagcg ttgacatcag cgagatgatc ctcgaggcca 1740gttccgacat gaccgacatg aacgtttgta cgtttggcct cgcagtgatc gaaaatgagg 1800ccctgctggg cgataccttc ctgcgcagcg catacgtcgt ctacgatctc ggaaacaacg 1860agatctccct ggccaaggcc aacttcaacc ccggcgagga ccacgtcctg gagatcggca 1920ccggatcgga tgccgtgccc aaggcgacgg gggcgacggc gaccggcgcg gcagccacat 1980ccacggcctc gagcgacaag tcggacaagg agagttcggc tacagtgccg cgcagccaga 2040ttgtctcgct ggtggcggga gtcttggtcg gtgttttctt ggttctgtaa atatagagat 2100ttcacgttgc atgttgatga tacataccat agatttgctt ctaattgccc cttacatctc 2160gaaatgtttt ctgtttttag cttgatatcc catcgcttca ggtttcagat atggaaatga 2220aatgaaaatc ggaatgcaag atctgatcga atagttgttt cactgccgcg tggctggtcc 2280gatcggcacg aagccagtaa tcgacaacca atcatacatt gtgatttcct gtcaacctcc 2340ttgcgactac tactaatttt atcatatcat gccgttgtga cctatcctac tcggtgtccc 2400cacaccgatg atagccaccc gcgaccggat aatcggtaac ctgccaagag tcgaacggct 2460ttcctgtgga aagggtggct gcaacctgtt tgtttcagtt tttgtgttgc agaattgact 2520atccttctga cctgtgaatg atactgggat ggtgacgtag tgaaaatgtt ggtggagcga 2580ttaaggtttg tgcctgtcag cctcgtcaag tccatcatca tgtcttttcc ggactatcac 2640ttcctctact ctgaagtacc gggactcccc gccagtattc gtttcgccaa tcagagcatt 2700cgatgtgaac cggattgaag agtgcccggt 2730503231DNAAspergillus niger 50ccgacgcgac ggcattagtt cctcgatagc gtgggaagac catggagaga ccggccgata 60agctgcagag gagctttctg tgggctgacc agtgcctatc agcaaatgga cacgcggtga 120cacccccgca atcgcaagac cgcctcgaca ccgtccatcc aggcaccatc gcaacggcaa 180accagcctct cctccaatca aaccatcgat gtgatattgc tagcggcggt gagaacagca 240ggtcgaatgt cgcaattaat tctcgcatcg tccctcactg caaggggccc actaccagag 300ctctgcggcg ttgttattta aatccgttgt tgggaccttt cggtcatcag ccactgtgtc 360tggtcactat cgcgctggtt caacctcaac atgttggtcc gtcagcttgc cctggctctg 420gccattgcgg ccttgtccga tgccattccg acatccatca agcatgtcct gcacgagaaa 480cgtcacaagc ccgcatccga ctgggtgaag ggtgcgcgcg ttgagagcga tgcggtcctg 540cctatgcgca ttggccttgc ccagaacaac ttggacaagg gctatgactt cctgatggaa 600gtgtgagtca aaatctacct tttttatgct atatgcctag ttttaggatc gcaatggatg 660acctcgaaac atgctgacat gagattggcg cagatcggac cccaagtctt ccaaatacgg 720ccagtactgg tcggcagacg aggtgcacga catcttttcg ccatccgagg aggctgttga 780ggcagtgaga gaatggcttg tcgcctctgg tatccatccg tcgcgggtgg tgcactccga 840caacaagggc tggctcgcgt tcgacgccta cgcccatgaa gccgagaggc tgttcatgac 900ggaattccac gagcacgaga gcgaccgaag tgctaagatc agggttggat gcgaccagta 960agaagattct tctatcacct tccatgagta gctattaatc ggaatctaga taccacgtcc 1020ccgaacacat ccagaagcac atcgactaca ttacccctgg agtgaagctc acccaggtcg 1080tgaagaggac caacaaagtc aagcgtgctt cccaactagc tcactcttcc aaggccaagt 1140ctgctgccca aggtccgcag ccactcccca acaaggccaa gttcctgcct gaagacctcc 1200gcggctgcgg ttacaacatc accccctcgt gtatcaaggc cttgtatcag atcccagacg 1260ctaagacggc gaccccgaac aacagcctgg gtctgtacga gcagggtgac tactttgcca

1320agtccgacct cgacctcttc tataaggagt atgcgccgtg ggttccccag ggtacctatc 1380ccatcccagc cctgattgat ggcgccaatt actcggttcc ttcctacagc tccctgaaca 1440cgggtgaatc cgacattgac attgacatgg cgtgagtcat ttctgcacct tgtcatcaga 1500cccctactga cgttttgaag ctactccctg ctctaccctc agcaggtgac cctctaccag 1560gttgacgacc agctctacga accagtcgag gtcgacacaa ccaatctgtt caacaccttc 1620ctcgacgctc tcgatggcgt gagtacagac ctcgttctca gtcttaccca gctaacaccc 1680ctagtcctac tgcacctaca gcgcctacgg cgagaccggc gatgacccgt cgatcgaccc 1740cgtatacccc gacacccgcc ccggcggcta caaaggtacc tacctacacc acctcttccc 1800catacaatcc aacctaacac accaacagga aagctccagt gcggcgtcta taagcccact 1860aacgtaatca gcgcctccta cggccaatcc gaagccgacc tccccgtcag ctacaccaag 1920cgccaatgca atgagttcat gaagctcggt ctacagggac actccatcct cttcgcgtct 1980ggcgactacg gcgtcgcgtc tttcgccggc gacggtgacg agaacggctg tctcggccca 2040gagggcaaga tcttcaaccc ccagtacccc tccaactgcc cctacgtcac ctccgttgga 2100ggtaccatgc tgtacggcta ccagaccgtc aacgacagcg agagcgtcat gcacgttaac 2160cttggcggaa ccgcaagtaa cttcagcact tctggtggct tctcgaatta cttcccccaa 2220ccggcatatc agtttgctgc tgtggagcaa tacttccagt ctgcgaacct gtcgtatccg 2280tattactcgg agtttgaggt cgatgttaac acgaccaagg gtctctacaa taggcttggt 2340cgtgcttatc cggatgtctc ggcgaatgga gcgcatttcc gcgcttatat ggatggatac 2400gattatcatt ggtatggatc gagtttggcg tcgcctttgt tcgcgtcggt tcttactttg 2460gtgagctttg tcacccccca ttactaatta ttgacacatg gctgaccgac ttagctcaac 2520gaggaacgct tcgctatcgg caagggcccc gtgggattcg tgaatcccgt gctttatgct 2580tatccgcaag tgctgaacga tatcactaat ggtactaatg ctgggtgtgg aacttatggg 2640tttagtgcta ttgaggggta agtgctcagt acttggttct gtcaggaggg gtgtgctaat 2700tgatgactat agatgggatc ccgctagtgg tttgggtacg cctaactacc cattgatgaa 2760ggagctgttc ctctctttgc cttaggattg aacggtgctg tgtcagaggg tgataggtgg 2820tcaagctgtg tatatatgtc tgatggggaa atatttacga tcataggata atgtgtcgac 2880gagcatgaat ggccaattat ctcgcctgtc accgtgaata aggtcaaatg tagatcggtt 2940taatagttca actacagaga attcttggat attgtcaaat gttgactatt cgctgtctct 3000ttatcgtcta atgtataata tcatcaaata acctaaccca agggatatca aaaacataag 3060aaaataataa accggtacta tgtgtcgaaa aaaggaatgt ttgtgaattt tttaaaaccg 3120ttcatacctc ccgtccatgt ccaccaaatg cacagcgctg gtcgaatccc tctccgaccg 3180tgtcgtatag tcaacggaga tattcactga cttggaaatc ttgctgttgg t 3231512660DNAAspergillus niger 51tcctgagcaa gcagctaccg gtaatctgag acctaatcct ggtaagtgga tcgagttcat 60ttacctcatc atctaacctc gcttcatgat tcgcaggcgc tttccgcgac tagtcgatgc 120cagtatccat ttgcctgcag atccgatgct tccaccgacc accgttactt ctctccagac 180ccccatccgg ctttccgacg gcctcctctg catcccctca caaagcaagc ggagacctgc 240ctgaataggg agagtttttt caatgagccc acacgcagtt acctcgcttc cgcatgagat 300gggtccattc ttgacaatgc tgcctaatgc gcagaagggc cgtcatgcgc ctggagaact 360acataaatag ggaccacgca tgccccgacg atgtatgaat tgttcaaact tctccgccca 420agtgagttct cttttcattc cattccgaag ggagaatcac cagtatgcgg gttaccacgg 480caattgcttc attactactg gtcggctcgg ccaccagtct ccaaaatcct catcgtcggg 540ctgttccgcc ccctctctcg catcgcagcg tagcgtctcg ctccgtgccc gttgagcgcc 600gaaccaccga ctttgagtat ttgactaaca agactgcaag tgcgtgattc cgttttttaa 660ctaccgcatt tatcgttcta agatcaattg caggattcct ggtcaatggc acaagcatcc 720ccgaagtcga tttcgacgtc ggcgagtcct acgccggcct tctccccaat acgcccactg 780gcaattctag cctattcttc tggttcttcc cctcgcaaaa tccagaggcc agcgatgagg 840ttagtggtcg ctctgttttt tccggtcatg cgtcagccag ctaacaatta acaaagatca 900ccatctggct caacggcggc cccggatgta gctccctaga cggcctgctt caagagaacg 960gcccattcct ctggcagcct ggcacttaca agcccgttcc taatccatac tcatggacca 1020acctcaccaa tgtggtttac atcgaccaac ccgccggcac aggcttctcc ccgggcccct 1080cgaccgtaaa taacgaggaa gacgtggctg cccagttcaa cagctggttc aagcacttcg 1140tcgacacctt cgacctgcac ggccgcaagg tctacatcac cggtgaaagc tacgcgggca 1200tgtacgtccc ctacattgcc gatgccatgc tgaacgagga ggatacaacc tacttcaact 1260tgaagggtat ccagatcaac gacccgtcca tcaacagcga ctcggtcatg atgtactgta 1320tgtttccctt catatacctc cacctccacc accaccacca ctaacaacat cacccaccag 1380cccccgccgt ccgccatctg aaccactaca acaacatctt ccagctaaac tccactttcc 1440tctcctacat caacgccaaa gccgacaagt gcggctacaa cgccttcctc gacaaagcca 1500tcacctaccc accccccagt cccttcccca ccgcccctga aatcaccgaa gactgccaag 1560tctgggacga agtcgtcatg gccgcctacg acatcaaccc ctgcttcaat tactaccacc 1620tgatcgactt ctgcccctac ctctgggacg tgctcggctt cccctccctc gcctccggcc 1680caaacaacta cttcaaccgc tccgacgtcc agaagatcct gcacgtccct ccaacggact 1740actccgtgtg ctcggagacc gtcatcttcg cgaacggcga cggcagcgac cccagctcct 1800ggggtcccct acccagcgtc atcgaacgca ctaacaacac tatcatcggc cacggctggc 1860tcgattacct cctcttcttg aacggctcgc tcgccacaat ccagaacatg acctggaacg 1920gtaagcaagg gttccagcgt cctcccgtgg aaccgctctt cgtcccttac cattatggtc 1980tggctgagct gtactggggc gatgagcctg acccgtataa ccttgatgct ggcgctggat 2040acctgggtac agcgcatacc gagcgcgggt tgactttcag ctcggtgtat ttgtctggtc 2100atggtaagtt tattatatcc ccttggaagc ggtatgatga acgttagaga gtgctgactg 2160ttgcttcctc ctcgtgatag aaatcccgca gtatgttcct ggtgcggctt accgccagtt 2220ggagttcctg ctcggtagga ttagtagtct ttcggcgaag gggaactata cctcttgatt 2280tcagcggatg acgacaaaaa gatgatgagg aagatgattg gatgctttca gatgggaatg 2340cgtgcatagg agatgagatg agatgatgta tcattgaggt gtgatgactt gtacatatgt 2400agatcggtag taaaagggat actataggat atggtatttg atgtatcatt tatgtacacc 2460acgtggattc aattgagggg agcttcaatt cctggttatt acttatcata tttccaacat 2520gtccgcgtat aaccggtaac aactaacggc ttcatgtttg tcaagtgact gtcttggtac 2580aatactactg tttctatatt ctactgttgg taacttaatc tggacatatt ctatatccac 2640gtacagattc tcgctagatt 2660523150DNAAspergillus niger 52ccaatcaacc acggatgatt gggttcaggt cctggaggca cggagtcgga ccaagacact 60aaggtacagc actagcgaga caatgtgtta tcgctattat tggcaaaatg gccgcgggat 120ctcttatgca gggttcggct ccatcctccc ccctcttcct atccagtcaa tccgcctcgg 180ttattgaagg agatcctgag ctgtttaact gacgcctcac cgatcaggcc ggaaatggtg 240gcgggataca acatcgtttc cacacaatag tgcttgtctc ctgcgatctg catggcatgc 300taatctccgc cagcatgtat cttctatcca ctggatatga attttcctcc cctcacacca 360tgtgggcctg ggggttttcc ctcaaacttt gtcgctcatg taacgatgta tataaagccc 420tgaggatggc atcccccacc catcggtctt ttgctgaccg ttctccttga agaaattctc 480gagtggcttg tggtgcatgt atagatttaa tcttcgaggg ttattaacta ggtatagctg 540tgactaagtc tgtccttgca ttgaacaaca caccatgcgt ggctctcggt tggtgctctt 600gttgcccctg gctgcactta gttgtgctat gcccgagaat gaatggtcat ctacgataag 660aaggcagtta ccaaaagcgt ccactggcgt caaatcgata aaaaccccaa acaatgtcac 720tatcaggtat aaagaaccag gaaccgaagg aatttgtgag acaacacctg gggtcaaatc 780atactccgga tatgtcgatc tttcgccaga gtcgcatact ttcttttggt ttttcgagtc 840acgccgtgac cccgaaaatg atccagtgac tctgtggctg aatggtggcc ctggaagcga 900ttccttgatt gggctttttg aaggttggcc aaatatcctg acggaaaaga taaaattcag 960cttgcatgtt ctgacgcctt cacaacagag ttgggtccgt gtcacatcac accagagtac 1020gaatcaatca tcaatcagta ctcctggaac gaggtcacca atcttctttt cttgtctcag 1080cccctcggtg tgggtatgga atattgctgc cttcatacat cctgagtaca ttgcttacgg 1140tcttatctgc gaagggttct cttacagtga aaccgaggcc gggtccttga atccatttac 1200tggagccgtc gagaacgcct cctttgctgg agttcagggt cgatacccag ttattgatgc 1260cactatcatc ggtaagttgt ccggtttgac tctcacctag cattctcctc aatgtcctac 1320tttacagaca cgaccgatat cgctgcacgc gcaacctggg aggtgcttca gggcttcctc 1380agtggcctgt cgcagctaga ttccgaagtc aagtccaagg agttcaacct gtggacagag 1440agttacggag ggtgagtgca actttcatac cagaccgacg taagctgact tgatcaagac 1500actatggacc agcggtaggt tgtcttttct ggttgcacac atattgatct aatgaccgaa 1560gttcttcaat catttctacg agcaaaattc gaagatcgct agcggggaag tcaatggcgt 1620ccaactgaat tttaactccc tcgggattat caacggcatc attgatgccg cgattcaggt 1680acttagaaat gcagctcgcg cagaggctgc ggcctagaag gacatcgcta aagtaattaa 1740taggcagact actacgcaga ctttgccgtt aataatacat atggaatcaa agctgtaagt 1800ttaaatacac gtacatcgtg gatttaagat caaccgtgct catgcttgct aggtcaatga 1860cacagtgtac aactatatga agttcgccaa cacgatgcca aatggatgcc aggatcaggt 1920tgcttcgtgt aaattgacca ataggacctc gctttctgat tatgctatat gtacagaagc 1980agccaatatg tgcagggaca atgtcggtga gtggttctac tgtttctctg caggggtgca 2040atgatgaagg actttgctaa gctgtcatgt acagaagggc cttactacca gtttggcggc 2100cgtggcgtgt atgatattcg gcacccctac aatgtaagtg gcaaggataa ggattgtact 2160ttccgaacag ggacactgct catatgtcaa cgtaggaccc gaccccgccg tcctactttg 2220ttgactacct caagaaagac tcagtcatgg atgctatcgg cgtggacatt aactacaccg 2280agtccagcgg cgaagtatat tatgcattcc agcagaccgg cgactttgta tggccgaatt 2340tcattgagga cctcgaagag atcctccaac tccccgtacg cgtgtcgttg atctacggcg 2400atgccgacta tatctgtaac tggttcggcg gtcaggccat ctcactcgca gttaactacc 2460cccatgcagc tcagttccgt gcagcgggat acacacccat gacagtagat ggggtcgaat 2520acggtgagac tcgcgagtat ggcaactttt cgttcacccg cgtatatcag gctgggcacg 2580aggttccata ctatcaaccg atcgcagcgt tgcagctgtt caaccgtact ttatttggat 2640gggatattgc agcgggtaca actcagattt ggcccgaata tagcaccaac gggacatcgc 2700aggctacaca cacggagtcg ttcgtgccac tgtccacggc gtcgagtacc accgtcaatt 2760aggattgggg gaaatttttc cctctttggt atggctaatg ctgtgttatc cattccgata 2820cttgtccata acctaaaaga gtggcacgga agctttccta gacatgcttg ctctagtcaa 2880cttttatcct accactgtgt ggtcctacca taatgtcatc ctaaacttat caggtgtctt 2940acatcatttt gcagtgacca taaaagtcat gtcatattaa gtccattacg gtagttcgta 3000acttgctgat ggcttacgta attgtgcctc agcaggatgt cgtgatacgc tccaaaaccc 3060aatctgatca tggatatcca gcggaataac acaaaagaaa aaataaacat aaccaaccac 3120caaaatgaca gaggctaatg cctggacaac 3150533221DNAAspergillus niger 53ccatcagctc ttgttgttat gttttatgtc atagtgtaat gctagcctta gcgtgcgtgg 60tgtttgaatt tcagattggg catggatacc tgggcgtctc gggatggata ctgggacgtg 120gtaagatgct tggaagcgtt gattttgagt ttgacaatat atccctatgt ttctcttctc 180cacacccttt taccgtaatg cgacagcatt gtgtagagtg cattgcctta attagaacct 240acgaatcctt gatttgtata tgacacccga tcaccatcga gccacctaca tcatggcgcg 300ctctcagatc ctccgaacca aaacagtaat gtcgatcgtc gcgcctgaac caaggctgat 360tttccctgct gaagcgtgtc ataaagtgaa acatactttg tagataaact cggcaattaa 420ctgccactta ccccatacat cgctaccgga gagtggagcg agtgcacggc catcaagtga 480aactgataac cggcgatccg ccggcttatc ggcgatggcg ttatcagagg gaccttagta 540ggttgcacag ttcactagta tttattacta agtacttcct tcgccttgct tattgcccat 600gattcgtcct tctctttttc tttggttaat tgaactactc tccatgagag ttctgtacag 660gttgagatag accaaccacc accaccatgc cttttccctt ttcgtccgct cttctcggct 720atatcttaac tacgagcact actctcacct ccctagtcgc aggacagtat taccctccga 780cgcctgagga tctcaccgtt attcattcgg agatattccc tggtgcgagg atctcctata 840agcaagtgag aaatacacca cccttctcct caatcccaat ctaacacccc atactaatac 900tatgtgacca gcccctcggc atctgcacca ccaccccctc cacccccagc tactccggct 960acatccacct ccccccacac acccttacca atctctccat tccaggaatc agcatctcgc 1020aaccataccc tatcaatacc tttttctggt actttccttc ccgccatcac cacaacaatg 1080atacatcccc actcaccatc tggatgaacg gcgggcccgg cggatcctcc atgattgggc 1140tatttcaaga gaacgggcca tgtactgtga atacggactc gaattccacg gcctataatc 1200cctggtcgtg gaatgagtac gtcgatatgt tgtatattga gcagccggtg cagacgggat 1260ttagttatga tgtgttgagg aatgggacgt tagatttggt tagtggggag atagatgtta 1320gtattagtga tggtgagagg gatggagtag gacagaatga gacgtttttg gtggggacgt 1380tgccgagtca ggatgtgcat gggacggtga atgggacggt taatggggga agggcgcttt 1440gggttgcgtt gcaggtttgg ttgggtgaat tctctgaata tgtttcttct gttgacggga 1500atggtggtgg tgatgacagg gtgagtatat ggacggagtc atatggggga cggtatggac 1560cggcatacac ggcgctcttt caggagatga atgagaggat tgagagtggg gaggtaagca 1620ccgggaagaa gatccatttg gatacgctgg gcattatcaa tgggtgtgtg gatttactcg 1680tgcaggtccc ttcgttccct gagcaggcgt ataacaatac gtatgggatc gagggaatca 1740atcgcacgct ctacgaccgg gctatggata gttggagcaa gcctggcggg tgcagggata 1800tgatcatcga gtgtcgcgat gctggcgagc tcggagatcc cctcatgtat ggcgacaatg 1860agacggtaaa tagcatctgc gaggaggcgt cggactactg ttcgcgggag atcaagagcc 1920tgtatacgaa tacctccggg cgaggatact acgacatagc gcatttcacg ccggatgcag 1980ctctcgtgcc ttacttcgtc gggttcttga atcgcccatg ggtgcaaaag gcacttgggg 2040tcccggtgaa ctataccatg tcgtcagagg cagtggggaa cagtttcgcc tcgacgggcg 2100attatccgcg aaatgatccc cgcggaatga tcggggatat tggatacttg cttgactccg 2160gtgtcaaggt ggctatggta tatggggacc gggactatgc ttgtccgtgg cgcggcgggg 2220aagatgtcag cctgctggtg gagtacgagg atgcggagaa gttccgtgct gctgggtatg 2280ccgaagtgca gacgaagtca tcctacgttg ggggtctagt aaggcagtat gggaacttct 2340cgttcacgcg tgtctttcag gcgggccatg aggtgccatt ttatcagccc gaaacggcgt 2400atgagatttt taatcgcgct cagtttaatt gggatattgc gacgggaggc atttctctgg 2460agcagaatca gagctatggg acggagggac cgtcgtcaac gtggcatatc aaaaacgaag 2520tgccggagag ccctgagccg acgtgctatt tgttggcgat ggattcgact tgtacggatg 2580agcagaggga acgggtgctg agtggggatg cggtggtgag ggattgggtt gttgttgatg 2640atattgaggc tgaaagctcg ttcagcggtg ttggtgatca gctggcacag gtccctttgg 2700gacattgacg ttggttgcca tatgttgaca gtgttggtgg atgaaagtga tatagatgga 2760taaagttagt gcataagtgc atagctgact aagaatgagc atcattcata tatggataag 2820tctggctagc tcgatccggc aagtggccgg ctgactgcct aaagtggaag actggaagcc 2880ttcagatttc catcagtcca tctcaatatc tccatctggc ttgtcaaact cctatatcca 2940ccggccggac ccttctatta ttaacagcgc cgctatcacc cggacaatcc gtatggcatc 3000acgggttgac ccctccattg cggccatcga accttctcga accttctatt ggtcgaccgc 3060tgcggtcaac gtcacacgtc accgcaggct cacctgaaag ccgccggcgt tgcactatac 3120atcagccctc gtcctcacac ctggctttct ccgctaatcc tccaagtaca cccttcactg 3180tgccttgatg tcttgaatca acatctataa aaactgcatt a 3221542590DNAAspergillus niger 54gagtgagtaa attgatctaa cggcgtcgcg ctgacaaaca tcatagctat caatcagaaa 60aagcgaagca tatttcacat acgatcggat agcctaccaa ggaactgagg atatacgtac 120agctttcgct tggctgacac gtaaagtcat ttggtgattt tggagcgact ttggatctcc 180ttccatgtaa gttataacct accgcaattc caaagtatag ctagtagctg tcagtcactc 240aagaacttgc agcaaggcga tggcaagaca aaacaatcga tggtacggag tagatagaag 300acactaaagc actttcacat gacactgttg acatagtgct tatgctcttt acactcaaca 360tgagtcactt tgataaggtg atttcgccag atggtggcat tattgactcc tgattggatc 420caccgataag gaaccacttt ttggctggca atgtactatg ttattgacag gcatcgaact 480tccccaaatc tcaggctggg ccgccagcaa atggcgcggt tccggactcc ggcgggggct 540gacagggcca accgttggct gcttgtccct tgccgccgga gagcttattt aactcttgtc 600tctcctcttc ccccacaaag ctcactcagc actcaaggcc tcaccgcgcc atagtcccgc 660tcttgatcat ccttagcaaa acggctgtaa atcatgagaa catctactct tttgctcctc 720tggagcactg caggagcagc tttggcttct ccgtacccgc ttcccgactc gcaagtagtc 780ttcgccgcgg atcacgaggt cccgaataca cagggcaaac acgtcgtgga cgaggccata 840ctctcggcgc tgaacgctca ttctgaccca gtcgctgcaa tggtgtctct acgtcccgaa 900actgcagctt ttctagctga acctcgtctc ttgcacattc ggggcgaaga gaaggcggaa 960tggatgaccg aaggcgacaa gctgcgcctc cgccaacgcg gaaagaagtt catggacatt 1020accgagcatc aggacttcta cgcagagcag gcgatggctt cgtttgctgg ggatcctagt 1080taatctccct tttgtcgagg taattaatac tgtgttaacg ccctttagat cttcccaagc 1140tgtcccataa aggtctcgtc aagccgctgt tctctcaaat cgagacggaa cgaatgcacg 1200atatcctgca gcacatgacc tcctactaca atcgatacta cggtgattat cacggcgaga 1260tgagctccga atggctgcac gactacattg ctgcggtatc tccaccccct acagccacaa 1320tttttgaaca tgaacttact caaccaagat catctccaaa tcgcctttcc gcacccacat 1380ctctctcgaa tacttcaccc atcctttccg ccaatcttca attattgcac gcttcgagcc 1440taaagttcgc agcttctccc aacctttgac catcattggt gcgcaccaag attcggccaa 1500ttatcttttt cccctgctgc ccgcccctgg cgctgacgat gactgttccg gcactgtcag 1560tatcctcgag gccttccgcg ttctggcgga gaatggctac acgcccaagg acgggcctgt 1620tgaattccat tggtatgcgg ctgaagaggc cgggctactg ggcagccaag ccatcgcgcg 1680gtacaagaag gagcagggcg ctaaaattga tgccatgatg gagtttgtag gttcccatca 1740tccaacggac ttggaatcac ttttgacttt cggttattaa catctgcata ggatatgacg 1800gcttttattg cccgtaacgc caccgagacc atcgggtttg ttgcaaccca agccgatgca 1860gcgctcacaa actgggccct caacctcagt cgagaataca tctccattcc ggcggaagtc 1920tatgaacttg gcccgtaaga ccccagaata tccccagagg catgtcaagt gctgaatgat 1980ttcttagcaa cgctggatcc gactacatgt catacactaa gctcaactac cccgctgcct 2040ttgcatccga aggcaacccg ctcgctgggg gctctttccc gggtgaaatg gacccctacg 2100tacacggcat caaggatagg atggacgttg acgatgaaac gggcgtcttc tctatcgaag 2160taagttgacc gcactcaacc tgtccatctt cttgctaacg atttgccagc acatggctcg 2220gttctccgag ttggctatcg catttgttgt cgagcaggct gggtgggata atacatggcg 2280gtagagtata tacagggatg tttccagctt catagcatat agagctggta tatagtcatt 2340gtgcttacaa tatataccat tctattgagt tcttgacaga gttattatgt cagaatggta 2400atcagtctaa atcaatgcgc ccttaaatca agaagtacac tagtgcccat gaccaaaaca 2460atttccactt acacatacca cctatctgcc tcactacgaa acccttacca tacaatgttt 2520acgttgtgct cctttcaata ctccatttcc atagttcatg ctatcgtggg ataaacatgc 2580acatatcctc 2590553290DNAAspergillus niger 55gagaggcaga aggagtcatt tatcacttgt attccaatgt attttccatt tatagatact 60gcattcaaat gcaccgttta gcatagcatc ccacattcta tttcattcca atctcatgcc 120attgccatcc ccggtattaa tttacttctc cgccttatct tgcaatcttg caatctcttt 180ctcctcgtta tcacgcgttc ctgcaggcgc acctccgatg gcactgcagc cggagtcccc 240gcggcgccgg cactactaaa gactaaagtg tctagtctag cctccaatgt gctcacctcc 300atcagcatct catccattta tcttctgacg atgtcatctg caggctccac cccctccggc 360cgccccgacg ctctccgacg gtgcacaaca atcaattctg cagtcacgct caagattcgt 420ccctgccgga ctcctcatgc cgtgcctggt ttaatctatg caatggagta aggtagtatc 480gcctagcagg agcggagttc ctgctgcgct cacgccatgg tgccggcgca gacataaatc 540gctcgtttcc tccggcgctg gccgttctct cgagccagtt tgtctgttgt ggttgtagga 600tcctctgttc ccctcgacag ctcacaatgc gttccttctc cgttgtcgct gccgcgtcac 660tggcgctctc ttgggcgtct ctggcccagg ctgctcgccc ccgtcttgtg cccaagccta 720tctctcggcc agcttcgagt aagtcggctg cgactacggg tgaggcttat tttgagcagc 780tgctggacca tcacaacccg gagaagggaa cgttttccca gcggtactgg tggagtactg 840aatactgggg tggacctggg tcaccggtgc gtctctgaca tttggtctta tgaccggcca 900tattgaaact tagccggtgg caaggtccgc aatcatgagg aacattgctg attaaactag 960gtggtcctct ttaaccctgg agaggtctct gccgatggct atgaggggta tctcaccaac 1020gatactctca ctggtgtcta tgcgcaggag atccagggtg ccgtcattct cattgaacgt 1080gagtgtcact gctaccatgg aaaaaagaca ttcgctgatc gaccccaatc tagaccgcta 1140ctggggcgac tcttcgcctt atgaggtgct caatgccgaa acacttcagt atctcacact 1200ggatcagtcc attctggaca tgacctactt

cgccgagacg gtaaagctgc agttcgataa 1260tagcagccgc agcaatgcgc agaatgctgt atgttacctt caccgctcta tgtttctgat 1320aggtactgac aacgtagccc tgggtcatgg tcggtggctc atacagcggt gccttgacgg 1380cttggaccga gtctatcgcg cctggaacgt tctgggctta ccatgccacc agtgcgcctg 1440tggaggctat ctatgacttt gtaggtgtag cctgctcttg ttatctatac ttgcagctaa 1500ccaagccagt ggcaatactt ctaccccatt cagcaaggta tggcacagaa ctgcagcaag 1560gatgtgtctc tggtagccga gtatgtcgac aaaattggga agaatggaac tgccaaggaa 1620cagcaggagc tcaaagaatt gtttggtctg ggagctgttg agcattacga tgactttgcc 1680gcgtgagtac ttcaaagtct atagacgagc ttttctgaca ggaacagtgt cctgcccaac 1740ggaccgtacc tctggcaaga caacgacttt gtcacaggat actcttcctt cttccagttc 1800tgtgatgctg tcgaggtgag ttaccaccag attcctcttg attgaagcaa tatactaacg 1860gacacagggt gtcgaagccg gcgcggcagt gacccccggc cccgagggcg tcggacttga 1920aaaggccctg gccaactacg caaactggtt caattcaacc atactcccta actgtatttc 1980accatctctt gtctcgttcc tctcccttat cctcccagac taacctagtg acagactgcg 2040caagctacgg ctactggacc gacgaatgga gcgtcgcctg tttcgacagc tataatgcct 2100cgagccccat cttcaccgac acctccgtgg gtaaccctgt cgaccgccaa tgggaatggt 2160tcctctgcaa cgagcctttc ttctggtggc aggagtgcgt accccttacc tcattcatga 2220taacacacga acaattccac taacaaagat ccagcggtgc ccccgaggga acctccacta 2280ttgtgccccg gctcgtcagc gcctcctact ggcaacgcca atgcccgctc tacttccccg 2340aagttaacgg ctacacgtac ggcagcgcga agggtaaaaa ctccgctacg gtgaacagct 2400ggacgggtgg atgggatatg acccgcaaca cgacgcggtt gatctggacg aacgggtagg 2460tctcccccta atttccgttg aatgtgatgt gaagataaac tcaatgctaa taaattgaga 2520aggcaatatg acccctggcg cgactccggt gtgtcgagca ctttccggcc cggtggtccg 2580ctggttagca cggcgaacga acccgtgcag attattccgg gcgggttcca ttgctcggac 2640ttgtatatgg aggattacta tgcgaatgag ggtgtgagga aggtggttga taatgaggtg 2700aagcagatta aggagtgggt ggaggagtat tatgcttgat gaagatactg gtggacatat 2760ggagtgtaca taagatgaat ggtcataaaa tgatgatggt agatacggct atggctgttg 2820attagatggt cctttcgcat ttcctaatta ctgagcacgt gctccatggt atgggaagtg 2880gagacgttgc tatatatatt gactgtcggg ctattgttca cggcgtagaa gctagacgct 2940ttgtctatgt ggccttcact aaagaccgtg actctgccca gtcttccccc cttcgaggac 3000ctggtattag ccaaacccac ccacaaacct aacaaagatc atcgtgacat tgaagtcact 3060ctaggtactg ctggcgctga ttacagtggc tcaattcgaa catttcaaca gcacataagg 3120gaagggtcgc ttcacttgct accttgatac gaaagcagcc acgcccaaca cttatagggg 3180tgacaaccat cggcatgctg ggttatctac tatatctcct gattctgtgg atcctggaga 3240tcgatctggt acactaatct actacaatgc atgtgaagta gggataggca 3290562044DNAAspergillus niger 56ggctttgttg ggctgagcgc tacttctttc tctctcttgg tctgttcgtt gctccgccag 60ttggttcact cagcctcgta acatcagtat accaggctaa gtcaggactt tggcccccat 120actgcttccc ctttttttat aaaactcaat ccttctggaa aggattctat ttctcaattc 180tcagactact taatacgttc tttgttttca aattgttttg tttctgaaac ttgccgggcc 240ctatcccctc ttttttatag tccgcctgtc gacatcatat ccagagtgag ccaccatgca 300gctcctccag tccctcattg ttgccgtttg cttcagctac ggcgtcctct ccttacccca 360tggcccgtca aaccagcaca aagcacgttc cttcaaggtt gaacgggtcc gtcgtggaac 420cggtgctctg catgggcccg ctgctctccg caaagcatac cggaagtacg gaatagctcc 480cagcagtttc aacatcgatc tggcagactt taaacccatt acgacaaccc atgctgctgc 540tgggagcgag attgcagagc ctgatcagac tggcgctgtc agtgctactt ccgtcgagaa 600cgatgccgag ttcgtttcgc ctgttcttat tggcggccag aagatcgtca tgacatttga 660cactggttct tctgacttgt aagtcttgga tgcagctgtt tactctttgg tacagtgatt 720aacgtcgatc tacagttggg tgttcgatac gaatctcaat gaaaccttga cgggacacac 780ggagtacaac ccttcgaact cctcgacctt caagaagatg gacggataca ccttcgatgt 840ctcgtatggt gacgactcgt acgcctctgg ccccgtcgga acggataccg tcaacattgg 900cggcgccatt gtcaaggagc aagccttcgg tgtccccgac caggtatccc agtcgttcat 960cgaggacacg aactccaacg gcctggtcgg gttgggcttt tcctccatca acaccatcaa 1020accggaggcg caagacacgt tcttcgccaa tgtcgcacca agtctggacg agcccgtcat 1080gaccgcctcg ctcaaggctg acggagtggg cgagtacgag ttcggcacga tcgacaaaga 1140caagtaccag ggcaacattg ccaacatcag cgtggactca tcgaacggat actggcagtt 1200ctccactccc aagtactccg tggcagacgg agagctgaag gacattggaa gcttgaacac 1260ctcgatcgcg gacaccggta cctcccttat gctgctggat gaagacgtgg ttactgccta 1320ctatgcgcaa gttcccaact cggtctacgt gagcagtgcc ggtggttaca tctacccctg 1380caacaccact cttcccagct tctcgcttgt cctcggcgag tcgagcctgg ccacgatccc 1440cggtaacctg atcaatttct ccaaggttgg caccaacacc accaccggac aggcctgtaa 1500gttgctcccc ttcttttgca tgattgaaca tgattgactg attgtgctgg ttagtgtgct 1560ttggcggcat tcaatccaac ggaaacacct cgctgcagat tctgggcgat attttcctga 1620aggccttttt cgttgtcttc gacatgcgcg gcccctcgct tggtgttgcc tctcccaaga 1680actagtttcc ttttcctgta cttttccccc gcgtgtaata atatcgtctg attttttgga 1740ctgtctccta cgtgggcaag atggatggat agtttgctca cgtgcattgc tttaccttgg 1800gtctgtgagt caaggcagga gtgcgtggct gtatctacaa ttcaagttac agtgccgacc 1860gttattgcct tccacatcga aaaacataga cactctttct aaccctaatc catgatacaa 1920gtatatactt cgagtccata ttatggtggt gtatcaaggc gccatgttta tatctaatga 1980aaccaacgta ggtctcatct tcatacgttg tttaaaaggt gccgaagaat atacgaagat 2040agat 2044573916DNAAspergillus niger 57ttcgcagata ttcgagtcaa taccttgtat attaacggaa aagggtttgg gaagcgttgc 60cttcaaggat gaaattcaaa acgtagagta tcttgacctc aatgacctca tgatcccctt 120gaccgtacag ctagtgatct cacggtggta attgctcgat tcgattccaa actacagcaa 180gaagcatgcc cgacaggaaa gtcaagttac aagagatcta gaacggggct gctacggctc 240tgaccaacct ttgtctgttc tagatgaggc tgcagtgacg taactccggc ccaagaaaat 300gggtggtaac cgaccgttgg aaatcccatg gaactggcgg ggttcaaatt cccgataact 360gtaccgaatc cttgtatccg gatataggcg accgatagta gtagctatag tcagacgtag 420cacagcatta ctgtgtcccc ctggtcataa gagtatttgt tacaataaga agggaccgtc 480tagttgtgta tcacaacaac tgacacttgc ggaacaggta tcagatcctt gcgctggcat 540cgactccagc aatggcttgc tctgtttcgg acgaatatca tcgggctaga ctgtgacctg 600aaggatcgat ccaggagttt gacggcttgg gtttctaatc cgatctggaa gattattgtt 660tagtcaagac cgggaacagc aagaaccgga agattatctg tttaactact ttgccaaaac 720agttattcaa tgtcatgctg agtgcgatgg ggacccaagc tcacgagtga tgctgatcaa 780agggtccgtt cggtttggga aaggaagggc gccctgtgct tgccgttgga atccacggaa 840cgattccgat tgactgcacg ggatttgcaa actgactccc agtgggacga agaaagaaac 900ccatcttact ttgcggaggc aggatggcac tttgtgtcgg aagggtggtg actcctggtg 960ttgccgagaa gatggaatgg tggagaattg ccttgaaaat gaggctgtag gggcactaac 1020ccagtcgggc cgagcgtgac gcctttcccg atgaggcagg tcaggtgggt gtcacgggtc 1080tatcttatcg cttatcatct gaccggttcc tggcagaagc tccccttccc agctcctcgt 1140atttattcct ccccaggttg ttgtttgctc ttctccctgt ctcgccttct ctccagcctc 1200cattcaacgg gctccatccc cttctctccg gatccctcta tcccttattc ttccttagat 1260atcattattc atatagtgcc ttgtttcgct caccatgcgc attgactccg cggcgctaca 1320tctggtccca gtcctcctgg gccaggtcgg tgctttacaa ttacccttgg tccaagactc 1380caattcacag tggcagaaac caaatgcagg tgataaaccc ctaattagct ctccgttgct 1440tcaagagcag gtcaaggcgg agaatctgtt ggacagggcc cggcagcttt acaagattgc 1500ggagctggga gaagacgagt ataaccaccc cactcgcgtc attggcagta aaggtacgat 1560atattttttc atcatgtccc tggaatacga taattagctg acaacctttg ctccccaggt 1620caccttggca cgctcgacta catatactcc acccttaccg acctcggtga ttattatact 1680gtcgtcaatc agtccttccc tgccgtgagc ggtaatgtct tcgagtctcg ccttgtcctt 1740ggtcacgatg ttcccaagtc agctacacca atgggtctca ctcccccaac gaggaataag 1800gagccggtat atggctccct ggttgctgta tccaacctcg ggtgtgaggc ctcggactac 1860tcgtccaact tgaaaggcgc cgttgcattt atcagtcggg gaagctgtcc gttcgggacc 1920aagtctcaat tagctggtaa agcgggagct gttgctgccg tcatctacaa caacgagcgg 1980ggtgacctaa gcggaactct aggaaaccca acccccgatc atgttgctac ctttggtatc 2040tcagacgagg atgctgcccc agtcctggag aagttgaata aaggcgagaa ggtggacgct 2100atcgcctacg ttgatgcgat agtagagacc atccacacca ccaatatcat cgcgcagacc 2160acggatggtg acccgaacaa ttgtgtaatg ctgggtggcc acagtgacag cgtggccgag 2220ggcccgggta tcaatgacga cgggtccggt actctgaccc ttttggagct tgccacattg 2280ctcacccagt tccgtgtcaa caactgcgtg cgatttgctt ggtgggccgc cgaggaggaa 2340ggccttctcg gatctgacta ttacgtgtcc gttctcacac cggaagagaa ccgcaagatc 2400cgcttgttca tggactacga catgctcggc tcgccgaact ttgcgtacca agtttacaat 2460gccactaatg ctgtgaaccc cgagggatct gaggagcttc gtgatctgta caccgacttt 2520tacgaagatc atgggttcaa ctacacgtac attccgtttg acggacgcag cgactatgat 2580gccttcattc ggcatggtat cccgggtggt ggcattgcca cgggagcaga gggtatcaag 2640actgtcgagg aagcggacat gtttggtggg gttgctggcc aatggtatga cccgtgttac 2700catcagatct gcgatacggt ggccaatgtg aacttgactg cgtgggagtg gaacaccaag 2760gtaggaccgc atccagcatt agttactgtt atgccgatca ttcttttgct aactgggatg 2820atttacctta gctcgttgcc cactccattg cgacttacgc caagtccttt gacggattcc 2880cggaacggtc cgatgaaccc atcagccctg ctgcttttga ggaaccgaag taccatggcc 2940acgcgttgca attgtaagat ccgtgtgccc caaagcttgg tagtggggca aatatctgta 3000gcagagacca agtcctttct cgaacctgag tcccacttgg tctttccatc ttttgagttg 3060aacaagtaga ccgttactcg tcatgtagac gaagacctgg cagaaccgtt gtactatgta 3120gacatttatc ggggattgtc tgttatgaat tcatgtgctt gtgggatatg gttaggtatt 3180tctcgcaaat gaccacggct tcctctatca tttcccgcct cgcaccctca taccgatttc 3240cgttaactta atatcatctg tagacttcgc ggtaatacta cagggaccca gagcgtcctg 3300tggggagccc aaatccagaa tggaacagct gcatcggtgc ttaatctatt gtccatacga 3360cgcagaggca ctttcagtct aagctaaaag caagcattat tcagagatac agtgagtgtc 3420aatatgccgt tggttcatgc gcgattcgtg caaaaacagc ccaccgccct atataacaga 3480gtatattgct ctctgcctct ccgggtagag atcgacattt ccgggaccgc catgaaacgt 3540tggtgggcct cggagcgtcg aggattgaca ctagggccgc gctagaatcc cccagggtct 3600gcaaaatacc ctatggggtg acctcgaaca gggcgtgaaa cggcaattcc tccgaaagcg 3660ttgcgaaagt gtctacaaag tggtgatcca gaccatcacg cggttccgga acaattgccc 3720ttcttatttg gcactttacg gcgtggagtg gagtcatccc cctttgttga aacaacacgg 3780gcatgtttcc tttgccgtcc ggttcgttac ctataaagac agggtaggtc tgttcgggaa 3840aaagacacaa tcagcgccta tcccgtccgt cgaagtctat tgccataccc tatcacggat 3900catcagactc ataaca 3916581443DNAAspergillus niger 58atgcatctcc cacagcgtct cgttacagca gcgtgtcttt gcgccagtgc cacggctttc 60atcccataca ccatcaaact cgatacgtcg gacgacatct cagcccgtga ttcattagct 120cgtcgtttcc tgccagtacc aaaaccaagc gatgctctag cagacgattc cacctcatct 180gccagcgatg agtccctgtc actgaacatc aaaaggattc ccgttcgtcg tgacaatgat 240ttcaagattg tggtagcgga aactccctct tggtctaaca ccgccgctct cgatcaagat 300ggtagcgaca tttcatacat ctctgtcgtc aacattgggt ctgatgagaa atctatgtac 360atgttgctcg acacaggcgg ctctgatacc tgggttttcg gttccaactg cacgtccaca 420ccctgcacga tgcacaatac cttcggttcg gacgattctt cgacccttga aatgacatcg 480gaagagtgga gtgtgggcta tggaactggg tctgtcagcg gcttgctagg aaaagacaag 540ctcacgattg caaatgtcac tgtacgcatg actttcggac ttgcttccaa cgcatcggat 600aacttcgagt cgtacccaat ggacggcatt ctcggtctcg gtcgaaccaa cgatagttcc 660tacgacaacc caacattcat ggatgccgtt gcagaaagta acgttttcaa gtcgaatatc 720gttggcttcg ccctttcacg tagccccgcc aaggatggca cggtcagctt tggcactact 780gacaaggaca agtacaccgg cgatatcacc tacaccgata ccgtcggatc ggacagctat 840tggcgcattc ccgtggacga tgtctatgtt ggcggcactt catgcgattt ctccaacaaa 900tcagccatca tcgataccgg aacttcttat gctatgctgc cttcaagcga ctcgaagacg 960ctgcacagtc tcattcccgg cgccaaatct tcggggagct accacattat tccgtgcaac 1020acaactacta agctacaagt ggcattctct ggtgtgaatt acaccatctc gccgaaggac 1080tacgtgggag caacttcagg ttctggatgc gtttcgaaca ttatcagcta cgacttattt 1140ggtgatgaca tctggctcct gggtgacacg tttctcaaaa atgtgtatgc tgtgtttgac 1200tacgatgagt tacgggtcgg atttgcagag cgttcctcga acaccacctc tgcgtcgaac 1260tctacgagct ctggaacaag cagcacctcg ggatccacta caacgggcag ctcaacgact 1320acgacgagct ctgctagctc tagtagttca tctgatgctg aatcaggaag tagcatgacc 1380attcccgctc ctcagtattt cttctctgct ctggcgattg cttccttcat gctttggctc 1440tag 1443593300DNAAspergillus niger 59atgcttcgtg gtcttcgtga tgtcgtatta ttacaatttg caatcccctt gttcttgcta 60ttgcatttta gattatcgct acggggtgtg atcacaggat ttggttctaa atcacatttc 120cagagaccat tgagcaaaat gtcatctact caaaagagcc atttcaagct actccagaag 180ttcaaaccgg agtactcgcc tagcgagttt gctcagtatg agtcggagag aacaggcatg 240agggtagtgg tcattgacca aaaaggaccc aaagtcacag gttattttgt tctagccaca 300gagattctcg atgattcagg tgctcctcac acgttggagc acttgtgctt tatgggctcg 360cggaactata gatataaggg cttccttgac aagctagcaa cacgtgttta ttcgagcacc 420aatgcctgga cggccacaga ccacacggcc tacaccttgg acacagcagg ctgggaaggg 480ttcgctcaaa tcttgcccgt gtacctagag catgttatag ctccaacact gacagatgaa 540gggtgctata ccgaagtgca tcatattgat ggcgctggag acgacgctgg agtcgtctac 600tcggagatgc agggtgtgca gaataactct gcagagttaa tcgatctaac cgctcgtcga 660ttgacttacc cgcatggtgt aggttttcgc tacgagacag gcggtatgat ggagcagctc 720cgcgtcctca ccgcggaccg tatccgagcg ttccatcgtg agatgtacca gcccaagaac 780ttatgcctaa tcatcacagg cgaagtagat caccagaaca tgctggagac cttggacaag 840ttcgaagata ctattctaga tgtcattccc agtcctgatt cacctttcaa gaggccgtgg 900gtagattcca agcaggcgcc gccattggag aagtccattg tccagactgt ggaatttccg 960gaagaagatg aatctttcgg ggagatagaa attagattcc tcggtccgga ctgtaccgac 1020cctgttcaaa ccggggctgt caatgttgca ttgctgtatc tggccggttc atctgcttct 1080ctattggata acatcctggt tgagaaggag cagctcgcca gtgctgtcta ttatgctacc 1140gaagatcatc ccagcattga gatccgcttc acattaacca gtgtggagac agagaaactc 1200gcgaaggtag agcaacggtt tttcgaagtg ctcaaggacg ctatggagaa agatttagac 1260atgaggtata tcaaggagtg cattgaccgg caaagacgga cctggaagtt ctctaccgaa 1320agctccgcct cttcctttgc ggagtacgtg atctcggatt ttcttttcgg aaagagagac 1380ggatcgacta tgcttgatgt tgcgaccttg caagagtacg acgtgctgga gaagtggagt 1440gaagaacagt ggcgcagttt tatcaaaaca tggatttctg atgccaacca tgtcactatc 1500cttggtgttc cgtccgttaa gatgtctgac acattaaaga aggaggagga agctagagtc 1560gcagagcaaa agaagcgctt gggtgatgag gggctgaaga agttggccga caagctggaa 1620aaagctaaag ctgaaaatga caaggagatc cccaaggaga tgctggagag gttccaaatc 1680cctggaatag agtctatcca tttcgtggac actactacag ccaggtctgg tgcagccctc 1740gatgccgggc gcccatccca caaggcgcaa aaactggtgg atgctgatgg ctctgatctg 1800cccttgttca tccatttcga gcatatcccc agtagcttcg tgcagctctc cctcctcatc 1860tcggcacagg ccgtacctgt gcagcttcgt ccactgctgt ctgtgtatac tgaggcattc 1920ttcaacctgc ctgtcaaccg gaacggggaa accatcaact ttgagcaggt ggttgtcgag 1980ttggaaaggg atactgttgg ctactccatg gaaggagcta gaagcctagg aaactcggag 2040atgttgcgga tctcattcca ggtggagctt gagaagtatc acacggcgat cgcatggatc 2100caggaacttt cctggaactc gattttcgat gtcgagcgac tccgagcgat taccagtcga 2160ctgctctccg atgtgcccga ttccaagcgt agtggcgacg acatgctcgc ggctgttcat 2220gtgatggtcc actatgcagc agagtctatt gttcgggctc ggagcacctt ggtgaaggcg 2280cgttatttga aacggatcaa gaagcaatta gcagaagagc cgaagtctgt cgttgcgcgg 2340atggaagaaa tcagagatgc gcttttccgt ttcgagaaca tgcgagtctt agttatcgct 2400gacctggaga aacttcaaaa ccctgtgtca gcatggaaac catttgctga gcgtttgggt 2460gcaggtgccc ctctacagcc tatcacgact agaagaccgt tgctcagtga ggcaggccag 2520aagttgggcg gtaagtcgta tgtggttcct atgccgacga ttgattcatc gttcgcatat 2580gctaccgcac gtggtttgga ttcttatgat gatccaagac ttcctgcctt aatggttgca 2640attgcataca tgaacgcggt tgagggtccc ctctgggttg cagttcgagg caagggtttg 2700gcatatggca cgaactttgc ctataacatt gataccggat tcgtcaactt cgacgtttac 2760cgctccccca acgcccataa agccttcgac tccagcaagc agattgttga ggatcacctc 2820tctggtgcga tgcccttcga tcccttgatg ctggagggtt ccattagcag cattgtggta 2880agctttgcga atgaacagtc gacaattggt agcgcagcct caggcagttt catccgacag 2940gtgattcggc gcctgcctag cgactacaag gagcgggtgc tcaagcaggt gcgggctact 3000agcgttgatg acgtgaaagg cgctctgaag gacatcattc tgcctttgtt taacccgtcc 3060acggccaata tcgtggttac ctgcgctaca gtgcttgagg agactatcaa ggaaggtctc 3120caggcatcgg gattcacgcc tgcggtgcag ccactcaaag aattcgaaga tgactatggg 3180ctgaaggtcg gcgatgacga ggacgaggag tccgacgatg acgacgatga gtatgaaacc 3240ggatctgaag atgaagatga cagtgatgaa gacatggagg atgacgaaga tgatgagtga 3300602181DNAAspergillus niger 60atgggagctc ttcagtggct gtccatcacg gctgctgcgg cctccgcagt gtcagccttg 60accccggagc agatgatcgg tgccccacgg agaaccgaag ttataccaaa cccctccggt 120gacaccggtc tattctcgac ctcccaatgg tcgtttgaca ctcattctga gagcacctgg 180tggagcttga tcgacctcca atcgggcaag accaccactc tcaccgatga tagcgatatc 240gaggagatca tctggcttgg ctctgacaat tctacgctcc tctacatcaa cagcaccaac 300gcgcaggttc ccggtggcgt ggagctgtgg attgcggact cttctgactt tgcaaatgct 360tacaaggcag cctctctctc cgccggtttt ctcggcatca aatcaaccgt gacagattcc 420ggcgacgtgc atttcatcct tcgtggaaag tcctatccca acggaacggc atacaatgat 480cagctcgccg agacctatcc cagtacagcc cgcatctacg acagcatctt tgtgcggcac 540tgggacactt acctgaccac cgcctcccac gctgtattct ccggtaccct gcaaagctcg 600accagcgacg acggcaatgt tcaatatacc tcttcagggg gattgaccaa cctggttaac 660ccagtcaagg gtgccgaaag cccattccct ccttttggag gcaacgacga ctatgacctc 720tcgcctgacg gcaaatgggt taccttcaag agcaaagcgc cagagctgcc tcttgctaac 780aacacggctg cctatgtcta tctcgtccca cacgacggct ctgcgactgc ctttgccgtc 840aacggccctg atagtcctgc aaccccggag ggagttgaag gagaatccaa caatcccgtg 900ttctcccctg atagcgacaa aatagcgtac ttccaaatgg ctactaatac atacgagtcg 960gaccgcaacg tgctatacgt atactccatc gccgatgaca ccatcactcc ccttgcaaag 1020gactgggacc gatcgcctag ctccgtgaca tgggtcgatg gagacaacct cgtcgtggca 1080agccaagatc taggacgaac cagacttttc gccatcccag gcgatgcagg ggacgacttc 1140aagcccacga acttcaccga cggcggctcc gtgtcggctc aatacgtcct atccaactct 1200accctcctcg tcacgtccag cgccttctgg acaagctgga gcgtctacac cgccagccct 1260gacgagggcg tgatcaacac actggcctca gccaacgaga tcgaccccga gcttagcggc 1320cttagttcct ccgactttga agagttctac tttgacggca actggactac cctccaagga 1380tggatcacct acccccaaga cttcgactca tccaagaaat accccctcgc cttcctcatc 1440cacggcggcc ccgaagacgc ctgggcggat gaatggaacc tgaaatggca ctccaaggtc 1500ttcgccgacc agggatacgt cgtcgtccag ccaaacccca caggaagcac cgggttcggc 1560cagcagctca cagacgctat ccaacttaac tggaccggcg ccgcctacga cgacctaacc 1620aaagcctggc aatacgtgca cgatacctac gacttcatcg acacggacaa cggcgtcgcc 1680gcgggtccca gcttcggcgc gttcatgatc acctggatcc agggcgatga ctttggacgc 1740aagttcaagg cgctggttag ccatgatggt ccgttcattg gcgatgcgtg ggtcgagacg 1800gatgagttat ggtttgttga gcatgagttc aacggcacct tctggcaagc gcgcgacgca 1860ttccacaaca cggatccatc cggccccagc cgcgtcctcg catacagcac cccccagctc 1920gtcatccaca gtgacaagga ttatcgcata cctgtggcaa atgggattgg actgtttaat

1980acgctgcagg agaggggcgt gcccagtcgg tttttgaatt tcccggatga ggatcattgg 2040gtcaccgggc aagaaaacag cctcgtctgg tatcagcagg tgctgggatg gattaatcgg 2100tattctgggg tgggagggtc gaatcctgat gcgattgctt tggaggatac ggtgaatccg 2160gtggtggatt tgaatccttg a 2181611695DNAAspergillus niger 61atgacgaggc agacttctct cgttcccagg ctactaacgc tagcctcact agctgcactt 60tcacaagcag agctaggcaa gatccaatgg aaaggatctt gcaacttgac cacttatccg 120gcattgatct gtggaacact agacgtgcca tacgactaca cggagtcaaa ttccagcaag 180acactgactc tcgacatcgc caagtggcca gcgaccaaga aaccagtctc ggagcccatc 240atatttaact ttggaggacc tggtgtcaat tcgttcgagg gccttgggct ttatggagag 300gaatttcagg ctattcttgg aggtcacaat gatttgatag cttttaacaa ccgaggcgtt 360ggaaacacca tcccgttctc ctgctacagc gatgacgcca cccgtgaact cgtcgccctt 420caagctccta acgacggcag agcgtccagc acggctttgg gagaaatctg ggcccagaac 480gcaaacatcg cacaggcatg ctatgctacg aacaatcaaa ctggtagtct tattggaact 540agctttgctg caagggacat catgcaggtc gctgatgcgc tcagtggaaa ggatagtttg 600gtcaactact ggggattctc atacggcact acaatcggtg ctgttctcgc agccatgttc 660ccggatcgaa tggggaatgt cgcgcttgac ggagtggaca accccagaga ggctctttat 720ggatacaacg cacaagcggt tgtggacgtc gacaaagttt tcgaaggatt ctgcacgggc 780tgcatggccg caccggacct ctgccctatc gccaaggagt acaccagcgc cgccaacttg 840gaagccgcaa tttacctgat gctggaaaac ctcaagtaca acccgattgc cattcccgaa 900accggtggaa tcgtaacttg gagcgacgtc aagtcgacca tttttgaggc catgtacctg 960ccaagctctt ggcccttgac ctctgagctt ctttactacg tgcaaacccg caacacaacg 1020atccttggca actctgaagt atacgacacc atcaaatcct acggtcaatc ggcttctttg 1080acttcggctt ccgatgaggt cggcacggcc attacatgct ccgacaagca tcgatctgcc 1140accattaaag aggtcctccc gtacgtcaaa gccagacagg ctctgaccaa gatcggaagt 1200gatggctcgg acggcgacat gagatgcgcg cagtggaatc cgaagatgtt cgccaaggag 1260cgctactccg gtgactttga agtcaagaca gccaacccgg tgttgattct gagcaacact 1320tacgatccag cgactcctct tcccgcagcg aagaacctga cagagacctt tgagggaagt 1380gtcttgctcg agcagaacgg atacggtcat actaccctgt ctatgccatc tctttgcact 1440gccaaggccg tccgggctta cttcaccaat ggcacattgc ccgctgacgg aacgatctgc 1500caggtggacg tgcctctgtt cacgaacttg acctacaagg atgtgtggcc gaagagtttc 1560caacggagcg ttgagtcgag ggatgatgcg actatcctca aggctttgat gtcggtccgt 1620gataagatgt cgcgacgcag gatgtgtatt tatttgtaca ccaacagcgc ttcatggaga 1680ccggaacttc cctga 1695621581DNAAspergillus niger 62atgtactact ctctctgggt tgctgccttg gtggccgcgc tgcccgtctc ccgggcccag 60tttgtggctc cgcccacgga tctcattccc accaagggat atctcgacat ccccgtccgc 120tacaaacagg tccccaccgg catttgtgag actgatccca gtgtcaagag cttctccggt 180tacgtcgatg tcgctgagca tgagcacatc ttcttctggt tcttcgaggc gcgcaaccaa 240gatcccaccg aggctccctt gaccgtctgg atcaatggag gcatgtctga ccccggtcct 300ggttcctcct ccatgatcgg cttgttccaa gagcacggcc catgcggcat tgacgccaat 360ggctccgtct acaacaaccc ctactcctgg aacaacgcca gcaacatgct ctacatcgac 420cagcccgtgc agaccggctt ctcctacagc attccggttc ccggctatgt ggattcttcc 480acagacaatg gttttatggg cgcatttcct cagtactcgc gcgaaacctt ccacttcacc 540acggagagtt atggcggcca ctacgggccc gtcttcaacg agtacatcga ggagcagaac 600gcccatctcc agccgggagc caagaagatc caactgggca gtgtgatgat cggcaatggc 660tggtatgacc cgattattca ataccaggcc tactacaact ttacggtata tccgggcaac 720acatacgact acctgccatt caacaagtcc atcagctcgc tgatgtacaa caacctctat 780ggccccggaa actgcctcga ccagctctac gactgcgccg cccgaggcat cgacgagatc 840tgcagcactg ccgacgattt ttgcgccaac gaggtcgaaa acgtctacga catttactcc 900ggtcgggatg agtatgactt tcgtgaactc actccggacc cgttccctta cgagttctac 960gttgactacc tgaacaaagc gtccgtgcag gccgccatcg gcgcatacat caattacacg 1020gagagcaaca acgctgttgg actcgccttt tcgtccaccg gtgacgacgg gcgactcatg 1080aacaccatcc aggatgtggg caagctgctc aaacagggtg tcacggtggt catgtacgcc 1140ggggatgccg actataactg caactggctg ggtggggaag ccgtgtcgtt gcaggtcaag 1200gccgccaact tcagtagtgc gggttacacc aacattgtca cctcggatgg agtgacacac 1260ggccaggtgc gccaggcggg gcaatttgcc tttgtgcgag tgtatgagag tggacatgag 1320gttcccttct atcaaccctt gcttgcgctg gagatgtttg agcgcgtcat tggcggcaag 1380gatgtggcga cgggaaagat tcccatctcg tcgagtttac agacggtggg cacgcccaag 1440agttactacc gggagggcaa cagcacgatt cagtgggagg tgttggattc tctggcgacg 1500tacaacacaa ccacgaatgc tccgaacccg gtgagccgga ggctgaagcg gatgggacca 1560gctttgcggt ttcagatgta g 1581633471DNAAspergillus niger 63atgtcttgcg tctggctcca catccacaaa aggagcctac tgtctgtcgc tacgaacaat 60tctgttgcga gggccgctgc ctctacctcc gccgcgccgc cgccgccgtc atcgccgccg 120cctggttcta atacttattc gcctctttat cgccccatca ccaatcccat cggatttact 180ttgtcgcctg cgaggtcact agtttctcgc aatcctaaat ttcctgccta tcggcgctct 240agtcgacact tttctttgtg cccggccgct gcaacgcccg gtgtcaccac gagcatctgc 300cctggtcagg cgcccgtccg ctctctcagc tcgctcatta tacactctac gagaccccgt 360gctatacgta tccgtaccga ccagatggat ttgaatggag acgcaggcgc caagcgcaag 420cgcagctcca tcaccacacc cgccgaacgg cccgtaaagc accttcgccc cgaatcgagc 480gcattgacac ccggggattc gacgcctgcc aatgggactg tatacgatgt ggaggatgat 540gaagatgcga gtcgtctgct gcctgtaggg cctgctcagg ccgactcacc ggaatggcaa 600gctaccatag aggaggttgt gaaaagcgta gtgtctatcc acttctgtca gacctgctcc 660ttcgacacgg agctgtccat gagtagtcag gctactgggt ttgtggtaga tgcagagaat 720gggtacatat tgacaaaccg acacgtggtt tgcccgggac ctttctgggg atactgcatc 780tttgataacc atgaggaatg cgacgttcgt cctgtgtatc gggaccctgt tcacgacttt 840ggaattttga aattcgaccc gaaggctatt cgatatatga aattgaggga actgaaactg 900cagccggatg cagctaaagt gggatcagaa attcgcgttg tgggtaatga tgcaggagaa 960aaactgagta ttctgtctgg tgtcattagt cggctggata gaaacgcgcc cgaatacggc 1020gatggctaca gtgacttcaa tacgaattac atccaggccg ccgcagcagc tagcggtgga 1080agttccggca gtcctgtagt taacattgat ggccatgcga ttgctctgca ggccggtggt 1140cgtgcagacg gtgcagcgac ggattacttc ctccctctgg accgaccgct acgcgcactg 1200gaatgcatcc gtcgcggaga gcctgtcacg cgtggaacga ttcagacgca gtggatcttg 1260aagccgttcg acgagtgtcg tcggttgggc ttgacgcctg agtgggaggc gaccgtgcgt 1320aaagcagcgc ccacggaaac cagcatgctg gtggccgaga tcatcctgcc tgaaggcccg 1380gcggacggaa agctcgagga aggagacgtg ctcctgcagg tcaacggggt gcttctcacc 1440caattcatcc ggttggatga catcctggat tcgagtgttg ggcagacagt gcgtctgctt 1500gtccaaagag gcggtcagaa tgtggagatt gagtgccagg ttggcgacct gcatgccatc 1560acgcccgacc ggttcgtgac ggtggctgga ggcacgttcc ataacctgtc ttaccagcag 1620tcgcggctgt atgccatcgc tactcgcggt gtctacgtct gcgaggctgc cggctccttc 1680aaactggaaa acacactgtc aggatggatc atcgactcgg tggacaagcg gcccactcgc 1740aatctggatg agttcgtgga ggtgatgcga acgattcccg atcgttcgcg cgtggtcatc 1800tcgtatcggc atattcgcga tctccacacc cgaggcacca gcatcgtcta tatcgatcga 1860cactggcacc ccaagatgcg actggctgtg cgcaacgacg acaccggtct gtgggacttt 1920tcggacctcg cggaccctat cccagctctt cctccggttc cgaggaaagc cgatttcatt 1980caactcgatg gtgttagcca gcctgctgcg gccgacattg tgcgcagctt cgtacgagta 2040tcctgtacga tgcccctgaa gctggacggc tacccccagg ccaagaagac tgggttcgga 2100ttggtcgtcg atgcagagaa gggtttggtg gttgtgtcgc gagcgatcgt gccgtacgac 2160ctctgcgaca tcaacgtcac ggtggccgac tccatcatcg tgaacgctaa agtagttttc 2220ctgcatccgc tccaaaacta cagcatcatc cagtacgacc caagcctggt gcaggcgccg 2280gttcagagtg ccaaactcgc caccgactac atcaagcagg gacaggacac gatctttgtg 2340ggattcaacc agaacttccg gattgtcgtg gccaagaccg ccgtaaccga catcaccact 2400gtttctattc cagccaacgc gtccgcaccg cgctaccgcg cgatcaacct ggacgccatc 2460actgtggaca ccggactcag cgggcagtgt tctaacggtg tcctgattgg cgaggacgga 2520gtggtgcagg cattgtggtt gaactatctt ggagaacgca catctaattc gcataaggat 2580gtggaatacc atctaggatt tgcgactcca tctcttcttc ctgtcctgtc gaaggtgcag 2640cagggagaga tgccggaatt gcggattctg aacatggaga gctacgtggt ccagatgagt 2700caagctcgta tcatgggcgt gtcggaggaa tggatcgaga aggtgacgca agctaaccca 2760tcgcggcatc agctcttcat ggtgcgcaag gtcgattgcc caccgcctgg gttcaactca 2820gcggccgaca cgttcgagga gggtgatatc atcctgacct tggacggaca gctgatcacc 2880cgcgtctcgg agttggatat catgtacgag aaggatacgc tggaagccct gattgttcga 2940aatggacaag aaatgcggat ccaggtgccg actgttccaa cagaggacct agagactgac 3000cgtgcggtcg tgttctgtgg tgctgtgttg cagaaaccac accatgcggt ccgtcagcag 3060atttctaagc tacacagcga agtctacgtc agcgcaagaa gtcgcggatc cccctcctac 3120caatacggct tggccccaac caatttcatc accgccgtaa acggcgttcc aaccccgaac 3180ctggaccgct tctccgaaga agtgagcaaa atccccgaca acacatattt ccgcctacgg 3240gcggtgacat tcgacaatgt gccgtgggta gtgaccgtga agaagaacga tcattacttc 3300cccatgtccg agtatatcaa agaccagtcc cagccttccg gttggcggac cgtgtctcac 3360gacaaggata aatataaaga cggcattgca ccggatgctg cgaacttgaa cccggatgct 3420atggacgaag ggtttgatgg agtcagtgat attgagccgg atttggagtg a 3471641611DNAAspergillus niger 64atgagagtcc ttccagctgc tatgctggtt ggagcggcca cggcggccgt tcctcccttc 60cagcaggtcc ttggaggtaa cggtgccaag cacggtgccg accatgcggc cgaggtccct 120gcggatcaca gtgccgacgg gttctccaag ccgctgcacg cattccagga ggaactgaag 180tctctctctg acgaggctcg taagctttgg gatgaggtgg ccagcttctt cccggagagc 240atggatcaga accctctctt ttccctcccc aagaagcaca accgccgtcc cgactcgcac 300tgggaccaca tcgtcgatgg caagctggaa gcctatgatc tcagggtcaa gaagaccgat 360cctggctctc ttggcatcga ccccggcgtg aagcagtaca ccggttatct cgatgacaac 420gagaatgata agcatttgtt ctactggttc ttcgagtctc gcaatgaccc cgagaatgat 480cccgttgttc tgtggctgaa cggtggccct gggtgctctt ccctcaccgg tctcttcatg 540gagcttggcc ctagcagcat caacaagaag atccagccgg tctacaatga ctacgcttgg 600aactccaacg cgtccgtgat cttccttgac cagcctgtca atgtcggtta ctcctacagt 660aactctgctg tcagcgacac ggtcgctgct ggcaaggacg tctatgcctt gcttaccctc 720ttcttcaaac aattccccga gtatgctaag caggacttcc acattgccgg tgaatcttat 780gctggtcact atatccccgt cttcgcttcg gagatcctgt ctcacaagaa gcgcaacatc 840aacctgcagt ccgttctcat tggcaacggt ctcaccgacg gatacaccca gtacgagtac 900taccgtccca tggcctgcgg tgacggcggt tacccagctg tcttggacga gagctcctgc 960cagtccatgg acaacgctct tcctcgctgc cagtctatga ttgagtcttg ctacagttcc 1020gagagcgctt gggtttgtgt cccggcctcc atctactgta acaacgccct ccttgcccct 1080taccagcgca ctgggcagaa cgtctatgat gtccgtggta agtgcgagga tagctctaac 1140ctttgctact cggctatggg ctacgtcagc gactacctga acaagcccga agtcatcgag 1200gctgttggcg ctgaggtcaa cggctacgac tcgtgcaact ttgacatcaa ccgcaacttc 1260ctcttccacg gtgactggat gaagccctac caccgcctcg ttccgggact cctggagcag 1320atccctgtct tgatctatgc cggtgatgct gatttcattt gcaactggct gggcaacaag 1380gcctggactg aagccctgga gtggcccgga caggctgaat atgcctccgc tgagctggag 1440gatctggtca ttgtcgacaa tgagcacacg ggcaagaaga ttggccaggt taagtcccat 1500ggcaacttca ccttcatgcg tctctatggt ggtggccaca tggtcccgat ggaccagccc 1560gagtcgagtc tcgagttctt caaccgctgg ttgggaggtg aatggttcta a 161165840DNAAspergillus niger 65atgaagttca caaattatct cttgacgact gcaacgctcg caagcagtgt cctagcggct 60cctgctcccc gcaccggttt ggaggacaga ctccgtgccc ggtcattgca gcgtcaatca 120catcctctgg cacctattcc acttgacaca tccaccaaag agaattccag actcctcgaa 180gccgacgaga ataccaccca tgttacatac agcagtaact gggcgggcgc agtgcgcgag 240caaccacctc cgcaaggcac gtattctgcc gtgtcggcaa cctttcgtgt accagaaccc 300acggcgcaag gggggagcgg aacgcaggct gggtcggcct gggtcgggat agatggcgac 360acatacagca acgccattct acagacagga gtcgacttct acgtggaaaa cgggcagacg 420tacaacgatg cctggtatga gtggtaccca gactatgcat atgacttcga cctagatgta 480agcacagggg acacgatcgt cgccaaggtg gaagccatct cgccaagtca aggtgtagcc 540actattgaga acatatcgac ggggaagaag gccacgcaga cgatcagagc cccagctgcg 600acagctaccc ttgccggcca gaatgccgac tggatcgtgg aggatttcca gtctggcgac 660tcaatggtcg atctggctgg ctttggcgag atcagcttct ggggcgtgca agcacaagga 720ggagggtcta catggggtgt agatgatgcg actattgtcg aactgaagca gggcaacgaa 780gtgttgacag acgtggaggt gcaaagtgat tcggccttta cggtgaaata tacgagctga 840661722DNAAspergillus niger 66atgatatatg tcaactatat cctgggactt ctgtccctct tacacaccgc tgtagccaca 60gctcctgatt atgtcgtggt agaccaactg aacagcatcc ccgacggatg gacaaaaggc 120gcagctcccc cgccatttac tccgatgaag ttctggttgt cgatgcatca cgagtacaag 180gcggacttcg agcagaaagt catcgatatc tcgacacccg gtcaccggga ttatggacgg 240catatgaaac gcaacgatgt catggccttt atgcgcccat ccgatcaggt ctcaaagatc 300atcttctctt ggcttgagtc ggagcatgtt ccaccaaatg ccatcgaaga tcgcggggat 360tgggtcgcct tcacagtccc gttggcccaa gcacaatcaa tgatgaagac cgatttttac 420aacttccacc acctggaaac aaacacaacc caaattagga ccctcaagta ctccgttccc 480gagcaagtcg atgctcatct gcaaatgatc cagccaacga ctcgcttcgg ccgacctaag 540acacaaacca gcctaccgag cctcatgcca gtgtcggtta acattgatga aataagcgaa 600gactgcttga caggcgtgac gcccatttgc cttcgccagc tctatggttt acctagcacc 660aaggcaagcc ccgactcgag aaacgtcctc ggaatttccg gctatctgga ccagtacgcg 720cgctacagtg acctcgacga gtttctagcc gtatactctc caaacagcgt agacgccgac 780ttctccgtag tatcgatcaa cggaggccaa aacccacaaa actcacaaga gggaagcaca 840gaggccagtc tcgacatcca atacgccctc tccatggcat ttgacgctaa cgcgactttc 900tacactaccg ccggacgtgc gccatccccg tatctcgaac agctccagta tctggtgggt 960cttccggacg aggatcttcc tgcagtgctt agcacgtctt acggcgagga tgagcaaagt 1020ctgccggagg aatacacaga agccacgtgc aatttatttg cccaattagg tgcacgcggg 1080gtctcggtga tcttcagcag cggagactcg ggcgtcggag gatcgtgtgt atctaacgac 1140ggaagccaga ggacccgctt tcagcctatc ttcccggcgt cgtgcccgtt tgttacatcc 1200gtgggtggga ctgagggcgt cgggccggaa aaggctgtgg acttttcgag tggagggttc 1260tccgagcgct ttgctcgccc gtcgtaccag aatgcgagtg tggaagcata ccttgcccgc 1320ttaggagata aatgggatgg attgtataat ccagacggac ggggtattcc tgatgtgtcg 1380gcccaggcta gcaactatgt aatcagggac catgggcaat ggctacaaac tgcgggaaca 1440agtgctgccg cccctgtctt tgcagcagtc atctctcgac tgaacgctgc acgtctcgag 1500cagggtaaac ctacactagg gtttctgaat ccttggctgt actcactcga ccagcaagga 1560tttacggata ttgtagacgg cggatcagtg ggttgtgacg ggtcaaatgg aggagctctt 1620gtcccgtatg ccagttggaa tgccaccaag ggatgggatc cggttactgg gctggggaca 1680cctctgtatc agactctgga gcagttggcg cagtctgctt ag 1722671758DNAAspergillus niger 67atgcgttctt ccggtctcta cacagcactc ctgtgctccc tggccgcctc gaccaacgcg 60attgtccatg aaaagctcgc cgcggtcccc tccggctggc atcatgtcga agatgctggc 120tccgaccacc agataagctt gtcgatcgcg ctggcacgca agaacctcga tcagcttgaa 180tccaagctga aagacttgtc aacacctggc gaatcgcaat acggccagtg gctggaccag 240gaggatgtcg acacgctgtt cccggtggcc agcgacaagg ctgtgattaa ctggctgcgc 300agcgccaaca tcacccatat ttcccgccag ggcagcttgg tgaactttgc gaccacggtc 360gataaggtga acaagcttct caacgccacc tttgcctact accaaagcgg ctcttcccag 420agattgcgca caacagagta ctccatcccg gatgatctgg tcgactcaat cgacctcatc 480tccccaacga ccttcttcgg caaggaaaag accactgctg gtctgaacca gcgggcgcaa 540aagattgaca cccatgtggc caaacgctcc aacagctcgt cctgtgccga tgtcatcacg 600ctgtcctgcc tgaaggagat gtacaatttt ggcaactaca ctcccagcgc ctcgtcgggc 660agcaagctgg gcttcggcag cttcctgaac gaatccgcct cgtattctga ccttgccaag 720ttcgagaagc tgtttaacct gccctcccag agcttttccg tggagttggt caacggcggt 780gtcaatgatc agaatcaatc gacggcttcc ttgaccgagg cggacctcga tgtggaattg 840ctcgtcggag ttgctcatcc cctcccggtg actgagttca tcacttctgg cgaacctgcc 900gccgacaacg agaacgagcc ttacctccag tactatgagt accttctctc caagcccaac 960tcggctctgc cccaagtgat ttccaactcc tatggtgacg acgaacagac cgttccagag 1020tactacgcca agcgagtctg caacctgatc ggacttgttg gcctgcgcgg catcagtgtc 1080ctcgagtcgt ccggtgacga aggtatcgga tctggctgcc gaaccaccga cggcaccaac 1140cgaacccaat tcaaccccat cttcccggcc acctgtccct acgtgactgc cgtgggagga 1200acaatgtcct atgcccccga aatcgcctgg gaagccagtt ccggcggatt cagcaactac 1260ttcgagcggg cgtggttcca gaaggaagct gtgcagaact acctggcgca ccacatcacc 1320aacgagacca agcagtacta ctcgcaattc gccaacttta gcggtcgcgg atttcctgac 1380gttgctgccc atagctttga gccttcatat gaggttatct tctacggcgc ccgctacggc 1440tccggcggta cctcagccgc gtgtcccctt ttctctgcgc tagtgggcat gctgaacgat 1500gctcgtctgc gggcgggcaa gtccacgctg ggtttcttga accccctgct ctatagcaag 1560gggtacagag cgttgactga tgtgacgggg ggccagtcga tcggatgcaa tggcattgat 1620ccgcagaatg atgagactgt tgccggcgcg ggcattatcc cgtgggcgca ctggaatgcc 1680acggtcggat gggatccggt gactggattg ggacttcctg actttgagaa gttgaggcag 1740ttggtgctgt cgttgtag 175868798DNAAspergillus niger 68atgaagacta ctgctctctt gaccgccggc ctgctggcca ccactgctat ggccgctcct 60ctgacggcca agcgccaggc tgctcgggcc aagcgctcca cgaaccgcca gagcaaccct 120cccttcaagc ctggcaccaa cgaggtcctc gcccttaacg gcaccaagaa tgtggagtac 180agctccaact gggccggtgc cgtcctcatt ggcactggtt acactgccgt gaccgccgag 240ttcgtcgtgc ccaccccctc cgtgccctcc ggtggctcga gccgcgagga gtactgtgcc 300tccgcctggg tgggcattga cggtgacacc tgtgacactg ctatcctcca gaccggtgtg 360gacttttgtg tccagggcag cgaggtgagc ttcgatgcct ggtacgagtg gtaccccgac 420tacgcctacg acttcagcgg catctccatc tcggccggtg ataccatcaa ggtcaccgtc 480gatgccagca gcgacaccac cggtactgcc acgattgaga acgtgagcac tggtaccacg 540gtcacccaca gcttcacggg cggtgttgat ggtgatctgt gtgagtacaa cgctgagtgg 600atcgtcgagg acttcgagga ggatgactcc ctcgttccct ttgccgactt tggcaccgtg 660actttcacca gctgctccgc taccaaggat ggttcctctg ttggccctga ggatgctacc 720atcatcgaca tcgagcagaa tgaggtgctg acctccgttt ccgtctccag tagcgaggtc 780gttgtcaagt acgtctaa 798691743DNAAspergillus niger 69atggtcgcct tttcccgcat ctcggcaggc ttcgcccttg ccgcccctgc cctggccagc 60gtcgtcctgg agaccgtcaa gtctgttccc agcgactgga agctcgtgga ggctgctgat 120accagctcca caatttcttt gtccgttgct ctggcgcgtc agaacctgga ccagttggag 180gagaagctcc tggccgtgtc cacccctggc aaggacacct acggccagtt cttggatctg 240gacgacatca atgagcagtt tcctctcgca gatgacgctg ctgttgtggc ttggctgaag 300aaggcaggcg tcacccagat ccataaggag ggtggtctgc tgaactttgc gaccactgtg 360ggcacagcca accagcttct caacaccacc ttctcggtgt acaagagcgg atctacccag 420aagctgcgca caacgcaata ctctgttccg gatgagctga ccgggtccat tgatctcatc 480tcgccgactg ttttctttgg aaagtccaac gctgcgcgct cggcggccgt gcgtgcttcg 540cagactacca aggagaccag cagaaagaag agcagtaatg tgtgcgagta catcactccg 600gattgcctca aagagcagta tagcattgac tatacgcccg aggcatcgtc gggaagtcgt 660gttgggtttg gcagtttctt gaacgagtcg gccttgtact cggatttgga tctgttcacc 720cagtactttg acattcccca gcagagtttc actgttgaga ctatcaacgg gggaatcaac 780aaccaggaga atgatccgga tggtgaagcc gatctcgatg tccagaacat cgtgggcatc 840tcgcatccct tgccggtgac ggagtacatt

accggaggat ctcctccatt cattcccgac 900gtcgagacta ctaccgacga gaacgagcct tacctgcagt actacgagta tctgctggcc 960aagaccaacg acgagctgcc actggttatc agcaactcgt acggcgatga cgaagatacc 1020gttcccattg cctacgccac ccgcgtatgc aacctcatcg gcctgatggg cacacgtggt 1080atctccatcc tcgagtcttc cggcgactct ggtgtgggcg gcgcatgcat gtccaacgac 1140ggcaccgaca agaccgaatt cacccccatg ttcccaggaa catgcccgta catcaccgcg 1200gtcggcggca cccaagacgt gcccgaagtc gcctgggtgg acagctccgg cggcttcagc 1260aactacttct cgcagccgtc gtaccagtcg gatcaggtgg agacctacct ggacaagtac 1320atctctgcct cgacgaagaa gtactacgag cagtacacca acttcagcgg tcgcgcgttc 1380cctgacgtgt ctgcgtttgc aggttctcct tactacgaaa cttatattga tggtcagctc 1440ggccttgtgg cgggtacttc tggcgctagc cctgtgtttg cggggatcgt cgcgctgctg 1500aacgatgccc gtctgcgggc caacaagaca tccttgggct tcctgaaccc ttggctgtac 1560tcgagcggct acaagagcct gaatgacatt accagtggcg aggcagtggg ctgccaaggc 1620gatgtggagg gcgctggagt cattccttgg gcgagctgga atgccacgac gggatgggat 1680ccggcgacag ggctgggaac gcctaatttt gccaagctga aggaggcggt tcttgcgttg 1740taa 1743701896DNAAspergillus niger 70atgcatggtc tgcgcctagt atgcagcata gggacattgc ctttggttat cctggcatat 60ccggcggctt cattgcatac aacttcagca gccgtggact tggactccct tcgtctgacc 120tctaactccg aatacgtcaa ttctgtccat gtagacacga atcgatcagt cgcagtgtcc 180gctgaagaac attataccga tacagcagct cgactggttc agaacattgt tcctggagcg 240agctttcgtc tcatcgatga ccactttgtc ggcgacaatg gagttgcaca tgtatacttc 300cgccaaacgc tccatggtat tgacattgac aatgcggatt tcaatgttaa tattggaaaa 360gatggactgg tcttgtcttt cggacattcg ttcttcacag gcgcgttgcc gagcagccat 420ctggacaata ccaacgtttt gagtccggag gctgcactta gaggagcaag ggacgctata 480cagcttccac tgactattga caatgtttct actgaagctg cagaggggcg gaacgagtac 540atattcagag aggcagtggg agcggtatct gaccccaaag ctaagctagt ctaccttgtc 600aagccagaag ggactctggc gctcacctgg aggatagaaa cagacatgta tgagcactgg 660ctactgacat acattgatgc agagactacc actgtccacg gcgtggttga ctatgtcgca 720gacgcgacat atcaagttta tccctggggc acaaacgatc cagcagaagg acatcgcacc 780attgtcaccg acccctggga cctatccgca tccgcataca cctggataag cgatggacgg 840gacaactaca ccacaaccag aggcaacaat gccatcgcac actggaatcc gaccggcggt 900ggctcctatc tctacaacct acgtccatcc gaccccaact tgaatttcca atggccatac 960tccccaaaca tgtccccacc ccgatcatac atcaacgcct ccatcgtcca actcttctac 1020acagcaaacg cctaccacga cctcctctat acactcggct tcaccgaatc cgctggcaac 1080ttccaatgga ataacagcgc ccacggcggc cgagacaaag actacgtgat cctcaacgca 1140caagacggct ccgggttcag caacgcaaac tttgcaaccc cacccgatgg tatccccggc 1200cgtatgcgca tgtacatctg gatcgagtct actccgtcgc gtgatggaag ttttgacgcg 1260ggcattgtaa ttcacgaata cactcacggt gtatccaatc gtctcaccgg cggctcccac 1320aacgccggat gcctcagcgc cctcgaatcg ggtggcatgg gcgaaggctg gggcgacttt 1380atggcgacgg ccatccgaat caagcccaac gatacacgca caacgtctta cactatgggt 1440gcatgggcag ataatgataa atgtggtgtc cgggactatc cttattctac ctcctttact 1500gagaaccctt tgaactatac gagcgtgaat accatgaacg gcgtgcacgc catcggaact 1560gtctgggcaa ccatgctata cgaggtcttg tggaacctca tcgacaagta cgggaagaat 1620gatgggtcga ggccggtgtt tagaaacggg gtgcctacag atggaaagta cttgatgatg 1680aagttggtgg tggatgggat ggcactgcaa ccatgtaatc cgaacttcgt gcaagccagg 1740gacgcgatcc ttgacgcaga cattgtgttg actggcggga agaatcgctg tgagatctgg 1800agggggtttg cgaagagagg attggggcaa ggagcggctc atagtagttt aaattggatg 1860cggaggggga gtacacttct tcctacggga tgttag 1896711185DNAAspergillus niger 71atggtcgtct tcagcaaaac cgctgccctc gttctgggtc tgtcctccgc cgtctctgcg 60gcgccggctc ctactcgcaa gggcttcacc atcaaccaga ttgcccggcc tgccaacaag 120acccgcacca tcaacctgcc aggcatgtac gcccgttccc tggccaagtt tggcggtacg 180gtgccccaga gcgtgaagga ggctgccagc aagggtagtg ccgtgaccac gccccagaac 240aatgacgagg agtacctgac tcccgtcact gtcggaaagt ccaccctcca tctggacttt 300gacaccggat ctgcagatct ctgggtcttc tcggacgagc tcccttcctc ggagcagacc 360ggtcacgatc tgtacacgcc tagctccagc gcgaccaagc tgagcggcta cacttgggac 420atctcctacg gtgacggcag ctcggccagc ggagacgtgt accgggatac tgtcactgtc 480ggcggtgtca ccaccaacaa gcaggctgtt gaagcagcca gcaagatcag ctccgagttc 540gttcagaaca cggccaatga cggccttttg ggactggcct ttagctccat caacactgtc 600cagcccaagg cgcagaccac cttcttcgac accgtcaagt cccagctgga ctctcccctt 660ttcgccgtgc agctgaagca cgacgccccc ggtgtttacg actttggcta catcgatgac 720tccaagtaca ccggttctat cacctacacg gatgccgata gctcccaggg ttactggggc 780ttcagcaccg acggctacag tatcggtgac ggcagctcca gctccagcgg cttcagcgcc 840attgctgaca ccggtaccac cctcatcctc ctcgatgacg aaatcgtctc cgcctactac 900gagcaggttt ctggcgctca ggagagcgag gaagccggtg gctacgtttt ctcttgctcg 960accaaccccc ctgacttcac tgtcgtgatt ggcgactaca aggccgttgt tccgggcaag 1020tacatcaact acgctcccat ctcgactggc agctccacct gctttggcgg tatccagagc 1080aacagcggtc tgggactgtc catcctgggt gatgttttct tgaagagcca gtacgtggtc 1140ttcaactctg agggccctaa gctgggattc gccgctcagg cttag 1185721197DNAAspergillus niger 72atgaagtcag cctccttgct cacagcatcc gtgctgttgg gctgtgcctc cgccgaggtt 60cacaagctca agcttaacaa ggtgcctctg gaagagcagc tttacacgca taacatcgac 120gcccatgtcc gcgctctggg ccagaagtac atgggtatcc gcccgtccat ccacaaagag 180ctggtcgagg agaaccctat caatgacatg agccgtcatg atgttctggt ggacaacttc 240ctgaacgcac agtacttctc tgagatcgag ctgggtactc ccccccagaa gttcaaggtt 300gtcctggaca ctggcagctc gaacctttgg gttccttcga gcgaatgcag ctctatcgcc 360tgctacctcc acaacaagta tgattcgtct gcctccagta cgtatcacaa gaatggcagt 420gaattcgcca tcaagtacgg ctctggcagc cttagcggat tcatttctca ggacaccctg 480aagattggcg acctgaaggt caagggacag gacttcgctg aggcgaccaa tgagcctggc 540cttgcctttg ccttcggccg gttcgatggc attctcggct tgggttatga caccatctcc 600gtgaacaaga ttgttcctcc cttctacaac atgcttgacc agggactcct cgacgagccg 660gtctttgcct tctaccttgg agataccaac aaggagggtg acgagtccgt ggcgaccttc 720ggtggtgtcg acaaggacca ctacaccggc gagctgatca agattcccct ccgtcgcaag 780gcttactggg aggttgagct tgacgccatt gctcttggcg atgatgttgc tgagatggag 840aacaccggtg tcattctgga cactggtacc tccctgattg ctctgcctgc tgacctggct 900gagatgatca atgctcagat cggtgctaag aagggctgga ccggccagta caccgttgac 960tgcgacaagc gctcgtccct gcccgatgtt actttcaccc ttgccggcca caacttcacc 1020atctcctcgt atgactacac cttggaggtg cagggctctt gcgtcagtgc cttcatgggc 1080atggacttcc ctgagccggt tggtcccttg gccattttgg gcgatgcgtt cctgcgcaag 1140tggtacagcg tgtatgacct gggcaacagc gctgttggtc tggccaaggc caagtaa 1197731182DNAAspergillus niger 73atgcgcaagt accgcttcca tcccaccaag cctggtccct acactctcag cagctccatc 60caacagaccg gtcgtccgta cactgaaaag cccatcgggg gtcgggccca tatccggcag 120ctggtgcgga agaagagcac caccagcgat gaggttggcg aggttccggc cgaagatgtg 180cagaacgact ccatgtatct ggcgaccgtg gggatcggaa ccccggcgca gaacctgaag 240ttggactttg acactggttc agctgatctt tgggtctggt ccaacaaact cccctcaacc 300cttctatccg agaacaagac ccatgcgatc ttcgactcgt ccaaatcgag caccttcaag 360accttggaag gtgaatcctg gcaaatctcc tacggagatg gatcctccgc atcagggagt 420gtgggcaccg acgacgtcaa cattggcggc gtagtcgtca agaaccaagc cgttgagctg 480gcagagaaga tgtccagcac attcgcccaa ggcgaagggg acggattgct cggtctagca 540ttcagcaaca tcaacacggt acagccaaag tccgtgaaaa cgcccgtcga gaacatgatc 600ctgcaggatg acattcccaa gtcggctgag ctgttcacgg ccaagctgga tacctggcgg 660gacactgatg acgagtcgtt ttacaccttt ggcttcattg accaggatct ggtgaagacg 720gcaggtgaag aggtctacta cacccctgtc gataacagtc aaggcttctg gctattcaac 780tcgacctccg cgacggtaaa tggaaagacc attaaccggt cgggtaacac cgccattgct 840gataccggta cgacgctggc cttggtggac gatgacacgt gtgaggccat ttatagtgca 900attgacggcg cctattatga tcaggaagta cagggctgga tctatccgac cgatacggcg 960caggataagc tacccactgt gtcgtttgcc gtgggtgaaa agcagttcgt ggtgcagaag 1020gaggacctgg cgttttcgga ggcgaagacg ggctatgtct atggaggaat ccaaagtcgt 1080ggtgatatga ccatggacat cttgggagac acatttttga agagtattta tgctgtaagt 1140gcattgctgt tggcgttaag gggtgatatc gaagctcact aa 118274849DNAAspergillus niger 74atgaagttct ctaccatcct taccggctcc ctcttcgcca ctgccgctct ggctgctcct 60ctcactgaga agcgccgtgc tcgcaaggag gcccgcgccg ctggcaagcg ccacagcaac 120cctccctaca tccctggttc cgacaaggag atcctcaagc tgaacggcac ctccaacgag 180gattacagct ccaactgggc tggtgccgtc ctgatcggcg acggctacac caaggtcact 240ggcgagttca ctgtccccag tgtctctgct ggatctagca gctccagtgg ctacggcggt 300ggctacggct actacaagaa caagagacaa tccgaggagt actgcgcctc cgcttgggtt 360ggtatcgacg gtgacacctg cgagaccgct attctccaga ctggtgtcga cttctgctac 420gaggatggcc agacttccta cgatgcctgg tacgagtggt accccgacta cgcctacgac 480ttcaacgaca tcaccatctc cgagggtgac accatcaagg tcactgtcga ggccaccagc 540aagagcagcg gtagcgccac cgttgagaac ctgaccactg gccagtccgt cacccacacc 600ttcagcggca acgtcgaggg tgacctttgc gagaccaacg ccgagtggat cgtcgaggac 660ttcgagtctg gtgactctct tgtggctttc gctgacttcg gctccgttac cttcaccaat 720gctgaggcta ccagcgacgg ttccactgtc ggcccctctg acgctaccgt tatggacatt 780gagcaggatg gcaccgtcct caccgagacc tccgtctctg gcgacagcgt cactgtcacc 840tacgtttaa 84975822DNAAspergillus niger 75atgggagatt acggccccgg agtgtcgtca ctcacggcac agctacctgg aaatccgcct 60gtctctgaaa cagatcagga tgagatctca gtacttgtaa cgggctttgg gccattcaag 120tctaatctag tgaacgcctc atatctgata gcctcgtccc taccaccctc tttcacattc 180tcacctgcat cttcagacgg ctctgatgct gttccccgtc gagtttcgat aaatgtccat 240ccttcaccca tacccgttgc atattcatcg gtgcggacga ccctccccgt cattctcgat 300gactatgcca agacgcacgg aggccgacgc ccagacatcg tcatacacat tggcatagca 360gcaatgagga actactattc cgtggagacg caggctcacc gtgatgggta tctgatgtcc 420gacatcaaag gcagatccgg gtacgaggat ggcgagaagc tgtggaggga gctcgacttg 480ccactggtgc ttagggctgg cccttcagag ggacacgcct cggagaagaa acatctcagc 540ccccgtccac cggacgaaga tttcctagca gcatggaaga cattttgccc tccagaaacc 600gatgcgcgga tctccactga tgccggacgt tatctctgcg agttcatcct gtacaccagc 660ttggcactgg cataccaggc gggtgaggat cgcaatgtca ccttcttcca tgttcccgcg 720tcatgcttgg atgaggatat agagacgggc aaggaggttg ccgtcgcgct aatcaaggct 780cttgtgacta gctggagtga gcagcagcac agcgttccct ag 822761629DNAAspergillus niger 76atgggctcaa ggcagggaaa ggcccccttt ggctggggta ctcagtcact tgctcacttt 60ggtatcaacc cagaccttgg gttgcacaac cagcagaacc tcaactccct catttcacat 120tcagcgatgg ccactgcgtt ggagacggaa tatgccacca tccctattga ccataacaac 180gcatcggctg gcacttatca aaatcggttc tgggtcagcg atgaattcta tcagcctggc 240aacccgatat ttgtgtacga taccggggag tcggatggcg gatcgatagc ccagtcctac 300ctaacctcca ctctctcctt cttcagagaa ttcctgatcg aattcaacgc catgggaatc 360gcctgggagc acagatacta tggaaactcg accccggctc ccgtatccta tgaaactcca 420cccgaggcat ggcaatacct caccaccaag caggcgctcg cggaccttcc gtactttgct 480agtaacttta gccgcgagaa gtatcctgac atggacctga cgccgcaggg cacgccgtgg 540atcatggtgg gcggctcgta cgcagggatt cgtgctgcat taactcgcaa ggagtaccca 600gagacgatat tcgcagcctt ttcctcatcg tctccggtgg aagcacaggt caatatgagc 660gcgtattacg accaagtcta tcgtggcatg gttgccagcg gatggaccaa ctgctcggca 720gatatccacg ctgctctgga atatattgac gatcaacttt cggatgaaga tacagctacc 780tcggtcaaac aacttttctt cggatctggc gccgagacca actccaacgg tgatttcact 840gcagcgctaa ctgccatcta cggctacttc caaagttatg gtatggcggg aggtattgga 900ggtctaggcg cattctgcga gtatctcgaa attgatccca agacgaacgg gactacagga 960ccggatggcc ttgcccctac gtatggcggc cagtatgtcg ccgaacgatg ggccgcatgg 1020ccaacctttc tcgagctggt caatctgaat atggggacca actgcgggcc tcaggacgcg 1080tctcagccaa ttgactgtga cttttccaag ccatacggcg atccctcggc catcacttgg 1140acttggcaat actgcagcga atgggggttc ttccaggcga acaacgatgg gccgcactcg 1200ctggcctcgc gatatcagtc ggtggaatac cagcaagaag tatgtaaccg gcagttcccc 1260gatgcagtgg acaagggact gctgcctccg tcgccgcggg cggatgatgt caaccaagag 1320tttgggggat ggacgatccg cccgtccaat gtttacttca gcggaggaga attcgatccg 1380tggcgatcat tgtccattct gtcgacagaa gatttcgcac ctcaaggggt ggagtttacg 1440agcgcgatcc cagcctgtgg ggtgcagacc aatgaggaca ccgtctttgg atacgtcatg 1500cagaactcgg aacattgctt tgactttcaa gcgacgccga ccgtggggaa gttatcacgc 1560ggcatcttca catccgcctt gttgcaatgg ctcgaatgtt ttggacagaa ctcaagccaa 1620tccaggtga 1629771176DNAAspergillus niger 77atgaagctct caatagctct tgcactcggc gcaacggctt cgacgggggt gttggctgct 60gttgtaccgc agcaagaacc gctgataacc ccccaagatc ccccaactca tcatcatcag 120gagaagttct tgatcgagtt ggctccttat cagacgagat gggttaccga ggaagaaaag 180tgggacttaa aactggatgg cgtgaacttc atcgatatta ctgaagaacg aaacactggg 240ttctacccaa cgttgcatgc tggtagctat gttcactatc cgccgacgat gaagcatgcg 300gagaaggtgg ttccccttct gcggggtctc tccaaggaca acatggagca aaacctcaac 360aaatttacct catttcacac tcgctactat aggtcgtcca ctggtattga gtccgcaaag 420tggctataca gtagggtttc ggatgtcatt gagcagtcgg gtgcagcaga gtacggcgcc 480actgtggagc agttcgctca ctcatggggc caattcagta tcattgctcg gatcccaggc 540cagactaaca aaactgttgt cctgggcgca catcaggaca gcatcaatct tttcctcccc 600tccatcctag ctgcacctgg tgccgatgat gacggaagtg gaaccgtgac tatactcgaa 660gctttgcgtg gtctgctgca gtcagacgcc attgtccggg gcaacgcttc caacacaatc 720gaattccact ggtactcggc agaggaaggt ggtatgcttg gttcgcaagc catattctct 780caatataaga gagataagcg agacatcaag gcgatgcttc aacaggatat gactggttat 840acccagggag ctctggacgc cggtcgtcaa gaagccattg ggattatggt tgactacgtt 900gatgagggac tgacacaatt cctcaaagat gtcactactg agtattgtgg tattggctac 960atcgaaacca gatgtggcta cgcctgttcg gaccacacgt ccgcaagcaa atatggctat 1020cccgcagcta tggcgacgga atccgaaatg gaaaacagca acaagaggat ccacacgact 1080gatgacagca tccggtatct aagcttcgat catatgctgg agcatgcgag gttgacactt 1140ggcttcgctt acgagctggc ctttgctcaa ttctag 1176781329DNAAspergillus niger 78atgagaacta ctacgtcttt tgctaggctt gcattggcag tggcctcagt tggtattgtc 60tttgctagtc caacaaaaaa taacgatggg aaactggtat atggctcacc agaatccgtc 120ggcatgatat ccgccccttt gcaccaaatg gtccaaaatg ttagcgcata tacacatgct 180gccaactata gcaagttctc gtacgacaaa gtccatccca tcgagccagg gtctgttacc 240ctggtggctc tcgacggtgt catcgtcagc gaatttgcct tgggcaagag aaatctctac 300gccgatgtca acggcaccaa tttacctcga tacctgcagg aagacaccac cctggataca 360gtctacgata tggcaagcct cacgaagctg ttcaccacgg tagctgcttt acgggaactt 420gacgctggtc gaattgcgct taatgtaact gttgcaactt atataccgga ctttgcgacg 480aatgggaagg agaatattac tatcttggag ctgttcacgc atacaagcgg tttcgcttct 540gatccatcgc caccactttt ctctgcttat tatacgacgt atgatgaacg cattaaagca 600attttgacgc aaaaaattat caataccccc ggcagcacat acctctactt agatctcaac 660tttatgtcgc tgggcctcgt tatcgagacc gtaacgggac gtgccctgga tgatcttatt 720tatgacttca ccagaccgct tgaaatgaca tctaccttct tcaaccgcgg gaatatcgaa 780ggctctacac cccagtcacc caactacgac cgcacagccg tacaagaatt tcagatcgca 840gccctcggac cctcagaacc acagcgtcca caaccagtgc gcggcacagt tcacgacgag 900aacgcatggt ccctagacgg cgtatcaggt catgcaggtc tattctccac tgtgcgcgat 960acagcgacat tctgccagat gatcctcaac aacggcacat atgcaggcca acggatcctt 1020tctcgaacag cggtagacat gattttcaca aacttcaatg ccaggtttcc gggggatgct 1080cgtagtttag ggtttgagtt ggatcagtat tctactgcgg gaccgatggc gagtttgcaa 1140actgcgagtc acactggatt tactgggact acgttggtga tggataggac gtataacgcc 1200ttttggttgc attttagtaa ccgggtgcat ccgtctaggg catggtctag caatactatt 1260gtgagagagg ctattgggta ttgggttggg aagagcttgg ggttggatgt tgcgtttgct 1320ctgttgtaa 1329791839DNAAspergillus niger 79atggcgtcct ggttgctctc gacgctcctt tttctgagcc cgtccttggt gtcagccaaa 60tcggccgcag actattatgt tcactccttg cccggtgccc ccgaggggcc cttgctgaag 120atgcatgccg gccatattga ggtggatcca cagaacaatg gaaatctttt cttctggcac 180taccagaatc gccatattgc caaccgccag cggactgtga tctggttgaa cggtggtccc 240ggatgtagtt ccatggacgg cgcgttgatg gaggtcggtc cgtatcgcct gaaggacaat 300gaaaccttga cctataatga gggttcctgg gacgaattcg ccaatttgtt gttcgtcgat 360cagccagtcg gaaccgggtt cagttatgtc aacacggaca gctatcttca tgagctcgat 420gagatgtcgg ctcagttcat tgtctttctg gaagagtggt tcagattatt tccggagtat 480gaacgcgatg atatctacat tgccggcgag tcttacgccg gtcagcatat tccatacatc 540gccaaagcca tccaggaacg gaacaagaac gttcaaggga agaccatcgc ttcgtggaat 600ctaaaaggcc tattgattgg caatggttgg atttctccta atgaacagta catgtcctac 660ttgccctacg catatgaaga aggccttatc aaggaaggca gccggaccgc gaaggaactc 720gaagttttac agtcagtctg taagtccagg ctggaaactg gcaagaacaa ggtccacctc 780aacgactgcg agaaggtcat gaatgctctg ttggataaga cggtcgaaga caacaaatgt 840ctcaacatgt atgacatccg ccttcgtgac accaccgatg catgcggtat gaactggccc 900accgacctgg aggacgtgaa gccctatctg cagcgggaag atgtggttaa agcgcttaac 960atcaatccgg agaagaagtc tggctgggtg gagtgttcag gtgcagtgag cagcgctttc 1020aatccgcaaa agtccccgcc ctcggttcaa ctacttcccg gcttgctgga atcgggactt 1080caaatcctcc ttttcagcgg agacaaggac ctgatttgca accatgttgg aacggaacag 1140ctcatcaata acatgaagtg gaacggaggc acgggtttcg agacctcacc tggcgtctgg 1200gctcctcgac acgactggag tttcgaaggc gagccggcgg gtatctatca atatgccaga 1260aacctgactt acgtgctcat ctacaacgca agccatatgg ttccctacga ccttcctcgt 1320cagagccggg acatgctaga tcgcttcatg aatgtcgata tcgcgagcat cggaggcagc 1380cccgccgact cgcgcattga cggcgagaag ctgccccaga cgtcggtggg cggccatccc 1440aacagcaccg cggcggagga gcaggagaag gagaggatca aggagacgga atggaaagcc 1500tacgccaagt caggcgaagc cgttctcctc gtcgtcatta tcggtgtatt agtttggggc 1560ttcttcatct ggcgcagccg ccggcgtcac cagggatacc ggggcgtctg gcataaggac 1620atgagcggaa gctctgttct cgagcggttc cacaacaagc gcacgggagg cgcagacgtc 1680gaagcggggg atttcgacga ggcggagctc gatgaccttc attctccaga cctcgaaaga 1740gaacactacg ccgtgggcga ggacagcgac gaggatgata tttcacgaca gcattctcaa 1800caggcctccc gagccggggg cagtcataat ctatcctag 1839801596DNAAspergillus niger 80atgtttctga tttcacctgc agtgacagtt gcggctgcac ttctgctgat caacggcgca 60ggagcaactc aatctgaacg aagtcgggct gccgctcatt tttccaaacg tcatccgacg 120taccgtgctg cgaccagagc ccagtcgagc aacacttccg actaccgatt cttcaataat 180aggaccaagc cccacttggt ggaaagctta cccgatgtgc acttcgatgt tggggagatg 240tactcggggt cgatccctat cgatgacagc aacaatggat ctcgatccct gttttatatc 300ttccaaccta agataggcga accttcagac gaccttacca tttacctcaa tggagggcca 360ggctgttcct ccgaacaggg attctttcag gaaaatggca ggttcacatg gcagcctggt

420acctatgcac ccgtcatcaa cgaatattct tgggtcaatt tgacgaacat gctatgggtt 480gaccaaccag tcggaaccgg attttccgtt ggaaatgtta cagccaccaa cgaagaagag 540attgccgccg attttctcga cttctttgaa aagtttgaag atctatacgg gataaagaac 600tttcgcattt tcatgaccgg tgagagctac gccggtcgct atgttcccta tatctcgtcg 660gcaatgctag acaagaacga caccacgcgt ttcaatctga gcggagccct tctttatgac 720gcctgcatcg gccaatggga ctacatccag gccgaactcc ctgcctaccc cttcgtcaag 780cagcacgctt cactattcaa cttcaatcag tcctacatga acgagcttga aaccacctac 840gaagaatgcg gctacaaggc ctacttcgat gagtactttg cctttccacc aagcggcatc 900caacccccaa aatacatgaa ctactccgag tgcgacatct ataacatgat ctactacgaa 960gcctataacc cgaacccatg cttcaatccc taccgcgtca ttgatgagtg tccacttctc 1020tgggacgtcc tgggctggcc gacagacttg gcatacgagc ctgcgcccac cacatacttc 1080aaccgtatcg atgtcaagaa ggccctgcac gcccccatgg atgtggaatg ggagctctgc 1140agctacgacc tcgtcttcgc tggaggcgac gctgacccgg gtccggagca gcaaggggat 1200gactcaccca accccaccga gggtgtcctc ccgcgtgtta ttgaggcgac caaccgcgtg 1260ctcattgcca acggtgactg ggactacctg attatcacca acggcaccct cctcgccatc 1320cagaatatga cctggaacgg ccagctgggc ttccagtccg cacctgccac accgatcgat 1380attcagatgc ccgatctcca gtgggttgag atttttgagg cccaggaggg atatggaggg 1440ctggatggcc ctcagggggt tatgggtgta caacattatg agcgcggttt gatgtgggcg 1500gagacatatc agtcggggca taagcaggct caggatcagg gccgtgtctc gtatcgccat 1560ctgcagtggc tgttggggca agttgagatt ctttag 1596811596DNAAspergillus niger 81atgctgtttc gcagtctgtt gtcgacggct gtcctagccg tctcgctgtg cacggataat 60gcttcagctg ctaaacatgg tcgatttggc caaaaagctc gcgacgccat gaacatcgcg 120aagcgttccg ctaacgccgt gaaacactcg ttgaagatcc ctgtcgagga ctatcagttc 180ttgaacaaca agactaagcc ttaccgcgtg gaaagcctgc ctgatgttca cttcgatctg 240ggcgagatgt attccggctt ggtccctatt gagaagggca acgtgtcacg gtcccttttc 300tttgtcttcc agcccactat tggcgagcct gtggatgaga tcaccatctg gctgaatggt 360ggccctggtt gcagttccct tgaggccttt ctccaggaga atggtagatt cgtgtggcag 420cctggaacct accagcctgt tgagaaccca tactcgtggg tgaatctcac caatgttctg 480tgggttgacc aacctgtggg aacgggattc tctctgggtg tcccaaccgc tacgtccgag 540gaggagattg ctgaagactt tgtgaagttc ttcaagaact ggcagcagat ctttgggatc 600aaaaacttca agatctatgt tactggagaa agttatgcgg gccgttatgt tccttacata 660tccgctgctt tcctagatca gaatgataca gaacacttca acctaaaagg tgcactggca 720tatgatccct gtattggtca gtttgactac gtgcaggagg aagcacctgt tgttcccttt 780gtccagaaga acaatgccct cttcaatttc aatgcaagct ttttggcgga actagagagc 840atccatgagc aatgtggata caaggatttc atcgaccagt atctagtctt cccagcatcc 900ggtgtccagc cgccaaaggc tatgaactgg agcgatccca cctgtgatgt ttatgacatc 960gttaataacg ccgtcctgga tcccaacccg tgcttcaacc cctacgaaat caacgagatg 1020tgccccattc tctgggacgt tcttggattc cccaccgaag tcgactatct ccctgcgggc 1080gccagcatct actttgaccg cgctgatgtt aagcgtgcca tgcacgctcc taacatcacc 1140tggtccgagt gctcggtgga gagcgtcttt gtcgggggcg acggcggtcc cgagcaggag 1200ggcgactact cggccaaccc catcgagcat gtcttgcccc aggtcatcga aggcaccaac 1260cgagttctga tcggtaacgg tgattatgac atggtcatcc ttaccaacgg cacccttctc 1320tcgatccaga acatgacatg gaatggaaag cttggattcg acacggcccc cagcaccccc 1380atcaacatcg acatccctga cctgatgtac aatgaagtgt tcattgagaa cggctatgac 1440ccacaaggtg gtcagggtgt catgggcatc cagcactatg agcgtggtct tatgtgggct 1500gagaccttcc agagcggaca catgcagccc caattccaac ccagagtgtc ataccgtcac 1560cttgagtggc tgcttggccg gcgggatacc ctgtaa 1596821479DNAAspergillus niger 82atgaaaggtg cggcgctaat tcctcttgcg gcgggcattc cttttgccca tggcctgtct 60ctccataaac gcgacgggcc tgccgtcgtt cgtatgccca ttgagcgcag gagcgcccag 120tccttgcaga aacgagattc tacggtcggt gtgactttgc agaactggga tgcgacctat 180tacgcagtca acctgacgtt aggaacacct gcgcaaaagg tatcattagc tttggacact 240ggcagcagcg acctctgggt gaacaccggc aactcaactt actgctcaat cgacaatcta 300tgcacccctt atggcttgta caatgccagc gaatcgtcta ctgtaaagac cgtgggcaca 360cacctcaacg atacatatgc ggacggcaca aacctttacg gtccttatgt gaccgataag 420ctcacgatcg gcaacacaac aatcgataat atgcagtttg ggatcgccga gtcaacgact 480agtaaacgcg ggatcgccgg cgtcggttac aagatttcga cctaccaagc cgagcatgac 540gacaaagtct acgccaacct ccctcaggcc ctcgtcgaca gcggtgccat taagtctgct 600gcgtacagca tatggctaga tagtttggag gcgtcgactg gctccctcct tttcggaggt 660gtcaatacag ccaagtacaa gggcgatctg cagactcttc cgatcattcc tgtgtatggc 720aaatactact ccctcgccat cgcccttacg gagctcagcg ttgcgaccga ctccaactcc 780agtagcttca ccgacagtct ccccctctct gtgtcactcg atactggcac caccatgacg 840gcactgccca gcgacctggt caacaaggtc tacgatgcgc tcaacgcaac ctacgacaag 900acatacgaca tggcctacat cgactgcgac actagagagg cggattacaa tgtaacatac 960agtttctccg gggcaacgat caccgtgagc atgagtgagc tgattatccc cgcaacggag 1020ccggggtggc ccgacaacac gtgtgtcttg ggcctcgtgc ctagccagcc gggcgtgaac 1080ctgctcggtg atacattcct gcgcagtgcg tacgtcgtgt atgatctcga gaacaacgaa 1140atctctctcg ccaataccaa tttcaatcca ggcgacgatg atatcctcga aatcggaacg 1200ggaacgtctg ctgtgccagg agccacaccg gttccctctg ctgtctcttc tgcaactgga 1260aatggactga tctcgtctgg caccgcagtg cccacgctgt cgggtgtcac aataactgct 1320acagccacag caaccggctc aaccggcact ggctctagcg gtggttcgtc ggctgaagcc 1380acgagtactt cctcggaggg cgctgcggcg caagctacga gcaacccgat gaacctgctc 1440ccaggacttg cgggtatcgg cctacttctc gctctgtaa 1479831836DNAAspergillus niger 83atgctgtcgt ctctccttag ccagggagca gccgtatccc tcgcggtgtt gtcgctgctc 60ccttcgcctg tagccgcgga gatcttcgaa aagctatccg gcgtccccaa tggctggaga 120tacgccaaca atcctcaagg caacgaggtc attcgcttgc aaatcgccct tcagcagcat 180gatgtcgctg gtttcgaaca agccgtgatg gatatgtcca cccccggaca cgccgactat 240ggaaagcatt tccgcaccca cgatgagatg aagcgcatgt tgctccccag cgagactgcc 300gtcgactcag tccgcgactg gctggaatcc gccggtgtcc acaatatcca ggtcgacgcc 360gactgggtca agttccatac caccgtaaac aaggccaatg ccctgctgga tgccgacttc 420aagtggtatg tcagcgacgc caagcatatt cgtcgtctgc gcaccctgca atactccatc 480cccgacgccc tggtctcgca catcaacatg atccagccca ccacccgctt tggccagatc 540cagcccaacc gtgccaccat gcgcagcaag cccaagcacg ccgatgagac attcctcacc 600gcagccaccc tggcccagaa cacctcccac tgcgactcca tcatcacacc gcactgtctg 660aagcagctgt acaacatcgg tgactaccag gccgatccca agtccggcag caagatcggc 720tttgccagct accttgagga atacgcccgg tatgccgatc tcgagaggtt cgagcagcac 780ctggctccca atgccatcgg ccagaacttc agcgtcgtcc aattcaacgg cggcctcaac 840gatcagcttt catcgagtga cagcggcgaa gccaacctcg acctgcagta catcctgggc 900gtcagcgctc ccgtccccat caccgagtac agcaccggcg gacgcggcga actagtcccc 960gacctgagct cccccgaccc caacgacaac agcaacgagc cctaccttga cttccttcag 1020ggaatcctca agcttaacaa ctccgacctc ccacaagtca tctctacctc ctacggtgaa 1080gacgaacaga ctatccccgt cccctacgcc cgcaccgtct gcaacctcta cgcccaactc 1140ggcagccgcg gcgtctctgt aatcttctcc agcggcgact ccggcgtcgg cgccgcctgc 1200ctcaccaacg acggcaccaa ccgcacgcac ttccctcctc aattccccgc ctcctgcccc 1260tgggtaacct ccgtcggcgc aacctccaag acctcccccg agcaagccgt ctccttctcc 1320tccggcggct tctccgacct ctggccccgc ccctcctacc aacacgccgc cgtgcaaacc 1380tacctcacca agcacctggg caacaagttc tcggggcttt tcaacgcctc cggccgcgcc 1440ttccccgacg tctccgcgca gggcgtcaac tacgctgttt acgacaaggg catgcttggc 1500cagttcgacg ggacgagttg ctccgcgccg acgttcagtg gcgtcatcgc gttgttgaac 1560gatgcgagac tgagggccgg gttgcctgtg atggggttct tgaatccgtt cctgtatggt 1620gtcggaagtg agaagggtgc gttgaatgat attgtgaacg gcgggagtgt gggttgtgat 1680gggaggaatc ggttcggggg cacgcctaat ggtagtcctg ttgtgccgtt tgctagttgg 1740aatgccacga ccgggtggga tcctgtgtcg gggttgggaa cgccggattt tgcgaagttg 1800aaaggggtgg cgttgggtga ggagggtggt aattaa 1836841437DNAAspergillus niger 84atgtggctct ttctcgtgtg cagtatcctg ctgccacttg gagtagtcaa cgcacagtct 60caatacttca acaacaaaac caaagaattc gtcgtcaatg gctctgctat tccttttgtc 120gatttcgaca ttggcgagtc ctatgcgggc tacctaccca acacgccttc tggaatctcg 180agtctatact tctggttctt tccatcttct gatcctgatg cgtctgatga gatcaccgtc 240tggctgaatg gcggcccagg atgcagctct ctggcaggca tcatgctcga gaacggcccc 300tttctatggc aacctggtac ctaccgaccc gtgcgcaacc cttatgcctg gaacaacctc 360acaaatatgg tgtacattga tcagcctgct ggaacgggat tctcgcttgg cccgtctacg 420gtggtctcag aatttgatgt agccagacag tttatggact tctggaggcg gttcatgaaa 480acattcgatc tgcagaatcg aaagatatat ctcactggcg agagctatgc gggccagtac 540atcccataca tcgcgtcgca gatgcttgac caggatgatg atgagtattt ccgggttgcc 600ggcatccaga tcaatgatcc ctacatcaat gagctgccag ttttgcaaga tgttgcgacc 660gtcaatcagc accgctccct ctttcccttt aatgacacct tcatgagtca aatcaccaag 720ctttccgacg attgtggcta cacttcgttt cttgacgatg cccttacctt tccaccccgt 780tctcaattcc catcagtgcc ctataatgct agctgcaaca tctgggatat cataaacaac 840gcttctctag ctctcaaccc atgcttcaac cgctaccata tccccgacgc ctgccccacc 900ccctggaacc cagtcggcgg ccccatcgtt ggacttggtc cgaccaacta cttcaaccgc 960agtgacgtcc agaaagccat caacgcgtac ccaacggact atttcgtctg caaggatgga 1020atcttcccga cggccaacgg actggacaca tcccctccaa gctccctggg accgctgccg 1080cgcgtcatcg aacagaccaa caataccatc attgcgcacg gcctgatgga tttcgagctg 1140ctggcgcagg gaaccctgat cagtatccag aatatgacct ggaatgggaa gcaggggttc 1200gagcgggagc cggtggagcc gttgttcgtg ccgtatggtg gatcatcggg aggaggcgtg 1260ctgggaacgg cacatacaga gcgtggattg acattttcga cagtatttag ttcaggacat 1320gaaatcccgg aatatgcacc gggggcggca tatcgccagc tggagttttt gctggggagg 1380gttgcgaatc tgtcgacaat tattgagcag gtgcagataa cagagcagaa tggttga 143785633DNAAspergillus niger 85atgtccaaac tctccgctgc tatctccaag ctctccctct ccaccatagc caccactctg 60ctcctcctta cccccccaac caccgcctac ttctacaaat atcccgccct cttcgtctac 120aaagacacca actgcaccga tatctccttc tcacttgtct acccctccct gggtaactgc 180aacggcggat actacgacta cgcgggctca ttccagatgt tcaatatcga tgctgcgtat 240acctgtaatg gcagtgactc gacactgatg tttgagatgt ataatagctc cggctcggat 300tgtggagatg agagtgattt gttgtttaga cagccggtga cggaggagtg tactgttgcg 360gatgtggaga gtccggggcc gttggagatg ccggtttggt ttgagttggg gtcactattg 420gggaattgtg gtgggatggc tggtactatg ttgttcggtg tggggattct tgagggtggg 480ttagagacta aattatactg gaaatgttat tcatcaaggc tgaatacaag tgtaaccgtg 540cacagattat ctttgatact gtctatgggc tgtacgagcg tctctgactc ctacaatgag 600ttagcggctg cacattacta tgaggacctg tga 633861827DNAAspergillus niger 86atgcgtcacc tcttatcact gctggtgctt ctgatcgcat cggccgccct ggtctccgcc 60gtccccgccg gctccattat cactccacaa ccacccgtcg agcccgttca ccttctctct 120tcccagccct ctgatccccg aaggccatgg atccgcctcc gtgactggat catcgagtcc 180atatggggca tcgaaaaacc cgcatctcgt cgattcccac tcaacgattc cccgcgcaat 240cgctctcctc cctcccggat tctggcgcgc tacggtagtg acgtcgtact tcgtttcagc 300ctgcgcaatc acgatgaggc cgaggcattg gcccaggctg cagacattct attcctggac 360gtatgggcgt ctactccagc attcgtagat atccgactgg ccgaggaagt caccgcatat 420actcccctaa tagacaacct ggcagagaga atctatacga cctatccatc taaaaagccg 480ataggacttg aaggacaatc tggatttgcg tcctcgagtc gacctgcgcc aaagttcggt 540gacctttttt tccacgagta tcagcctttg tccgtcatta tcccctggat gcggctgctg 600gcttccatgt ttccatccca tgtgcgcatg attagcgttg gagtatctta cgagggtcgc 660gaaattcccg ccctccgact gagcgcaggc agctccaccg cggcgtcagg ccctcgtaaa 720acaatcatcg ttacgggtgg tagccatgcc cgcgaatgga ttggcacctc aaccgtgaac 780catgtaatgt acacgctcat taccaagtat ggcaaatcca aggccgttac ccgccttcta 840caggacttcg actggatcat gatccccacg atcaatcccg acggctatgt ttatacctgg 900gagacggacc gactatggcg caagaatcga cagcggacca gcctacgctt ctgtcccgga 960atcgatcttg accgcgcctg gggcttcgaa tgggacggcg gtcggacccg cgctaaccct 1020tgttcagaaa actatgctgg agacgagccc ttcgagggaa tggaagcaca acaattagca 1080cagtgggcgc tcaacgagac acaaaacaac aatgccgaca tcgtgagctt ccttgacctt 1140cactcttact ctcaaacaat tctctacccc ttctcctact cctgctcctc gatccctcca 1200acgctcgaga gcctggaaga gctaggcctt ggcctagcca aggccattcg gtacgcgact 1260cacgaaatct acgatgtcac ttctgcctgc gaaggcatcg tcacggccag tgcggcagat 1320aacaaccccg ggcggttctt ccccattggt ggcaactccg gtggcagtgc gttggactgg 1380ttttaccacc aagtgcacgc gacttattca taccagatca agcttcgtga tcgcggaagc 1440tacgggttcc tccttccgtc tgaacacatc atccccaccg gcaaggagat ctacaatgtt 1500gttctgaaat tgggatcctt cctcatcgga ggcgactcat ttgacgtcga ttgggaatca 1560gaactcttcg atctgtcaaa ggacgaatcc gatctggata gccgctattc aaaatccaat 1620gaccgctccc cggcgtatct acacaacgcc aacggccccc tgcccaacat tgacgaagac 1680gaagataagg aatgggtaat ggtggaggaa gaagactaca cagacgatga cgacgacgat 1740gatgatgatg atgaagaaga ggaagaggaa gaggaagata catattgggc caccgaacac 1800acatacgaat ttcggcgacg acgctga 1827871251DNAAspergillus niger 87atggctttcc tcaaacgcat tctcccgctg ctggccctca tcttacctgc agttttcagt 60gccacagaac aggtccctca tccgaccatc cagaccatcc cggggaagta cattgttact 120ttcaagtccg gcattgacaa tgcgaagatt gagtctcatg ccgcatgggt aacggagctc 180cacaggcgca gcttagaagg ccgcagtaca accgaagatg accttcccgc cgggatcgaa 240agaacgtaca gaattgccaa ttttgctggg tacgcggggt ctttcgatga gaaaactatc 300gaggagatcc gcaaacatga ccatgtagct tatgtggaac aagatcaggt ctggtatctc 360gatacgctag ttaccgaaag gcgagctcct tggggactgg ggagcatttc tcaccgtggt 420gggtctagca ccgactacat ctatgatgac agcgctgggg agggtacata cgcttatgta 480gtggacaccg gcatcttggc tacgcataat gagtttggtg gtcgtgctag cctggcatat 540aatgctgcag ggggtgagca cgttgatgat gttggacatg gtacacatgt agcagggacc 600atcgggggca aaacatacgg ggtttcgaaa aacgctcacc tactgtccgt gaaggtgttt 660gtaggtgaat ccagctcgac atcggtcatt ctggatggct tcaattgggc cgccaatgat 720attgtgagca agaaccggac cagtaaggcg gcgataaata tgagtcttgg tggaggctac 780tcctatgcgt ttaacaatgc agttgagaat gcttttgacg agggtgtgct ctcttgtgtt 840gccgctggaa atgagaatag agatgcagca cggactagcc cggcttctgc acccgacgcc 900attactgttg ccgctatcaa cagaagcaat gcccgtgcgt cattctcaaa ctacggctct 960gtggttgaca tttttgcccc gggagagcaa gtactttctg catggaccgg ctcgaactcg 1020gccaccaaca cgatctccgg cacgtccatg gctacacccc atgtgacagg tttgatcctc 1080tatttgatgg gcttgcggga ccttgctacc ccagcggctg caacgaccga gctcaagagg 1140ttggctacgc ggaatgctgt caccaatgtg gcgggtagcc ccaatcttct ggcctacaat 1200ggaaacagcg gcgtgtcaaa agggggtagc gatgatggag atgaggacta g 1251881368DNAAspergillus niger 88atgatcaccc ttttgtcggc cctgttcggc agcgtagtat atgccgctac gcagaccgtg 60ttagggccag agggggctga tccctttacg gtgtttcgca gcccacactc accggcattt 120tcaattcgca tccaggagca gaatgactcg atctgtgatg ctcgttcacc ccaattcact 180ggttggctcg acattggccc gaagcatctt ttcttttggt attttgaaag ccagaatgac 240cccttccatg atcccctaac gctatggatg actgggggcc caggagactc gagtatgatt 300ggacttttcg aagaagttgg cccttgccgg attaatgagt ttgggaatgg aacagatcac 360aacccctggg cctggaccaa gaattcatca cttctttttg ttgaccagcc agtcgatgtc 420gggttttcct atatcgatga gggctatgag ctgcctcatg actcacgtga agccgcggtg 480gacatgcatc ggttcttgcg attattcata tccgagattt ttcctcacaa acagttcctt 540cccgttcacc tttccggtga atcttacgca ggccggtaca ttccttatct ggcgacccaa 600atcttggaac aaaatgaact gtataaagat agccccagga taccgctgaa atcgtgcttg 660gtgggtaacg gattcatgtc acccaaggat gcaacgttcg ggtattggga aacactgtgt 720actactaact caggagtccc atctcctatc ttcaatgaaa ctaggtgcga tattatggcg 780gcgaatatgc cgcactgtat ggatctatat gacatatgca ttcaacactc agaccccgcg 840atatgtcatg cggcccagtc cgtctgttac gatagtgttg tagggctcat ggccaaatta 900ttgctaagga tgacgacagt cactgcacct tgtgagatcg acgaaatgtg ctatatcgaa 960gcggctctaa ttgagagata tttgaattcg ccatctgttt gggaggccct gtcgccaccg 1020caacaggtta ccgaatacaa attcgtcgct acttctgtta ttgatgcatt tgctcaatca 1080gcggacggca tggtgtcgag ctcgaagcag atcgctttct tactcgcaaa taatgttgac 1140ttcttagcgt atcaaggcaa ccttgatctc gcctgtaata cggctggcaa cctacgttgg 1200gcgaactcgc tttcttggaa aggccagaca gaatttaccg caaagccctt acttccgtgg 1260gaaattcagg tttcggtcgg tgaagggacg gacgaaacgt cacgctttgc ctttgtgact 1320gtggacaacg ctggacacct gttgcgggac tcaaagattt caaactga 1368892376DNAAspergillus niger 89atgcggtttc tcacttattc cctgcccttc attgcaagtg ctatctcgct ctttggggtc 60aatgtacaag ctcgatcaca agctccaagt gccatccgtc atgtgtcgac gcttgaccag 120cccaccatca agacaccctc acagcgggtc gatcaccttg accactttga catcaccttc 180aatattcatg acaagcacca gcggataaag ctggagctgg agcccaacca tgacatcctg 240gcggaagacg catccgtaca gtatctcgac gcggacggga acgtgcgacg gcacgagccc 300attgctccac atgagcataa ggtcttcaag gggaggagtc tactcgggcg aggaaaaggc 360atgtgggatc cggtcggatg ggcgcggatc tacttgaagc aggatggctc agagccacta 420tttgagggag tcttcagtat cgacggcgac aaccatcacg ttcagctgaa atcggcatac 480atggagaaga aacgccccgt ggatgtcgac cttcccgact cagcgactga ctatatgatc 540ttctaccggg attcggatat ggtgcgtcta catacggaac tcaagcggtc gtcgctcgga 600tcgacctcgt gtcaagccga tcagctcggc ttcaacacta accccaacca ccctgtgcta 660caaccgtatg gccaggcaga gaccgatacg tggggagcaa tttcattgaa ctccttgttt 720ggactcaaca agcgccaatc cgatatcgga agtgtgtctg gcaatgcggg cggagtcaat 780ctggcgtcga ccattggtga tacttcgggc tgtccgagta cgaagcaagt agctttgatt 840ggtgttgcaa cggactgcgc ctttaccggc tcattcaaca acgagactgc cgccaaggaa 900tgggtcatca gtactgtcaa cagcgcgtcc aatgtctacg aaaagtcctt caacattacg 960attgggctgc ggaatctgac tatcaccgac agctcatgcc ccgacaaccc gcccgcggcc 1020acggcatgga acatgccctg ctccagcggc aatctcacct cccgactgga tctgttttcc 1080aagtggcgcg gtgagcaatc ggatgacaat gcttattgga ccctgatgag cgattgcgcg 1140acgggcaacg aggtcggact gtcatggctt ggccaactct gcaatagcga tgcttcttcg 1200gatggctcga gcacggtcag tggaactaac gtcgtcgttc ggtcttccgg ctcggattgg 1260cagatctttg ctcatgaatc tggccacacc tttggcgctg tccacgactg tgactcccag 1320acctgcgcgg aggatctcga agcctcgtcc cagtgctgtc cgttgacctc gagcacctgc 1380aacgccaacg ggaaatacat catgaatcct acaactggaa cagacatcac tgcgttctcg 1440caatgcacta tcggaaatat atgcgcagcc ctgggccgca acagcgttaa gtccagttgt 1500ctctccgcca accgcgacgt caccacctac actggcagcc agtgcggcaa cggaattgtc 1560gagtccggcg aagactgcga ttgtggcggg gaagatggtt gcggcgacaa caactgctgc 1620gacgcgaaga catgcaagtt caagtcggga gctgtgtgtg atgactccaa cgacagctgc 1680tgttcaagct gccaattctc ctcagctggg acggtatgtc gtgccagtcg cggcgactgc 1740gacgtggcag agacctgcag cggcaactcc agtacttgtc ctaccgactc gttcaagaag 1800gacggcacga gctgcggcag cagtggctcg ggacttgcct gcgctagtgg ccaatgcacc 1860agccgcgact accagtgccg cagtgtgatg ggcagtctcc tccacagcaa cgacacctac 1920gcctgttcct ccttcagttc ctcctgcgaa ctggtctgca cctccccgaa gatcggcacg 1980tgctacagcg tcaaccaaaa cttcctcgac

ggcactccct gcggtagtgg cggctactgc 2040agcaacggcg actgcaaggg ccaaaacgtc gaatcctgga tcaagaacca caaaggtatc 2100gtcattggtg tcgcctgcgc cgtaggcgcc ctgatccttt tggccctgat gacctgcatc 2160gtaaaccgct gtcgccgggc tcgcgcgcca aaacccgtcc cgcgtccagt gccttacggg 2220ccgtggcccg gcgctaggcc tcccccgccg ccgcccatga accagtggcc ggcgcgaggc 2280tatcaaggct tagggaatga gccgccgccc ccgtatccag gtgtacctgg tcagccagta 2340ccgcaacata tgcctcccca ggggcggtac gcttga 2376901446DNAAspergillus niger 90atgcgtttcc taagcagtgc agccctattc ggcctggcgt atgcctccac ccaggcggtc 60ctccagccag aggaaccatc cgacttccgt acattccaca gcccatattc cccgcaccac 120tcgatccgca tccgccagca gaatgaatca atctgcgctg cccattccgc ccaatacacc 180ggctggctcg acatcggccg taaacatctc ttcttctggt actttgagag ccagaatgac 240cctgccaatg atcccctcac tctctggatg acaggagggc caggggggtc cagcatgatc 300ggtctgtttg aagaagtcgg gccatgtctg atcaatgagt acggcaatgg cacttactac 360aatccgtggg gctggtcccg gaactcctcc ctactatttg tcgatcagcc agtcgatgtg 420ggattttcgt acgtcgatga aggagaggac ctgccgggcg attcgcatca agctgcaatt 480gacatgcatc ggttcttgca gttgtttgtc tcggaggttt tcccgcaatt gcagactctt 540cccgttcatc tttctggtga atcgtatgct ggtcactatg tcccttacct cggcagtcag 600atcgtccaac agaacaagct ctatcccact gagccccagg tccttctgca ctcatgtctc 660gtaggcaacg gctactattc tcctcgcgac actacctacg gctactggga aaccctctgc 720accactaacc ctggagtccc cgagcccgtc ttcaaccgaa ccagatgcga catcatggcg 780gccaatatgc cgcgatgcat ggaagtatcc gacgtatgtg ttcggaaccc cgatccagct 840atctgccatg ctgcgtcgga ggtatgctac gagggcgtga tcggatggta tgatgacgag 900tctggtgaag gtggtcggaa taggtttgat ataaccgctc cctgcgccct tgacggcata 960tgctacatcg aggccgctcg catcgagcag tacctgaaca cacccgcagt ttgggctgct 1020ctatcaccac ccaaagaaat caaagaatac aaggttactt ccgacaatgt gtcgcgcgca 1080ttcgatctca cttcagacac gatgacgcca gcgtctgagc aagtcgcgtt cctgcttgcg 1140aatcaggtac atttcctggc gtatcagggc aatctcgatc tggcgtgtaa tacggcgggt 1200aatctgcgct gggcgcattc tctgccatgg agaggtcagg tcgagttcgc gtcgaaggcg 1260ctgcggccat ggagttgggt agatgtggta tctggaaaag gtggagtggc tggaacgacg 1320aaggaggagt cgaggtttgc gctagttacg gttgatgggg cgggacattt tcttcctcaa 1380gatagacctg atatcgcgtt ggatatgatg gtgcgctgga tatccggggc atcgtttact 1440gagtga 144691960DNAAspergillus niger 91atgacattgt tactcaactt ccacgcgctc tttacagtca ttcttgttgc caatctttca 60accagatgca gcgcactgct ctctggacgt gacttttgct ccacgccagc gcccggtgag 120tcactccgag cggagcatag gaggctgtat gatgtacagg cccaacgtga cagcaccgcc 180gaggagagcc gggaggtggt gccttggatt gaaatcgaga catggtttca tattgtaagc 240agcaatgaag cagcaaacac agtatcagac gacatgatca ccagccagct ttcctatctt 300cagaaggcat atgaaagtgc gactatcacc tatcggttgg agggcataac tcgtcacata 360aatgactcgt gggcgcgaaa tgatgatgaa ctggggatga agaatgccct acgaaggggc 420aattatggca cattaaatgt ctatttccaa acagatctcc aggcgtcatc cgacgagaat 480tctcgggact atccaaatga cggtaaccga cgaacagatg tgtcagatca atcatcatca 540actgtcctag gcttctgtac gttgcctgac ccgagtgtga attccagcag ccctcgttcc 600agctacatca aggatggttg taacgtgtta gcggatatca tgccgggtgg tagtttagcg 660cagtacaaca aaggcggcac agcggttcat gaggttggcc attggaatgg gctgctgcat 720acgttcgaag gtgaatcgtg ctcccctgat aatgaaggag attacattga tgacaccccg 780gagcaatctg agcctacgag cggatgtccc gccgagaaag attcatgccc cgatcttcct 840ggccttgatg ctattcataa ttttatggac tattcatctg atgactgtta tgagagtttt 900actccagatc aagcggagag aatgaggagt atgtggtccg ctatgcggga agggaagtga 960921920DNAAspergillus niger 92atgcatgtct cacttttcct actcagtgtt acggcagcgt ttgccagccc aacaccccat 60aactatgttg ttcatgagcg gcgcgatgca ttgcccagtg tctgggtaga agaaagccgg 120ctggacaaag gtgccctact gcctatgcgg atagggctta ctcagtccaa cctggatcgt 180ggccatgatt tattgatgga ggtgtctcat ccacaatcgt ctcgctacgg aaagcatctc 240tccagcgagg aggtgcacga cctatttgcc ccgtcgaatg aggccgtcga gaccgtccga 300acctggattg aatccgccgg aattgctcca agccgcatct cgcaatcata caacaagcag 360tggctacagt tcgatgccca tgcaagcgag gttgagcagc ttctgcagac ggaatactac 420atctacaccc atgccgacac gggaagttcc catgtgacat gccacgagta ccatgtgccc 480gaaaccatcc aatcgcacat cgactacata acaccaggag taaagatgct ggaagtgcgc 540ggcacgccct ccaaaaagag agatgcagag aagcgctctc ttggcagtct gcccccaatc 600ttagcaccac taccaatcaa tatcacgaag attttcgacg acccgctagc acactgcgat 660ctggcggtaa ccccagactg cattcgagcc atgtacaaca tcaccaaagg aacaacagcc 720acaaagggca acgagctcgg catcttcgag gacctaggag acatctacag ccaagatgac 780ctcaaccttt tcttcgccaa ctttgccagc gacatcccac agggaaccca tccaaccctc 840gactccatcg acggcgccac cgccccaaca gacgtcacca acgccggccc cgaatccgac 900ctggacttcc aaatcgccta cccaatcatc tggccccaga acaccatcct ctaccaaacc 960gacgacccca actacgaaga caactacaac ttcaaaggac tcctcaacaa cttcctctac 1020gccatcgacg gctcctattg caacgaaacc tcctctctag accctcaata cccagatccc 1080tccccaggcg gctactcctc ccccaagcaa tgcggcgtct acacccccac aaacgtaatc 1140tccatctcct acggcagccc cgaagccgac ctccccatcg cctaccaacg ccgccaatgc 1200cacgagttca tgaaactcgg ccttcagggc atcagcgtgg tcgtcgcatc gggcgactcc 1260ggcgtcgcct ccagcacggg cacctgcttt ggcgatgcag acaacgtctt cgtcccagat 1320ttcccagcca catgtcccta tctcaccgca gtaggaggca catacctccc cctaggcgca 1380gacgcagcca aggaccagga aatagcagtc acccgcttcc cctccggcgg cggcttcagc 1440aatatctacg cccgaccatc ctaccagaac cactccgtgg agacctattt ctccactacc 1500agcgacgacc tcacctaccc ttactactcc ggagtaaact acacagactt ctccaacaca 1560gatggggtat acaaccgcat cggacgagga taccccgatg tttcagctat cgcagacaat 1620atcatcatct acaaccaggg cgaagcgaca ctggtgggtg gtacgtctgc cgcggcgccg 1680gcgttcgcgg ccatgttgac gcgcattaac gaggagaggc tggcgaaggg gaagtccacg 1740gtggggtttg tgaacccggt gctgtatgaa catcctgagg cgtttaggga tgtgactgtt 1800gggtcgaatc ccgggtgtgg gactgatggg ttcccggttg ctggggggtg ggatccggtg 1860acggggttgg ggacgccgcg gtttgaggat ttgatggata tatttgtggg tgatgattga 1920931116DNAAspergillus niger 93atggcttcca agaccctcct actcattccg gcactggcca cagccgctct gggaagtgta 60ttggacctag atatcaaggt agaccttgga accccaggtg gcccgtttga tttgatgtac 120gacaccggat catcaacact ctgggtgctt gatagcaatt gtacagatga ttgtccaaat 180gttagcgggt actcccgaca cggctacaac ctcacctcta ctggtgtcaa cttaggtgtc 240aacgacagca ttgcttacag cggaggcact gtcagcggct tcactgccac ggatattctc 300acggttcccg acaccaacgt ctcatatcgc cagagctttg ccgtcattac cgacagtacc 360tgggcggcct tagcagccga tgggttcatc ggcctggcat cgtctaccat cgcattcaag 420aatactacga cagccgtcga acagatgatg caggatggac ttttggatga acctcgattc 480gccatatatg caggttcagg ggaatcgacc gtgaccaacc ctaatccgga gaataatggc 540gtgttcacct ttggtggcag ccatgaggaa acctatgcgg acggggaact gcaatggatg 600aagatgctct ccccctttga aatatacaaa acaaatctcc ttggaattca gggacacaac 660aactccgatg gccaggccct gtcaagcgac gtcctgaact ggtacggcca gactaatcta 720ttcaacgtcg caggtgcttc atcgataagc attcccaacg accagattga ggcgatgtat 780gccctaacgc ctttctcata cgctgacatc tcatctggat accgacctct gtgctccgat 840ttcaatgata catggtcgat ctcttttaca atgggcttct atggcgaggg tgtcaccttc 900aatttgaccg gtgatcagct ggccgtgcct ggctatcagg acgacgacca ctgcttccct 960cccttcaatc catgggacag ctacaacacg attattggtc agcattggtt gagcaatttc 1020tatgctgtat tcgacttcgg atcattcgac ccggagacat acgatatacg tgttgggctg 1080gctcctttga agaaggaata cctgccgagc gcttga 1116941245DNAAspergillus niger 94atgtttccct gctctcgtat ttggtctctg ctcgttgcag ccgccaccgc tagtgctgta 60cccaccagtc tggccaccac gcacctgcaa tcggttgact tgcttctgac tcgcagttct 120tacgggtttc ttactgacat agcccttgga actccgggtc agagcctgcc gtatctggtt 180gactggacct ggaccggcca ctatgtggtg accaccttgt gctacaacga tcccaccgcc 240acctacgatt gtctcaacgt cgatcagaaa attttcaacc agactttgtc atccactttt 300atcaaccaaa ctgaccagta tggctatctt tactgggatc ccaaccactt ctactttacg 360gagcccgcag cagccgatgt ggcgacggac atgctgcgca tcggtcccac cgcggtgaac 420accaccatcc aagcagccaa tttcgtcttc aacgagacta ttagcgcatt ccctttctcg 480ggagtatatg gactctcacc tgtttttcag ggtgacaatc gatccgtgca agcgtccttc 540taccaaggat ggaggagcgg cgcctggcac tctccaattg tctcttttat ctactgccac 600gacaatgcca ccaaagcggt atgcagtggt tacgacggcc ttcagacact aggcggatac 660aacacctctc acgtccaggg agatatcacc tggtacgaca tcattgtcac ggaggcgatc 720aacacgctgg actttgtcta tgcgccagcc gtgattaatt attgggcgtt gaacctcacg 780cgcttctcta tcggagacga agagcaagag ctcaacaaga ccactactct ggatggaaag 840caagccgccg ttgccgcgtt cgaccacgct tcgtatggtc gcggtgcccc agtgtctgtg 900tacggttacc agcgtctagt cgagctggtc ggggcaaaag ccgtcacgct ttccgatcct 960ccaaataacg gtgagcaggg attctatcag ttcgattgcc ggaactcgag tttactgcca 1020ccgctgcggt atgagtttgc cgggtcagag cgggcgtggg agattgtgcc cgagaactat 1080gtggaggtgc tggcgaacgg aaccaataag tgcaccttta atgtacgcac cctgggagat 1140ggagcgatgg taatgggaaa ttttggcgag acatttgcca ttgataagta tgtcatgttt 1200gactttgaga agttgcaggt ggggattgca gacttcgcgt ggtaa 1245951443DNAAspergillus niger 95atgcatctcc cacagcgtct cgttacagca gcgtgtcttt gcgccagtgc cacggctttc 60atcccataca ccatcaaact cgatacgtcg gacgacatct cagcccgtga ttcattagct 120cgtcgtttcc tgccagtacc aaaaccaagc gatgctctag cagacgattc cacctcatct 180gccagcgatg agtccctgtc actgaacatc aaaaggattc ccgttcgtcg tgacaatgat 240ttcaagattg tggtagcgga aactccctct tggtctaaca ccgccgctct cgatcaagat 300ggtagcgaca tttcatacat ctctgtcgtc aacattgggt ctgatgagaa atctatgtac 360atgttgctcg acacaggcgg ctctgatacc tgggttttcg gttccaactg cacgtccaca 420ccctgcacga tgcacaatac cttcggttcg gacgattctt cgacccttga aatgacatcg 480gaagagtgga gtgtgggcta tggaactggg tctgtcagcg gcttgctagg aaaagacaag 540ctcacgattg caaatgtcac tgtacgcatg actttcggac ttgcttccaa cgcatcggat 600aacttcgagt cgtacccaat ggacggcatt ctcggtctcg gtcgaaccaa cgatagttcc 660tacgacaacc caacattcat ggatgccgtt gcagaaagta acgttttcaa gtcgaatatc 720gttggcttcg ccctttcacg tagccccgcc aaggatggca cggtcagctt tggcactact 780gacaaggaca agtacaccgg cgatatcacc tacaccgata ccgtcggatc ggacagctat 840tggcgcattc ccgtggacga tgtctatgtt ggcggcactt catgcgattt ctccaacaaa 900tcagccatca tcgataccgg aacttcttat gctatgctgc cttcaagcga ctcgaagacg 960ctgcacagtc tcattcccgg cgccaaatct tcggggagct accacattat tccgtgcaac 1020acaactacta agctacaagt ggcattctct ggtgtgaatt acaccatctc gccgaaggac 1080tacgtgggag caacttcagg ttctggatgc gtttcgaaca ttatcagcta cgacttattt 1140ggtgatgaca tctggctcct gggtgacacg tttctcaaaa atgtgtatgc tgtgtttgac 1200tacgatgagt tacgggtcgg atttgcagag cgttcctcga acaccacctc tgcgtcgaac 1260tctacgagct ctggaacaag cagcacctcg ggatccacta caacgggcag ctcaacgact 1320acgacgagct ctgctagctc tagtagttca tctgatgctg aatcaggaag tagcatgacc 1380attcccgctc ctcagtattt cttctctgct ctggcgattg cttccttcat gctttggctc 1440tag 1443961401DNAAspergillus niger 96atgacgtctt ctaccttgcg ccttgccgtc gcgttggctt tgtcaacttg cagcagtgcc 60ctatcgagcc agcgagatga ttcacttgtg gttccatttc cttttggcaa tcttgaggat 120gtccatattg ccaagcggga tagctccaag acagtagaag ctcctctagt gatatatggc 180gacagctact ggatgaacgc ctcaattgga acccctgcgc agtcactaag tttcctacta 240gatcttacgc gctcaagggt cgagcccgca tacaccctcg atgagaatta cgaatgttct 300gacgatgaac tctgctccga attcggcttc tacaaaccca ccgattcatc cacttatcag 360catctcacct acacacagag acacgatgca ggtgtcgact actcctacct tgataccata 420actcttggag atcacgcaac cgacaatgtc ccactggaca tgtatctttt gtcctacatt 480tcctacagct ccctcggtct ctcctccgtc aacaccagct tcccctacat cctggtcgat 540cgcggcctca ccacctcccc atccttcagc ctaatcggcg acaacggaaa caccaccacc 600cccagcatca tctttggagg catcaacacc tccaaattca acgggcccct gcaagccttc 660tccttcgcag accacagcat caccaacaat ccattcgtca ccgtcgaagc tgactccctc 720caactaacca ccaacaccaa cgataattcc acctacccta ttccctcctc cacccccatg 780atgctcagaa ccgaagaact aatcacctac ctccccaact cgaccgtcca atccctctac 840accgacctta acataaccat ggacggcgtg atctccactt caagattcta cggggtcctt 900ccctgcgccc gccaggaaac cgaatctcac acaatctctc tagccatcgg caacatgacc 960ttctctgtgt cctgggatga gctcttcgtc ccgtggacgc gtgacggact atgcaagttc 1020ggcattcagg cccaggattc agattacaaa actcgtgcgg agctgggtgt tccctttctg 1080agacggatgt atgtcgctgt ggattataat aatcagtttg tgggcgttgc gacgctgaag 1140gatgatgatg atcagaatgg aggtgaagat gagattgtgg agattggcac tgggacggcg 1200ttgcctagtg ctgtcgggga ttggccggct agtgttacgg cgtatacgcc tgctgcttct 1260acagggacgg cggctgcgac gttgacattc acgacggcga cgtctagcgg gggaggtgtg 1320gtgccgacgg gtctatcaga gttgggtagg gcgtttttgg tgccgggggt gctggggatg 1380gctgttttgc aggctgttta g 1401971632DNAAspergillus niger 97atgatgcgac cgatacttct ccccctactg ggggtatttc tgcagacctc ctcggcatcc 60aatccctatg taatgagctg gtcttcccaa gcctacggtc cagatggccc gtggcaggcc 120gtatccatcg acgtgggcag caaccagcag acggtcgatc tttaccccgg agccaactat 180gctagcacga tcctgatgag cactctctgc acgaacaaaa ccctgtcatc cacctgctac 240gctgccgaag caggcacgtt caaccaaaac acctccacca ctgcctacac caccgccagc 300tcgtgggaaa caacttactg ggccgtcgag ggtggaagcc aagaggctgt gctcggcgat 360gaggtcacct tagggtcgtt tgtcgtcccc aatgtgagct tcgaagccat ctaccagacc 420taccagacct atcccaatgg catcgcctat cctgtctcgg tcggcagtct ggccctgggg 480ggtccgtact tgtcggatac cgtctccaat tcgacggtcc tgaacatgat cgcaggatgg 540ctttactcgt ccaacgacat tccgtcctac tcgtacggca tgcatatcgg gtcggtagac 600cccaaaatcc caggctccct gatcttgggg ggctacgata agagccgagt gatcggagac 660gtgagtgcgc agggagtagt gtcttcgagt ggtcttttgg aacttgaatt aaaggatatt 720gggctgggtg ttgcggcggg ttcctctccc ttcagcttca acaacgaaag tggcttgttt 780ctccaaagca gtggttcggt tcaggccaag accgtccaga ttgatccaac caagccctac 840atgtaccttc cccaggcgac atgcgatgcc atcacctcca ccatgccgat ctccttcaat 900tccagcttgg ggctatactt ctgggacacc acgagcgatg attatctgaa tatcacgtct 960tccgccgcat acctctcctt tgtgttcaac atgaatgggg tcaacaacaa gaacattacc 1020atcaagattc ccttttccca gctcaatctt acgctgcaag aaccgctggt cgatcaaaac 1080gtcacctact tcccgtgctt cctcactacc tccaccccgg tgctcggtcg agcctttctc 1140cagtccgcat tcgttggggt gaactggttc aacgggaaca actcgggcac atggtttctg 1200gcacaggccc ccggcccggg ttacgccagt gaagacatca cccggatcgc agtgagtgac 1260acgtcgcttt ctgcctctaa cggtacctgg gaagagacct gggctacgta ctggggcatc 1320aaaacatccg acaactcgag cagctccaag agtggcctgt cttccggtgc caaaattgga 1380attggcgtcg gggtgggtgt cggtggagca gtgttgatcg cagcaggtat agccattgca 1440ttctgtcttc gccgtcgccg cggggcgagt caagaggcgg ctggagagca acggaggtcg 1500atgtttaggg gctttgcgga gctaccggga ggtgctcaca gtgaaccggc gaaggagttg 1560gatacgaaga tgcataagcc gccgcaggaa atgatggctt cgcaggaggt agagcgatac 1620gagctggggt ga 1632982535DNAAspergillus niger 98atgcgtctta caggtggtgt cgctgcggct ctgggcctct gcgctgctgc ctccgcttct 60ctccatcccc atcgttccta cgagacccat gattacttcg ctctacacct tgatgaatcc 120acctcgccgg ccgacgtcgc ccaacgacta ggtgctcgcc acgaaggccc cgtcggagaa 180ttaccctcac atcatacctt ctcgataccc cgtgaaaaca gtgacgatgt ccatgcgctg 240ctggatcaat tgcgcgatcg tcggaggtta cgccgccgct ccggagatga cgccgctgtc 300cttccctcct tggtcgggcg agacgaaggt ctaggtggca ttctttggtc cgagaagctg 360gctccccaga gaaagctcca taaaagagtg ccgccgacag gatatgctgc cagatcgccc 420gtcaacactc agaatgaccc ccaagcgctt gcggcgcaga aacgcattgc ctcggaattg 480ggcatcgcgg accccatctt cggcgaacaa tggcatttgt ataatactgt tcagttgggc 540catgatctta acgtgacggg tatctggctg gagggcgtta cagggcaggg tgtcacgacg 600gctattgtcg atgacggttt ggacatgtac agcaacgatc ttaggccgaa ctattttgcg 660gcgggttctt atgactataa cgacaaagta ccagagccga ggccgcgctt gagcgatgac 720cgccacggta ctagatgcgc gggtgaaatc ggtgcggcga agaacgacgt gtgcggggtt 780ggtgttgcgt atgatagtcg catcgctggt attcggattc tctccgcacc cattgatgac 840actgatgagg ctgcggctat taactacgcc tatcaggaga acgatatcta ctcgtgttcc 900tggggtccct atgacgatgg cgccacaatg gaagccccgg gcaccctgat caagcgggcc 960atggtcaatg gtatccaaaa tggtcgtggt ggaaaaggct cggtttttgt gtttgcggct 1020ggtaacggtg ccattcatga cgataactgt aactttgacg gttacaccaa cagtatctac 1080agcatcacgg tgggtgccat tgatcgggag ggtaaccatc ctccgtattc ggaatcctgc 1140tcggcgcaac tggtggttgc ctacagcagc ggcgccagtg atgcaattca taccacggac 1200gtcggcacag acaagtgctc gactacccat ggtggaactt cggcggccgg cccgctcgct 1260gcgggaaccg tggcgctggc cctcagtgtg cggccggaac tcacctggcg tgacgttcag 1320tatttgatga ttgaggcggc agtgcctgtt catgaagatg atggaagctg gcaggacact 1380aagaacggga agaagttcag ccatgactgg ggatatggta aggtcgacac atatacgctg 1440gtgaaacggg cagagacctg ggatctggtg aagcctcaag cctggctcca ttccccctgg 1500cagcgggttg agcatgagat cccacagggc gagcagggct tggctagttc gtacgaggtg 1560acggaggata tgttgaaggg agccaacctg gaacggctgg agcatgtcac ggtcaccatg 1620aatgttaacc acacccgccg aggcgatctc agcgtggagt tacggagccc tgacggtcgg 1680gtcagtcacc tcagtacgcc ccggcggcca gataatcaag aggtgggcta tgttgactgg 1740accttcatga gcgttgctca ctggggcgag tccgggattg gcaaatggac tgtgattgtc 1800aaggacacca atgtcaacga gcatactggg caattcatcg attggcgact caacttgtgg 1860ggcgaggcga ttgacggagc cgagcagcct ctccacccca tgcctactga acacgatgac 1920gaccacagct atgaggaagg aaacgtggct accacgagca tcagcgccgt tcccacgaaa 1980accgagctgc ctgacaagcc cactggtggc gttgatcgcc cggtgaacgt taagcctaca 2040acatccgcga tgccgaccgg tagtcttaca gagcccatcg atgatgaaga actccagaag 2100acccctagta cagaggcaag ctcaacacca agtccttctc cgaccaccgc gtcagatagt 2160atcctgcctt ccttcttccc cacgttcggt gcgtcgaagc ggacgcaagt ttggatctac 2220gctgcgatcg gctccatcat tgtgttctgc attggcctgg gcgtctactt ccatgtgcag 2280cgccgcaaac gtattcgcga cgacagccgg gatgactacg atttcgagat gatcgaggac 2340gaggatgagc tacaggcaat gaacggacgg tcgaaccgtt cacgtcgccg gggtggcgag 2400ctgtacaatg cttttgcggg cgagagcgat gaggaaccgt tattcagtga tgaggatgat 2460gaaccgtatc gggatcgggg gatcagcggc gaacaagaac gggagggcgc agatggagag 2520cattctcgga gatga 253599450DNAAspergillus niger 99atgaagacct tctctaccgt cacctctctc ctcgctctct tctcctcggc tctggccgca 60cccgttgaca gcgctgaagc cgccggcacc accgtctctg tctcatacga cactgcctac 120gatgtctctg gagcttcctt gaccaccgtc tcctgctcgg acggtgccaa cggcctgatc 180aataagggct actccaactt cggctccctt ccgggcttcc ccaagattgg aggcgcccct 240accattgcag gctggaactc tcccaactgc ggcaagtgct acgccctgac gtacaacggc 300cagacagtca acattctggc cattgattcc gcacctggtg gcttcaacat cgctctggag 360gccatgaaca ccctcaccaa caaccaggcc

cagcagctgg gtcgtatcga agctacctat 420actgaggtgg atgtcagtct ttgcgcataa 450100891DNAAspergillus niger 100atggctcaaa tattctggct ttcactcttc ctgcttgtct cttgggtcag agccgagtcc 60aaccgcaccg aggtggacct gattttccca agaaatgata cctttgcgcc aatgcctttg 120atgccggttg tattcgccgt tcaagcccct tccgtcgccc ataaagttaa tacatacatc 180gagtacggct attacccagt aggccgtcca aatgaaacag ttattggcca gaccgaccat 240gtgtccgact caacaaacga aaccacttat ttcagtgtct ctggtatcgg cagaacgttc 300aataccactg gcagctggga gctgttttgg aggctgagat ggaccaattg ttcaatctca 360gaagactcga gatactacaa ccaatcctac ccctggatat cctccccata catcgacggt 420agcctcaaca tcgacaaggt ctatgagggc tttcactaca cagcatacaa tgtcattgtc 480gacagggtta ccttcagcac tcgcgaagat gctagccaac ccaacctcac gaccctcacc 540aatagcgaga actgcgataa agtctcgtct cttgctctat tgtcgattgt ggactcccta 600aggattccac cccagttacc ccaagaagat attgataccg tgtcaatgtg cccacaactc 660gccgatgcca ggctaaattc aacttcaact tcaagcccct gcagcgttag cattagtccc 720gaggttgagt ctaatatcct ggccaagatc gcagacaatg aatgcaataa cgcacttcac 780cccgctgtga gttgcaccac tgaagaaacc aaggaaggca gcgcgagcag ccatgaccac 840ggccatgctg tatggcttgt cattacgcta gcttttgcct tccttttcta a 891101933DNAAspergillus niger 101atgggtggtc gagatgtcgc cattctcagc aggcactttg ctgtgacatc ctcacaaagt 60gttaatggcg ttgtctctgg gatgttccaa cacacagtca cctcttcacc cagcttcact 120accaaccaat tcttcaagaa gaagttcact gctgcaattg ctactgccat tttcgcaagc 180gttgccgtcg cagctcccca gcgtggcctc gaggcccgcc tcaaggcccg cggcagcagc 240aagggatccc gacccctcca ggcagttgct agacctgcat caaccaagaa ccagaccaac 300gttgagtaca gctccaactg gtccggtgcc gtgctggtgg agcctccctc tgctgcagcg 360acctacactg cggtgaccgg caccttcact gtccctgagc ccaccggcaa ctctggaggc 420agtcaggctg catctgcctg ggttggtatc gacggtgata cctatggaaa cgccattctt 480cagaccggtg ttgacttcac cgtgaccgac ggagaggcct cgttcgatgc ctggtatgag 540tggtacccgg attacgccta cgacttcagc ggcatcgaca tctcggcagg cgatgagatt 600gttgccattg tggagtccta cacctcgact accggtattg ccattattga gaacaagagc 660accggccaga aggtgtccaa ggagctgtcg tccagctcca gcctcggtgg acagaacgct 720gagtggattg tggaagactt cgaggaaaat ggttcgctcg tcaacctggt ggactttggc 780accgtcacct tcactggtgc tgttgccaag gcggcgggtg gtgagagtgt tggacttacc 840gatgcgacca tcatcgagat tgaggagaat ggccaggttg tcactgacgt taccatcgac 900agcgactctg aggtgaccat cacctacgag taa 9331022046DNAAspergillus niger 102atgcgctgct ccctcatctc ccttctaggc ctggcggcca tcccggccct tggaggctgt 60cccttcgcac acactgcgaa catgggcatt gataacatgg tgaaagcaca cgctcacatg 120tcccgaccgt tgattgcctc caagagcagc ccctcaactg ttcctacctc ctctagcacc 180ccttctgtcg ggcagaaagg cgtgttcatg atgaaccgca ttgctcctgg cacatccgag 240ctctacattg ccaacacaga tggcagtaat gaacgcccac tcctctccaa ccccgtctac 300gagtaccatg cctccttctc cccggatgta gaatggatca ccttcaccag cgagcgcaat 360ggtgacggta actctgacat ctaccgcgta cggaccaacg gctccgatct ccaggaattg 420gttgccacgc ctgcagtgga agactccgtt gttatctctc ccaacggccg cctggcagcc 480tacgtctcca ccgccaacaa catgaaggca aacatctgga tccttgatct tcagaccggc 540gcgcagtgga acctcacaaa tacacccacc actgccgcca actcctccct catggagagc 600tatctccgtc ctgcctggtc tcctgatggc gaatggatcg ccttctcttc ggaccgcaac 660acccaatggg acggacacgg cgtaccgacc ttcctcggcc gcacgggctg ggagacgacg 720caagaactct ctctctacgc catccgtccc aatggctctg acttccgtca gatcatctcc 780aagccatact actctcttgg atctccgaaa tggtcagcag acggtaaacg catcgtctac 840tacgaaatga cccgggaaga cacctacaac gcccatcgtc cagaaaccat taccacagcc 900aactcgacga tcatgtccgt agacttcgag acaggcaccg atgtgcgcgt ggaagtcgcc 960ggctccggtg tcaagcaatt ccctcagtac ctggacaaga acggcaccat cgcctacacc 1020ctcaaaggcg gcaccagcga gggcttctac acgaccgcgg gactctacgt caacacgacc 1080tcggcgaccc tcaggtcccc ggcgtggtct cccgacggca agcaagtagt ctacgaaaag 1140agcacctgga gcatccgctc ggggtacaag cagctctaca gctgggacag tgactgggac 1200taccgcttca cggacgtctt ccctcaggtc tcgcaccagg agcgcgtcgc catcacacag 1260aagcagctgg gcaattcgtc catcgtgacg ttgaacacaa ccggaggcga cttgcaactc 1320gtctacgacc ccagcacggc ggactttgtc agcgatgacg aaaccacagg actgagcgct 1380taccagccca gctggtcacc ctgcggcgag tggctcgtct tcggcgtcgg attctggttc 1440gagacgagag aagcctcagg cggatggatc gtgcgggcca ccgccaacgg gagctactcg 1500gaggttctcg tgaacagcag ctactccatc accgaggatg gagccctgaa cagcgggttc 1560ccgagtttct cgccggatgg caagaaagtg gtgtatcggg tttggggagc cgacactgca 1620acctacggca acgccagcga gatcgggctg cgggtgctgg acctcgagac gcgaaagaca 1680accgtcctaa ccacagaatg ggacaatctg ccccagttct ctcccgatgg agagctcatc 1740ctattcacac gcaaaaccag cacgtacaat tacgatgtgt gcacgatccg gccggatggg 1800acagatctcc gcgtgttgac gagcagcggt gctaatgatg cgcatgcggt ctggtcgcag 1860gatggacgga ttatgtggtc taccggcatg tatgggttcc ggtttgagtg tgcgctgtat 1920ggtgatacgt tccagccgta tgggcaggtt atgattatgg atgcggatgg gggaaataag 1980aagttgatga ccaactcgat gtgggaagat tcgatgccgt tgttcttgcc gagggaggta 2040ctttag 20461031875DNAAspergillus niger 103atgcctccgg atgcaaaatc gcctggctac cagcctggta tggcagtatt accatctagg 60ccacatcctg ccaagggaaa agccattcga ttcctccttt cccttgcatt ggtcgcgttt 120gctattgttc aattatgtgg taatttccac aaaaatagga gcgttgaaca acagcttcag 180agtcaaacac ttgatgatga gtcctttaaa tgggaagatg ttactcctac caagcaactc 240gtataccatc catgctttgg tgatcacgaa tgcgctcgct tgtcgcttcc aatgaattgg 300aaccgaactg atggtgaagg gtcaaaaatt gccttggcgg ttatcaaact tcctgccaag 360gtacctgtca cagatgcgcg atatggtggt gccattcttc tgaatccagg tggtcctggt 420ggatccggag tgagcatggt ctttagatac gggaaagcta tccagaccat cgtcgactcc 480ccagaatcac caagtgcaga ttcagcgagc ggaaagtatt tcgatgttgt tagctttgat 540ccaagagggg tcaacaacac aacacctaat ttttcctgct tccctgaccc cgcgacgagg 600aaagcgtggt tactgcagtc agaggcagag ggtctacttg ggagttctga aggagtcttc 660gatactcgat gggcaaggta cgaagctttt gagcggctac tttcgacagc tccgaacact 720ttcccagttg gaacaaacgt tgacgccgag aggataaggc tgcacaaccg ttggaaaaaa 780ggggaggaga agctgctata ctggggcttt tcctatggga caatcctggg ttccacgttt 840gcggctatgc agcctcatcg cataaaccgt gctgtcatag acggagtctg caacgctgat 900gattattacg ccggcaactg gcttaccaat ttacaagatt cggatgcagc attcaataaa 960tttttcgagt actgctacac agctggccca tcagcgtgtc cgtttgcgct cggcggagat 1020cccgaagatc tcaagtctcg ttatgagcag attttgacca atcttacatc gagccctatt 1080gctgtgtctc cttctggaaa taggggccca gagataataa cctatagtga tgtgaagtca 1140ttggtcgtgc aagctctcta tgtgcctttg aaattattcg atttggtggc taggctatta 1200gctgagctcg agcaaggtaa cggctcttca ttcgctgact tgaagtatga agccaaacaa 1260tggccagtac cgcctccatg cgattcctcg tccacacaat acaaagtacc tggcgagagt 1320gatcaggagg ccgggaggaa tatcctatgt acagatggtc caggcctcga cggaactgcc 1380aaggaggatt tccggagcta ctggaatatg ctccggggac aaagtaaggc ggttggagat 1440ttctgggccg aggttcgcat gtcgtgtgtc aaactggaga cgcgacctga gtggcgctat 1500gatggtatgc gtatccaagg gcccttcgca ggcaatacat cgcacccatt gctgtttatc 1560gggaatactt atgatccagt aacgccgcta cggaatgctc atacgatggc gcgtggattt 1620cctgagtcaa tcgttctaga gcagaactct gtcggacatt gcacactgag tggcccatcc 1680ttgtgtacag cgaaagcgat acgccagtat ttccagaccg gagagttacc tgaccccgga 1740actgtttgcc aggtagagga gcttcccttt cgtcttgccg gatatgagag aagtcaggtc 1800atgtcgccag gtgacacaga attgatgtcc gccttgcatt cgctgagcga gttccgccat 1860ctgctaggcg cgtga 18751041665DNAAspergillus niger 104atgttgagta gtctgctgct tgggggtctt ctgggtctag cgaccgctca atttcctccc 60gagccggaag gcatcactgt gctcaagtcc aagttgcatg agaatgtgac tatttctttc 120aaagagcctg gaatttgcga aactacgccg ggtgtccgat cttattcggg ctatgtacac 180cttccccccg cctcaaccag cttcttttgg tttttcgaag cccgcaaaga tcccagcaat 240gcgcctctgg ccatctggct caatggcggt ccgggtggct cgtcgctcat ggggctcctt 300gaagaattag gtccttgttc cattgcatca gactccaaga ccacagtcct caatccttgg 360agttggaaca atgaagtcaa tcttctattc cttgaccagc caactcaagt cggcttctca 420tacgatgtcc caacaaatgg cactttgaca gctaatggga ctgcattcgc ggctcacgct 480ctatggcatt tcgcgcaaac ctggtttttc gagttcccac actacaagcc aaacgatgat 540cgtgtcagtc tctgggctga aagttacgga ggccattatg gtccaggcat ctttcggttc 600ttccaacagc agaatgacaa aatcgcagag gggactgcag aagacggtgc acagtatttg 660catctcgaca cgcttggcat tgtgaacggc ttgatggata tggtgatcca agaagaggct 720tacattactt ggccatacaa taacgtaagg ctcgcccctt cttcattcaa ctcgcgaggc 780tttcgcgatc aggccctcgc ctgcgaagcg gctttgaaag aacgcgattc cggcttgcct 840cactcaggga agaatatctc tgaaatttgc ggaggccttg cactagaatg gggagatggc 900cccatcacct actaccacac cttcaatcgc gggtggtacg acatcgccca tcctaagaac 960gacccattcc ctgccaagca catgctcgga tatttgacgc aggagtccgt ccttgccgct 1020cttggggtac cagtcaattt cacatcgtct tcgagtgccg tggctacaca gttcataaaa 1080acctttgata tcgtccacgg cggcttcctg gatgcaattg gctacctcct cgacagtggt 1140gtaaaagtac acatgatgta cggagatcgt gattacgcct gcaattgggt cgggggcgaa 1200aaagccagcc ttgcagttcc gtattcccgt atcaccgaat ttgccgacac gggatactcc 1260ccactcctta cgcccgacgg gatcagcggc atgacccgcc agctgggcaa ctacagcttc 1320actcgcgtct tccaagccgg gcatgaggtc ccctcctacc agcctgtcgc ggcgtatgag 1380atcttcatgc gggcgacatt caacaaagat atccctactg gcctcttggc tgttgatgac 1440gaattccagt cggttggacc taaggatacg tggcatatca agaatatccc tcctattatg 1500ccaaagccgc agtgctatgt tctaagtccc ggcacgtgta ccccggaggt ttgggagacc 1560gttttgaacg gatccgcgac ggtaaaggat tggtatgtcg tggatgatag cgcgggtgtt 1620gaggaccacg aggggttcag cattcttgga ggggatgagt tgtag 16651051737DNAAspergillus niger 105atgaccaggt ttcaattgct tccccttgtc gcagggctgc ttgccccttc aattgcagcc 60cttagcatcc cttccccgca gcagatcctc gattctctca ctttcggaga gcacaccgac 120ggcttttgtc cgctggcacc caaggttgag gttcctgacg atggtttctt tccagctctc 180aagttcgtag aagatgcctc gttcaagtcg cgccaagtca atcgtctctc cagggcggtt 240caagttccga ccgcaatcga cgactacatg aaggatccct acgacgaaaa gttcgcccca 300ttcctcgact tccagaagct cctgcagacc ctctttcccc tcacccactc ctacgcccgc 360gtagatcaca tcaaccgatt tggtctcgtc ttcaccctca atggcacaga tgactcgctc 420aagcccctgc tattcaccgc gcaccaggac gtcgtgccca tcaacgaccc tgccgactgg 480acctatcccc ccttcgatgg ccactacgac ggcgaatggc tctggggccg cggtgccagc 540gactgcaaga acgtcctgat cggtctcatg tccgttgttg aagacctact ctcccaaaag 600tgggagccaa cccgcacagt cgtcctggcc ttcggattcg acgaagaatc ccacggcttc 660ctcggcgccg gatccatcgc caaattcctt gagaagaaat acggaccgga cagcttcgaa 720tttatcctcg acgaaggcgg catgggcctc gaagttctag acgacaacaa caacggcgtc 780gtctacgctc tccccggcgt tggcgaaaag ggcagcatcg acgttgtgct cactctggcc 840gtaccaggcg gccacagctc cgtgccccct ccacacacgg gaatcggcat catcgccgag 900atcatctatg agctagaacg ccaggacctc ttcgtccccg tcctagacac tcaccacccg 960acccgcaaga tgctcgaatg ccaagtccgc cactccccct cgcaagtcga accgtggctc 1020gcctccgccc tccaatcaag cgactacatc tccctagcag agaaactggc ctcctcgcgc 1080ggcgacaagt tccgcttcat cctccaaacc tcccaagcag cggacatcat caacggcggc 1140gtcaaatcca acgctctccc cgagaaaatc aacgccctcg tcaactaccg catcgctctg 1200caccaaaccc cagacgatat caagaaccgc gctgtggaga tcatctctcc catcgtcaag 1260aaatataacc tctccctcac ggccttcccg gaaagcgaca ccgttgaccc ctccctcaac 1320aaccacctca cccttactac cctcagcggc gccctcagtc ccgccccggt cagcccaacg 1380gacatcgaca ccgacgccgt ctgggcccgt ttctcgggcg tcactcgctc ggtcttcgaa 1440tctgtcccta gtctcgaggg cagaaaggtc gtcgtgagcg gcgacatcat gaccgggaat 1500acggatacga gattctactg ggctttgtcg aggaatattt acaggtggag tccgtcgagg 1560gcgggtaaag cgctgaatat tcatactgtt gatgagagga tcgatattga tattcatctt 1620gaggcgatga tgctgtatta cgatcttatt cgctctttcg atggacggac cgattcatct 1680gtcatttctg ctgcgtcggc agctgctgat gatgaacttg ctcacgacgt gctgtga 17371061371DNAAspergillus niger 106atgaagagca ccactcttct ttccttggcc tgggctgccc agtccgccta ttccctctct 60atccacgagc gcgatgaacc cgctactctt cagttcaact ttgaacgtcg tcagatcgcc 120gaccggtccc gtcggaagcg atcgacggcc tcggccgacc tcgttaacct ggctacgaat 180cttggctaca cgatgaacct cacactcggc actcccggcc aggaagtcag tgtgacgttg 240gacaccggca gcagcgatct ctgggtcaat ggggccaact cgtccgtctg cccctgtacc 300gattacggct cttacaactc aagcgcttct tccacctaca ccttcgtgaa cgatgagttt 360tatatccagt atgtcgacgg cagtgaagcc acaggcgact atgtcaacga tactctaaag 420ttctccaatg tgactttgac gaactttcaa tttgccgtcg catatgacgg cgactccgag 480gagggggtcc tcggtatcgg atacgccagc aatgaagcca gccaggccac cgtcggtggt 540ggtgaataca ccaacttccc cgaagccctc gtcgatcaag gcgcgatcaa ctggccggcc 600tacagtctat ggctcgatga cctcgacgaa ggaaaaggca ccattctgtt cggcggagtc 660aacaccgcca agtactacgg cagcctgcag accctgccta tcgtctccat cgaagacatg 720tacgtcgagt tcgcggtcaa cctgacggcc gtgcaccttg agaagaacgg caactccgtc 780tcggtcaaca acagcgccac gcaattcccc atccccgccg tgctggacag cggcacggcc 840ctgacctaca tcccgacctc cgccgcagcc agcatctacg aggccgtcgg tgcccaatac 900ctgagcgagt acgggtacgg agtgatcgag tgcgacgtca aggacgaaga cttcaccttc 960ctgttcgact ttggatcctt caacatgagc gttgacatca gcgagatgat cctcgaggcc 1020agttccgaca tgaccgacat gaacgtttgt acgtttggcc tcgcagtgat cgaaaatgag 1080gccctgctgg gcgatacctt cctgcgcagc gcatacgtcg tctacgatct cggaaacaac 1140gagatctccc tggccaaggc caacttcaac cccggcgagg accacgtcct ggagatcggc 1200accggatcgg atgccgtgcc caaggcgacg ggggcgacgg cgaccggcgc ggcagccaca 1260tccacggcct cgagcgacaa gtcggacaag gagagttcgg ctacagtgcc gcgcagccag 1320attgtctcgc tggtggcggg agtcttggtc ggtgttttct tggttctgta a 13711071995DNAAspergillus niger 107atgttggtcc gtcagcttgc cctggctctg gccattgcgg ccttgtccga tgccattccg 60acatccatca agcatgtcct gcacgagaaa cgtcacaagc ccgcatccga ctgggtgaag 120ggtgcgcgcg ttgagagcga tgcggtcctg cctatgcgca ttggccttgc ccagaacaac 180ttggacaagg gctatgactt cctgatggaa gtatcggacc ccaagtcttc caaatacggc 240cagtactggt cggcagacga ggtgcacgac atcttttcgc catccgagga ggctgttgag 300gcagtgagag aatggcttgt cgcctctggt atccatccgt cgcgggtggt gcactccgac 360aacaagggct ggctcgcgtt cgacgcctac gcccatgaag ccgagaggct gttcatgacg 420gaattccacg agcacgagag cgaccgaagt gctaagatca gggttggatg cgaccaatac 480cacgtccccg aacacatcca gaagcacatc gactacatta cccctggagt gaagctcacc 540caggtcgtga agaggaccaa caaagtcaag cgtgcttccc aactagctca ctcttccaag 600gccaagtctg ctgcccaagg tccgcagcca ctccccaaca aggccaagtt cctgcctgaa 660gacctccgcg gctgcggtta caacatcacc ccctcgtgta tcaaggcctt gtatcagatc 720ccagacgcta agacggcgac cccgaacaac agcctgggtc tgtacgagca gggtgactac 780tttgccaagt ccgacctcga cctcttctat aaggagtatg cgccgtgggt tccccagggt 840acctatccca tcccagccct gattgatggc gccaattact cggttccttc ctacagctcc 900ctgaacacgg gtgaatccga cattgacatt gacatggcct actccctgct ctaccctcag 960caggtgaccc tctaccaggt tgacgaccag ctctacgaac cagtcgaggt cgacacaacc 1020aatctgttca acaccttcct cgacgctctc gatggctcct actgcaccta cagcgcctac 1080ggcgagaccg gcgatgaccc gtcgatcgac cccgtatacc ccgacacccg ccccggcggc 1140tacaaaggaa agctccagtg cggcgtctat aagcccacta acgtaatcag cgcctcctac 1200ggccaatccg aagccgacct ccccgtcagc tacaccaagc gccaatgcaa tgagttcatg 1260aagctcggtc tacagggaca ctccatcctc ttcgcgtctg gcgactacgg cgtcgcgtct 1320ttcgccggcg acggtgacga gaacggctgt ctcggcccag agggcaagat cttcaacccc 1380cagtacccct ccaactgccc ctacgtcacc tccgttggag gtaccatgct gtacggctac 1440cagaccgtca acgacagcga gagcgtcatg cacgttaacc ttggcggaac cgcaagtaac 1500ttcagcactt ctggtggctt ctcgaattac ttcccccaac cggcatatca gtttgctgct 1560gtggagcaat acttccagtc tgcgaacctg tcgtatccgt attactcgga gtttgaggtc 1620gatgttaaca cgaccaaggg tctctacaat aggcttggtc gtgcttatcc ggatgtctcg 1680gcgaatggag cgcatttccg cgcttatatg gatggatacg attatcattg gtatggatcg 1740agtttggcgt cgcctttgtt cgcgtcggtt cttactttgc tcaacgagga acgcttcgct 1800atcggcaagg gccccgtggg attcgtgaat cccgtgcttt atgcttatcc gcaagtgctg 1860aacgatatca ctaatggtac taatgctggg tgtggaactt atgggtttag tgctattgag 1920ggatgggatc ccgctagtgg tttgggtacg cctaactacc cattgatgaa ggagctgttc 1980ctctctttgc cttag 19951081563DNAAspergillus niger 108atgcgggtta ccacggcaat tgcttcatta ctactggtcg gctcggccac cagtctccaa 60aatcctcatc gtcgggctgt tccgccccct ctctcgcatc gcagcgtagc gtctcgctcc 120gtgcccgttg agcgccgaac caccgacttt gagtatttga ctaacaagac tgcaagattc 180ctggtcaatg gcacaagcat ccccgaagtc gatttcgacg tcggcgagtc ctacgccggc 240cttctcccca atacgcccac tggcaattct agcctattct tctggttctt cccctcgcaa 300aatccagagg ccagcgatga gatcaccatc tggctcaacg gcggccccgg atgtagctcc 360ctagacggcc tgcttcaaga gaacggccca ttcctctggc agcctggcac ttacaagccc 420gttcctaatc catactcatg gaccaacctc accaatgtgg tttacatcga ccaacccgcc 480ggcacaggct tctccccggg cccctcgacc gtaaataacg aggaagacgt ggctgcccag 540ttcaacagct ggttcaagca cttcgtcgac accttcgacc tgcacggccg caaggtctac 600atcaccggtg aaagctacgc gggcatgtac gtcccctaca ttgccgatgc catgctgaac 660gaggaggata caacctactt caacttgaag ggtatccaga tcaacgaccc gtccatcaac 720agcgactcgg tcatgatgta ctcccccgcc gtccgccatc tgaaccacta caacaacatc 780ttccagctaa actccacttt cctctcctac atcaacgcca aagccgacaa gtgcggctac 840aacgccttcc tcgacaaagc catcacctac ccacccccca gtcccttccc caccgcccct 900gaaatcaccg aagactgcca agtctgggac gaagtcgtca tggccgccta cgacatcaac 960ccctgcttca attactacca cctgatcgac ttctgcccct acctctggga cgtgctcggc 1020ttcccctccc tcgcctccgg cccaaacaac tacttcaacc gctccgacgt ccagaagatc 1080ctgcacgtcc ctccaacgga ctactccgtg tgctcggaga ccgtcatctt cgcgaacggc 1140gacggcagcg accccagctc ctggggtccc ctacccagcg tcatcgaacg cactaacaac 1200actatcatcg gccacggctg gctcgattac ctcctcttct tgaacggctc gctcgccaca 1260atccagaaca tgacctggaa cggtaagcaa gggttccagc gtcctcccgt ggaaccgctc 1320ttcgtccctt accattatgg tctggctgag ctgtactggg gcgatgagcc tgacccgtat 1380aaccttgatg ctggcgctgg atacctgggt acagcgcata ccgagcgcgg gttgactttc 1440agctcggtgt atttgtctgg tcatgaaatc ccgcagtatg ttcctggtgc ggcttaccgc 1500cagttggagt tcctgctcgg taggattagt agtctttcgg cgaaggggaa ctatacctct 1560tga 15631091656DNAAspergillus niger 109atgcgtggct ctcggttggt gctcttgttg cccctggctg cacttagttg tgctatgccc 60gagaatgaat ggtcatctac gataagaagg cagttaccaa aagcgtccac tggcgtcaaa 120tcgataaaaa ccccaaacaa tgtcactatc aggtataaag aaccaggaac cgaaggaatt 180tgtgagacaa cacctggggt caaatcatac tccggatatg tcgatctttc gccagagtcg 240catactttct tttggttttt cgagtcacgc cgtgaccccg aaaatgatcc agtgactctg 300tggctgaatg gtggccctgg aagcgattcc

ttgattgggc tttttgaaga gttgggtccg 360tgtcacatca caccagagta cgaatcaatc atcaatcagt actcctggaa cgaggtcacc 420aatcttcttt tcttgtctca gcccctcggt gtggggttct cttacagtga aaccgaggcc 480gggtccttga atccatttac tggagccgtc gagaacgcct cctttgctgg agttcagggt 540cgatacccag ttattgatgc cactatcatc gacacgaccg atatcgctgc acgcgcaacc 600tgggaggtgc ttcagggctt cctcagtggc ctgtcgcagc tagattccga agtcaagtcc 660aaggagttca acctgtggac agagagttac ggaggacact atggaccagc gttcttcaat 720catttctacg agcaaaattc gaagatcgct agcggggaag tcaatggcgt ccaactgaat 780tttaactccc tcgggattat caacggcatc attgatgccg cgattcaggc agactactac 840gcagactttg ccgttaataa tacatatgga atcaaagctg tcaatgacac agtgtacaac 900tatatgaagt tcgccaacac gatgccaaat ggatgccagg atcaggttgc ttcgtgtaaa 960ttgaccaata ggacctcgct ttctgattat gctatatgta cagaagcagc caatatgtgc 1020agggacaatg tcgaagggcc ttactaccag tttggcggcc gtggcgtgta tgatattcgg 1080cacccctaca atgacccgac cccgccgtcc tactttgttg actacctcaa gaaagactca 1140gtcatggatg ctatcggcgt ggacattaac tacaccgagt ccagcggcga agtatattat 1200gcattccagc agaccggcga ctttgtatgg ccgaatttca ttgaggacct cgaagagatc 1260ctccaactcc ccgtacgcgt gtcgttgatc tacggcgatg ccgactatat ctgtaactgg 1320ttcggcggtc aggccatctc actcgcagtt aactaccccc atgcagctca gttccgtgca 1380gcgggataca cacccatgac agtagatggg gtcgaatacg gtgagactcg cgagtatggc 1440aacttttcgt tcacccgcgt atatcaggct gggcacgagg ttccatacta tcaaccgatc 1500gcagcgttgc agctgttcaa ccgtacttta tttggatggg atattgcagc gggtacaact 1560cagatttggc ccgaatatag caccaacggg acatcgcagg ctacacacac ggagtcgttc 1620gtgccactgt ccacggcgtc gagtaccgtc aattag 16561101872DNAAspergillus niger 110atgccttttc ccttttcgtc cgctcttctc ggctatatct taactacgag cactactctc 60acctccctag tcgcaggaca gtattaccct ccgacgcctg aggatctcac cgttattcat 120tcggagatat tccctggtgc gaggatctcc tataagcaac ccctcggcat ctgcaccacc 180accccctcca cccccagcta ctccggctac atccacctcc ccccacacac ccttaccaat 240ctctccattc caggaatcag catctcgcaa ccatacccta tcaatacctt tttctggtac 300tttccttccc gccatcacca caacaatgat acatccccac tcaccatctg gatgaacggc 360gggcccggcg gatcctccat gattgggcta tttcaagaga acgggccatg tactgtgaat 420acggactcga attccacggc ctataatccc tggtcgtgga atgagtacgt cgatatgttg 480tatattgagc agccggtgca gacgggattt agttatgatg tgttgaggaa tgggacgtta 540gatttgaatg agacgttttt ggtggggacg ttgccgagtc aggatgtgca tgggacggtg 600aatgggacgg ttaatggggg aagggcgctt tgggttgcgt tgcaggtttg gttgggtgaa 660ttctctgaat atgtttcttc tgttgacggg aatggtggtg gtgatgacag ggtgagtata 720tggacggagt catatggggg acggtatgga ccggcataca cggcgctctt tcaggagatg 780aatgagagga ttgagagtgg ggaggtaagc accgggaaga agatccattt ggatacgctg 840ggcattatca atgggtgtgt ggatttactc gtgcaggtcc cttcgttccc tgagcaggcg 900tataacaata cgtatgggat cgagggaatc aatcgcacgc tctacgaccg ggctatggat 960agttggagca agcctggcgg gtgcagggat atgatcatcg agtgtcgcga tgctggcgag 1020ctcggagatc ccctcatcat ctgcgaggag gcgtcggact actgttcgcg ggagatcaag 1080agcctgtata cgaatacctc cgggcgagga tactacgaca tagcgcattt cacgccggat 1140gcagctctcg tgccttactt cgtcgggttc ttgaatcgcc catgggtgca aaaggcactt 1200ggggtcccgg tgaactatac catgtcgtca gaggcagtgg ggaacagttt cgcctcgacg 1260ggcgattatc cgcgaaatga tccccgcgga atgatcgggg atattggata cttgcttgac 1320tccggtgtca aggtggctat ggtatatggg gaccgggact atgcttgtcc gtggcgcggc 1380ggggaagatg tcagcctgct ggtggagtac gaggatgcgg agaagttccg tgctgctggg 1440tatgccgaag tgcagacgaa gtcatcctac gttgggggtc tagtaaggca gtatgggaac 1500ttctcgttca cgcgtgtctt tcaggcgggc catgaggtgc cattttatca gcccgaaacg 1560gcgtatgaga tttttaatcg cgctcagttt aattgggata ttgcgacggg aggcatttct 1620ctggagcaga atcagagcta tgggacggag ggaccgtcgt caacgtggca tatcaaaaac 1680gaagtgccgg agagccctga gccgacgtgc tatttgttgg cgatggattc gacttgtacg 1740gatgagcaga gggaacgggt gctgagtggg gatgcggtgg tgagggattg ggttgttgtt 1800gatgatattg aggctgaaag ctcgttcagc ggtgttggtg atcagctggc acaggtccct 1860ttgggacatt ga 18721111320DNAAspergillus niger 111atgagaacat ctactctttt gctcctctgg agcactgcag gagcagcttt ggcttctccg 60tacccgcttc ccgactcgca agtagtcttc gccgcggatc acgaggtccc gaatacacag 120ggcaaacacg tcgtggacga ggccatactc tcggcgctga acgctcattc tgacccagtc 180gctgcaatgg tgtctctacg tcccgaaact gcagcttttc tagctgaacc tcgtctcttg 240cacattcggg gcgaagagaa ggcggaatgg atgaccgaag gcgacaagct gcgcctccgc 300caacgcggaa agaagttcat ggacattacc gagcatcagg acttctacgc agagcaggcg 360atggcttcgt ttgctgggga tcctaatctt cccaagctgt cccataaagg tctcgtcaag 420ccgctgttct ctcaaatcga gacggaacga atgcacgata tcctgcagca catgacctcc 480tactacaatc gatactacgg tgattatcac ggcgagatga gctccgaatg gctgcacgac 540tacattgctg cgatcatctc caaatcgcct ttccgcaccc acatctctct cgaatacttc 600acccatcctt tccgccaatc ttcaattatt gcacgcttcg agcctaaagt tcgcagcttc 660tcccaacctt tgaccatcat tggtgcgcac caagattcgg ccaattatct ttttcccctg 720ctgcccgccc ctggcgctga cgatgactgt tccggcactg tcagtatcct cgaggccttc 780cgcgttctgg cggagaatgg ctacacgccc aaggacgggc ctgttgaatt ccattggtat 840gcggctgaag aggccgggct actgggcagc caagccatcg cgcggtacaa gaaggagcag 900ggcgctaaaa ttgatgccat gatggagttt gatatgacgg cttttattgc ccgtaacgcc 960accgagacca tcgggtttgt tgcaacccaa gccgatgcag cgctcacaaa ctgggccctc 1020aacctcagtc gagaatacat ctccattccg gcggaagtct atgaacttgg ccccaacgct 1080ggatccgact acatgtcata cactaagctc aactaccccg ctgcctttgc atccgaaggc 1140aacccgctcg ctgggggctc tttcccgggt gaaatggacc cctacgtaca cggcatcaag 1200gataggatgg acgttgacga tgaaacgggc gtcttctcta tcgaacacat ggctcggttc 1260tccgagttgg ctatcgcatt tgttgtcgag caggctgggt gggataatac atggcggtag 13201121581DNAAspergillus niger 112atgcgttcct tctccgttgt cgctgccgcg tcactggcgc tctcttgggc gtctctggcc 60caggctgctc gcccccgtct tgtgcccaag cctatctctc ggccagcttc gagtaagtcg 120gctgcgacta cgggtgaggc ttattttgag cagctgctgg accatcacaa cccggagaag 180ggaacgtttt cccagcggta ctggtggagt actgaatact ggggtggacc tgggtcaccg 240gtggtcctct ttaaccctgg agaggtctct gccgatggct atgaggggta tctcaccaac 300gatactctca ctggtgtcta tgcgcaggag atccagggtg ccgtcattct cattgaacac 360cgctactggg gcgactcttc gccttatgag gtgctcaatg ccgaaacact tcagtatctc 420acactggatc agtccattct ggacatgacc tacttcgccg agacggtaaa gctgcagttc 480gataatagca gccgcagcaa tgcgcagaat gctccctggg tcatggtcgg tggctcatac 540agcggtgcct tgacggcttg gaccgagtct atcgcgcctg gaacgttctg ggcttaccat 600gccaccagtg cgcctgtgga ggctatctat gacttttggc aatacttcta ccccattcag 660caaggtatgg cacagaactg cagcaaggat gtgtctctgg tagccgagta tgtcgacaaa 720attgggaaga atggaactgc caaggaacag caggagctca aagaattgtt tggtctggga 780gctgttgagc attacgatga ctttgccgct gtcctgccca acggaccgta cctctggcaa 840gacaacgact ttgtcacagg atactcttcc ttcttccagt tctgtgatgc tgtcgagggt 900gtcgaagccg gcgcggcagt gacccccggc cccgagggcg tcggacttga aaaggccctg 960gccaactacg caaactggtt caattcaacc atactcccta actactgcgc aagctacggc 1020tactggaccg acgaatggag cgtcgcctgt ttcgacagct ataatgcctc gagccccatc 1080ttcaccgaca cctccgtggg taaccctgtc gaccgccaat gggaatggtt cctctgcaac 1140gagcctttct tctggtggca ggacggtgcc cccgagggaa cctccactat tgtgccccgg 1200ctcgtcagcg cctcctactg gcaacgccaa tgcccgctct acttccccga agttaacggc 1260tacacgtacg gcagcgcgaa gggtaaaaac tccgctacgg tgaacagctg gacgggtgga 1320tgggatatga cccgcaacac gacgcggttg atctggacga acgggcaata tgacccctgg 1380cgcgactccg gtgtgtcgag cactttccgg cccggtggtc cgctggttag cacggcgaac 1440gaacccgtgc agattattcc gggcgggttc cattgctcgg acttgtatat ggaggattac 1500tatgcgaatg agggtgtgag gaaggtggtt gataatgagg tgaagcagat taaggagtgg 1560gtggaggagt attatgcttg a 15811131275DNAAspergillus niger 113atgcagctcc tccagtccct cattgttgcc gtttgcttca gctacggcgt cctctcctta 60ccccatggcc cgtcaaacca gcacaaagca cgttccttca aggttgaacg ggtccgtcgt 120ggaaccggtg ctctgcatgg gcccgctgct ctccgcaaag cataccggaa gtacggaata 180gctcccagca gtttcaacat cgatctggca gactttaaac ccattacgac aacccatgct 240gctgctggga gcgagattgc agagcctgat cagactggcg ctgtcagtgc tacttccgtc 300gagaacgatg ccgagttcgt ttcgcctgtt cttattggcg gccagaagat cgtcatgaca 360tttgacactg gttcttctga cttttgggtg ttcgatacga atctcaatga aaccttgacg 420ggacacacgg agtacaaccc ttcgaactcc tcgaccttca agaagatgga cggatacacc 480ttcgatgtct cgtatggtga cgactcgtac gcctctggcc ccgtcggaac ggataccgtc 540aacattggcg gcgccattgt caaggagcaa gccttcggtg tccccgacca ggtatcccag 600tcgttcatcg aggacacgaa ctccaacggc ctggtcgggt tgggcttttc ctccatcaac 660accatcaaac cggaggcgca agacacgttc ttcgccaatg tcgcaccaag tctggacgag 720cccgtcatga ccgcctcgct caaggctgac ggagtgggcg agtacgagtt cggcacgatc 780gacaaagaca agtaccaggg caacattgcc aacatcagcg tggactcatc gaacggatac 840tggcagttct ccactcccaa gtactccgtg gcagacggag agctgaagga cattggaagc 900ttgaacacct cgatcgcgga caccggtacc tcccttatgc tgctggatga agacgtggtt 960actgcctact atgcgcaagt tcccaactcg gtctacgtga gcagtgccgg tggttacatc 1020tacccctgca acaccactct tcccagcttc tcgcttgtcc tcggcgagtc gagcctggcc 1080acgatccccg gtaacctgat caatttctcc aaggttggca ccaacaccac caccggacag 1140gccttgtgct ttggcggcat tcaatccaac ggaaacacct cgctgcagat tctgggcgat 1200attttcctga aggccttttt cgttgtcttc gacatgcgcg gcccctcgct tggtgttgcc 1260tctcccaaga actag 12751141647DNAAspergillus niger 114atgcgcattg actccgcggc gctacatctg gtcccagtcc tcctgggcca ggtcggtgct 60ttacaattac ccttggtcca agactccaat tcacagtggc agaaaccaaa tgcaggtgat 120aaacccctaa ttagctctcc gttgcttcaa gagcaggtca aggcggagaa tctgttggac 180agggcccggc agctttacaa gattgcggag ctgggagaag acgagtataa ccaccccact 240cgcgtcattg gcagtaaagg tcaccttggc acgctcgact acatatactc cacccttacc 300gacctcggtg attattatac tgtcgtcaat cagtccttcc ctgccgtgag cggtaatgtc 360ttcgagtctc gccttgtcct tggtcacgat gttcccaagt cagctacacc aatgggtctc 420actcccccaa cgaggaataa ggagccggta tatggctccc tggttgctgt atccaacctc 480gggtgtgagg cctcggacta ctcgtccaac ttgaaaggcg ccgttgcatt tatcagtcgg 540ggaagctgtc cgttcgggac caagtctcaa ttagctggta aagcgggagc tgttgctgcc 600gtcatctaca acaacgagcg gggtgaccta agcggaactc taggaaaccc aacccccgat 660catgttgcta cctttggtat ctcagacgag gatgctgccc cagtcctgga gaagttgaat 720aaaggcgaga aggtggacgc tatcgcctac gttgatgcga tagtagagac catccacacc 780accaatatca tcgcgcagac cacggatggt gacccgaaca attgtgtaat gctgggtggc 840cacagtgaca gcgtggccga gggcccgggt atcaatgacg acgggtccgg tactctgacc 900cttttggagc ttgccacatt gctcacccag ttccgtgtca acaactgcgt gcgatttgct 960tggtgggccg ccgaggagga aggccttctc ggatctgact attacgtgtc cgttctcaca 1020ccggaagaga accgcaagat ccgcttgttc atggactacg acatgctcgg ctcgccgaac 1080tttgcgtacc aagtttacaa tgccactaat gctgtgaacc ccgagggatc tgaggagctt 1140cgtgatctgt acaccgactt ttacgaagat catgggttca actacacgta cattccgttt 1200gacggacgca gcgactatga tgccttcatt cggcatggta tcccgggtgg tggcattgcc 1260acgggagcag agggtatcaa gactgtcgag gaagcggaca tgtttggtgg ggttgctggc 1320caatggtatg acccgtgtta ccatcagatc tgcgatacgg tggccaatgt gaacttgact 1380gcgtgggagt ggaacaccaa gctcgttgcc cactccattg cgacttacgc caagtccttt 1440gacggattcc cggaacggtc cgatgaaccc atcagccctg ctgcttttga ggaaccgaag 1500taccatggcc acgcgttgca attacttcgc ggtaatacta cagggaccca gagcgtcctg 1560tggggagccc aaatccagaa tggaacagct gcatcggtgc ttaatctatt gtccatacga 1620cgcagaggca ctttcagtct aagctaa 1647115480PRTAspergillus niger 115Met His Leu Pro Gln Arg Leu Val Thr Ala Ala Cys Leu Cys Ala Ser1 5 10 15Ala Thr Ala Phe Ile Pro Tyr Thr Ile Lys Leu Asp Thr Ser Asp Asp 20 25 30Ile Ser Ala Arg Asp Ser Leu Ala Arg Arg Phe Leu Pro Val Pro Lys 35 40 45Pro Ser Asp Ala Leu Ala Asp Asp Ser Thr Ser Ser Ala Ser Asp Glu 50 55 60Ser Leu Ser Leu Asn Ile Lys Arg Ile Pro Val Arg Arg Asp Asn Asp65 70 75 80Phe Lys Ile Val Val Ala Glu Thr Pro Ser Trp Ser Asn Thr Ala Ala 85 90 95Leu Asp Gln Asp Gly Ser Asp Ile Ser Tyr Ile Ser Val Val Asn Ile 100 105 110Gly Ser Asp Glu Lys Ser Met Tyr Met Leu Leu Asp Thr Gly Gly Ser 115 120 125Asp Thr Trp Val Phe Gly Ser Asn Cys Thr Ser Thr Pro Cys Thr Met 130 135 140His Asn Thr Phe Gly Ser Asp Asp Ser Ser Thr Leu Glu Met Thr Ser145 150 155 160Glu Glu Trp Ser Val Gly Tyr Gly Thr Gly Ser Val Ser Gly Leu Leu 165 170 175Gly Lys Asp Lys Leu Thr Ile Ala Asn Val Thr Val Arg Met Thr Phe 180 185 190Gly Leu Ala Ser Asn Ala Ser Asp Asn Phe Glu Ser Tyr Pro Met Asp 195 200 205Gly Ile Leu Gly Leu Gly Arg Thr Asn Asp Ser Ser Tyr Asp Asn Pro 210 215 220Thr Phe Met Asp Ala Val Ala Glu Ser Asn Val Phe Lys Ser Asn Ile225 230 235 240Val Gly Phe Ala Leu Ser Arg Ser Pro Ala Lys Asp Gly Thr Val Ser 245 250 255Phe Gly Thr Thr Asp Lys Asp Lys Tyr Thr Gly Asp Ile Thr Tyr Thr 260 265 270Asp Thr Val Gly Ser Asp Ser Tyr Trp Arg Ile Pro Val Asp Asp Val 275 280 285Tyr Val Gly Gly Thr Ser Cys Asp Phe Ser Asn Lys Ser Ala Ile Ile 290 295 300Asp Thr Gly Thr Ser Tyr Ala Met Leu Pro Ser Ser Asp Ser Lys Thr305 310 315 320Leu His Ser Leu Ile Pro Gly Ala Lys Ser Ser Gly Ser Tyr His Ile 325 330 335Ile Pro Cys Asn Thr Thr Thr Lys Leu Gln Val Ala Phe Ser Gly Val 340 345 350Asn Tyr Thr Ile Ser Pro Lys Asp Tyr Val Gly Ala Thr Ser Gly Ser 355 360 365Gly Cys Val Ser Asn Ile Ile Ser Tyr Asp Leu Phe Gly Asp Asp Ile 370 375 380Trp Leu Leu Gly Asp Thr Phe Leu Lys Asn Val Tyr Ala Val Phe Asp385 390 395 400Tyr Asp Glu Leu Arg Val Gly Phe Ala Glu Arg Ser Ser Asn Thr Thr 405 410 415Ser Ala Ser Asn Ser Thr Ser Ser Gly Thr Ser Ser Thr Ser Gly Ser 420 425 430Thr Thr Thr Gly Ser Ser Thr Thr Thr Thr Ser Ser Ala Ser Ser Ser 435 440 445Ser Ser Ser Asp Ala Glu Ser Gly Ser Ser Met Thr Ile Pro Ala Pro 450 455 460Gln Tyr Phe Phe Ser Ala Leu Ala Ile Ala Ser Phe Met Leu Trp Leu465 470 475 4801161099PRTAspergillus niger 116Met Leu Arg Gly Leu Arg Asp Val Val Leu Leu Gln Phe Ala Ile Pro1 5 10 15Leu Phe Leu Leu Leu His Phe Arg Leu Ser Leu Arg Gly Val Ile Thr 20 25 30Gly Phe Gly Ser Lys Ser His Phe Gln Arg Pro Leu Ser Lys Met Ser 35 40 45Ser Thr Gln Lys Ser His Phe Lys Leu Leu Gln Lys Phe Lys Pro Glu 50 55 60Tyr Ser Pro Ser Glu Phe Ala Gln Tyr Glu Ser Glu Arg Thr Gly Met65 70 75 80Arg Val Val Val Ile Asp Gln Lys Gly Pro Lys Val Thr Gly Tyr Phe 85 90 95Val Leu Ala Thr Glu Ile Leu Asp Asp Ser Gly Ala Pro His Thr Leu 100 105 110Glu His Leu Cys Phe Met Gly Ser Arg Asn Tyr Arg Tyr Lys Gly Phe 115 120 125Leu Asp Lys Leu Ala Thr Arg Val Tyr Ser Ser Thr Asn Ala Trp Thr 130 135 140Ala Thr Asp His Thr Ala Tyr Thr Leu Asp Thr Ala Gly Trp Glu Gly145 150 155 160Phe Ala Gln Ile Leu Pro Val Tyr Leu Glu His Val Ile Ala Pro Thr 165 170 175Leu Thr Asp Glu Gly Cys Tyr Thr Glu Val His His Ile Asp Gly Ala 180 185 190Gly Asp Asp Ala Gly Val Val Tyr Ser Glu Met Gln Gly Val Gln Asn 195 200 205Asn Ser Ala Glu Leu Ile Asp Leu Thr Ala Arg Arg Leu Thr Tyr Pro 210 215 220His Gly Val Gly Phe Arg Tyr Glu Thr Gly Gly Met Met Glu Gln Leu225 230 235 240Arg Val Leu Thr Ala Asp Arg Ile Arg Ala Phe His Arg Glu Met Tyr 245 250 255Gln Pro Lys Asn Leu Cys Leu Ile Ile Thr Gly Glu Val Asp His Gln 260 265 270Asn Met Leu Glu Thr Leu Asp Lys Phe Glu Asp Thr Ile Leu Asp Val 275 280 285Ile Pro Ser Pro Asp Ser Pro Phe Lys Arg Pro Trp Val Asp Ser Lys 290 295 300Gln Ala Pro Pro Leu Glu Lys Ser Ile Val Gln Thr Val Glu Phe Pro305 310 315 320Glu Glu Asp Glu Ser Phe Gly Glu Ile Glu Ile Arg Phe Leu Gly Pro 325 330 335Asp Cys Thr Asp Pro Val Gln Thr Gly Ala Val Asn Val Ala Leu Leu 340 345 350Tyr Leu Ala Gly Ser Ser Ala Ser Leu Leu Asp Asn Ile Leu Val Glu 355 360 365Lys Glu Gln Leu Ala Ser Ala Val Tyr Tyr Ala Thr Glu Asp His Pro 370 375 380Ser Ile Glu Ile Arg Phe Thr Leu Thr Ser Val Glu Thr Glu Lys Leu385 390 395 400Ala Lys Val Glu Gln Arg Phe Phe Glu Val Leu Lys Asp Ala Met Glu 405 410 415Lys Asp Leu Asp Met Arg Tyr Ile Lys Glu Cys Ile Asp Arg Gln Arg 420 425 430Arg Thr Trp Lys Phe Ser Thr Glu Ser Ser Ala Ser Ser Phe Ala Glu 435 440 445Tyr Val

Ile Ser Asp Phe Leu Phe Gly Lys Arg Asp Gly Ser Thr Met 450 455 460Leu Asp Val Ala Thr Leu Gln Glu Tyr Asp Val Leu Glu Lys Trp Ser465 470 475 480Glu Glu Gln Trp Arg Ser Phe Ile Lys Thr Trp Ile Ser Asp Ala Asn 485 490 495His Val Thr Ile Leu Gly Val Pro Ser Val Lys Met Ser Asp Thr Leu 500 505 510Lys Lys Glu Glu Glu Ala Arg Val Ala Glu Gln Lys Lys Arg Leu Gly 515 520 525Asp Glu Gly Leu Lys Lys Leu Ala Asp Lys Leu Glu Lys Ala Lys Ala 530 535 540Glu Asn Asp Lys Glu Ile Pro Lys Glu Met Leu Glu Arg Phe Gln Ile545 550 555 560Pro Gly Ile Glu Ser Ile His Phe Val Asp Thr Thr Thr Ala Arg Ser 565 570 575Gly Ala Ala Leu Asp Ala Gly Arg Pro Ser His Lys Ala Gln Lys Leu 580 585 590Val Asp Ala Asp Gly Ser Asp Leu Pro Leu Phe Ile His Phe Glu His 595 600 605Ile Pro Ser Ser Phe Val Gln Leu Ser Leu Leu Ile Ser Ala Gln Ala 610 615 620Val Pro Val Gln Leu Arg Pro Leu Leu Ser Val Tyr Thr Glu Ala Phe625 630 635 640Phe Asn Leu Pro Val Asn Arg Asn Gly Glu Thr Ile Asn Phe Glu Gln 645 650 655Val Val Val Glu Leu Glu Arg Asp Thr Val Gly Tyr Ser Met Glu Gly 660 665 670Ala Arg Ser Leu Gly Asn Ser Glu Met Leu Arg Ile Ser Phe Gln Val 675 680 685Glu Leu Glu Lys Tyr His Thr Ala Ile Ala Trp Ile Gln Glu Leu Ser 690 695 700Trp Asn Ser Ile Phe Asp Val Glu Arg Leu Arg Ala Ile Thr Ser Arg705 710 715 720Leu Leu Ser Asp Val Pro Asp Ser Lys Arg Ser Gly Asp Asp Met Leu 725 730 735Ala Ala Val His Val Met Val His Tyr Ala Ala Glu Ser Ile Val Arg 740 745 750Ala Arg Ser Thr Leu Val Lys Ala Arg Tyr Leu Lys Arg Ile Lys Lys 755 760 765Gln Leu Ala Glu Glu Pro Lys Ser Val Val Ala Arg Met Glu Glu Ile 770 775 780Arg Asp Ala Leu Phe Arg Phe Glu Asn Met Arg Val Leu Val Ile Ala785 790 795 800Asp Leu Glu Lys Leu Gln Asn Pro Val Ser Ala Trp Lys Pro Phe Ala 805 810 815Glu Arg Leu Gly Ala Gly Ala Pro Leu Gln Pro Ile Thr Thr Arg Arg 820 825 830Pro Leu Leu Ser Glu Ala Gly Gln Lys Leu Gly Gly Lys Ser Tyr Val 835 840 845Val Pro Met Pro Thr Ile Asp Ser Ser Phe Ala Tyr Ala Thr Ala Arg 850 855 860Gly Leu Asp Ser Tyr Asp Asp Pro Arg Leu Pro Ala Leu Met Val Ala865 870 875 880Ile Ala Tyr Met Asn Ala Val Glu Gly Pro Leu Trp Val Ala Val Arg 885 890 895Gly Lys Gly Leu Ala Tyr Gly Thr Asn Phe Ala Tyr Asn Ile Asp Thr 900 905 910Gly Phe Val Asn Phe Asp Val Tyr Arg Ser Pro Asn Ala His Lys Ala 915 920 925Phe Asp Ser Ser Lys Gln Ile Val Glu Asp His Leu Ser Gly Ala Met 930 935 940Pro Phe Asp Pro Leu Met Leu Glu Gly Ser Ile Ser Ser Ile Val Val945 950 955 960Ser Phe Ala Asn Glu Gln Ser Thr Ile Gly Ser Ala Ala Ser Gly Ser 965 970 975Phe Ile Arg Gln Val Ile Arg Arg Leu Pro Ser Asp Tyr Lys Glu Arg 980 985 990Val Leu Lys Gln Val Arg Ala Thr Ser Val Asp Asp Val Lys Gly Ala 995 1000 1005Leu Lys Asp Ile Ile Leu Pro Leu Phe Asn Pro Ser Thr Ala Asn 1010 1015 1020Ile Val Val Thr Cys Ala Thr Val Leu Glu Glu Thr Ile Lys Glu 1025 1030 1035Gly Leu Gln Ala Ser Gly Phe Thr Pro Ala Val Gln Pro Leu Lys 1040 1045 1050Glu Phe Glu Asp Asp Tyr Gly Leu Lys Val Gly Asp Asp Glu Asp 1055 1060 1065Glu Glu Ser Asp Asp Asp Asp Asp Glu Tyr Glu Thr Gly Ser Glu 1070 1075 1080Asp Glu Asp Asp Ser Asp Glu Asp Met Glu Asp Asp Glu Asp Asp 1085 1090 1095Glu117726PRTAspergillus niger 117Met Gly Ala Leu Gln Trp Leu Ser Ile Thr Ala Ala Ala Ala Ser Ala1 5 10 15Val Ser Ala Leu Thr Pro Glu Gln Met Ile Gly Ala Pro Arg Arg Thr 20 25 30Glu Val Ile Pro Asn Pro Ser Gly Asp Thr Gly Leu Phe Ser Thr Ser 35 40 45Gln Trp Ser Phe Asp Thr His Ser Glu Ser Thr Trp Trp Ser Leu Ile 50 55 60Asp Leu Gln Ser Gly Lys Thr Thr Thr Leu Thr Asp Asp Ser Asp Ile65 70 75 80Glu Glu Ile Ile Trp Leu Gly Ser Asp Asn Ser Thr Leu Leu Tyr Ile 85 90 95Asn Ser Thr Asn Ala Gln Val Pro Gly Gly Val Glu Leu Trp Ile Ala 100 105 110Asp Ser Ser Asp Phe Ala Asn Ala Tyr Lys Ala Ala Ser Leu Ser Ala 115 120 125Gly Phe Leu Gly Ile Lys Ser Thr Val Thr Asp Ser Gly Asp Val His 130 135 140Phe Ile Leu Arg Gly Lys Ser Tyr Pro Asn Gly Thr Ala Tyr Asn Asp145 150 155 160Gln Leu Ala Glu Thr Tyr Pro Ser Thr Ala Arg Ile Tyr Asp Ser Ile 165 170 175Phe Val Arg His Trp Asp Thr Tyr Leu Thr Thr Ala Ser His Ala Val 180 185 190Phe Ser Gly Thr Leu Gln Ser Ser Thr Ser Asp Asp Gly Asn Val Gln 195 200 205Tyr Thr Ser Ser Gly Gly Leu Thr Asn Leu Val Asn Pro Val Lys Gly 210 215 220Ala Glu Ser Pro Phe Pro Pro Phe Gly Gly Asn Asp Asp Tyr Asp Leu225 230 235 240Ser Pro Asp Gly Lys Trp Val Thr Phe Lys Ser Lys Ala Pro Glu Leu 245 250 255Pro Leu Ala Asn Asn Thr Ala Ala Tyr Val Tyr Leu Val Pro His Asp 260 265 270Gly Ser Ala Thr Ala Phe Ala Val Asn Gly Pro Asp Ser Pro Ala Thr 275 280 285Pro Glu Gly Val Glu Gly Glu Ser Asn Asn Pro Val Phe Ser Pro Asp 290 295 300Ser Asp Lys Ile Ala Tyr Phe Gln Met Ala Thr Asn Thr Tyr Glu Ser305 310 315 320Asp Arg Asn Val Leu Tyr Val Tyr Ser Ile Ala Asp Asp Thr Ile Thr 325 330 335Pro Leu Ala Lys Asp Trp Asp Arg Ser Pro Ser Ser Val Thr Trp Val 340 345 350Asp Gly Asp Asn Leu Val Val Ala Ser Gln Asp Leu Gly Arg Thr Arg 355 360 365Leu Phe Ala Ile Pro Gly Asp Ala Gly Asp Asp Phe Lys Pro Thr Asn 370 375 380Phe Thr Asp Gly Gly Ser Val Ser Ala Gln Tyr Val Leu Ser Asn Ser385 390 395 400Thr Leu Leu Val Thr Ser Ser Ala Phe Trp Thr Ser Trp Ser Val Tyr 405 410 415Thr Ala Ser Pro Asp Glu Gly Val Ile Asn Thr Leu Ala Ser Ala Asn 420 425 430Glu Ile Asp Pro Glu Leu Ser Gly Leu Ser Ser Ser Asp Phe Glu Glu 435 440 445Phe Tyr Phe Asp Gly Asn Trp Thr Thr Leu Gln Gly Trp Ile Thr Tyr 450 455 460Pro Gln Asp Phe Asp Ser Ser Lys Lys Tyr Pro Leu Ala Phe Leu Ile465 470 475 480His Gly Gly Pro Glu Asp Ala Trp Ala Asp Glu Trp Asn Leu Lys Trp 485 490 495His Ser Lys Val Phe Ala Asp Gln Gly Tyr Val Val Val Gln Pro Asn 500 505 510Pro Thr Gly Ser Thr Gly Phe Gly Gln Gln Leu Thr Asp Ala Ile Gln 515 520 525Leu Asn Trp Thr Gly Ala Ala Tyr Asp Asp Leu Thr Lys Ala Trp Gln 530 535 540Tyr Val His Asp Thr Tyr Asp Phe Ile Asp Thr Asp Asn Gly Val Ala545 550 555 560Ala Gly Pro Ser Phe Gly Ala Phe Met Ile Thr Trp Ile Gln Gly Asp 565 570 575Asp Phe Gly Arg Lys Phe Lys Ala Leu Val Ser His Asp Gly Pro Phe 580 585 590Ile Gly Asp Ala Trp Val Glu Thr Asp Glu Leu Trp Phe Val Glu His 595 600 605Glu Phe Asn Gly Thr Phe Trp Gln Ala Arg Asp Ala Phe His Asn Thr 610 615 620Asp Pro Ser Gly Pro Ser Arg Val Leu Ala Tyr Ser Thr Pro Gln Leu625 630 635 640Val Ile His Ser Asp Lys Asp Tyr Arg Ile Pro Val Ala Asn Gly Ile 645 650 655Gly Leu Phe Asn Thr Leu Gln Glu Arg Gly Val Pro Ser Arg Phe Leu 660 665 670Asn Phe Pro Asp Glu Asp His Trp Val Thr Gly Gln Glu Asn Ser Leu 675 680 685Val Trp Tyr Gln Gln Val Leu Gly Trp Ile Asn Arg Tyr Ser Gly Val 690 695 700Gly Gly Ser Asn Pro Asp Ala Ile Ala Leu Glu Asp Thr Val Asn Pro705 710 715 720Val Val Asp Leu Asn Pro 725118564PRTAspergillus niger 118Met Thr Arg Gln Thr Ser Leu Val Pro Arg Leu Leu Thr Leu Ala Ser1 5 10 15Leu Ala Ala Leu Ser Gln Ala Glu Leu Gly Lys Ile Gln Trp Lys Gly 20 25 30Ser Cys Asn Leu Thr Thr Tyr Pro Ala Leu Ile Cys Gly Thr Leu Asp 35 40 45Val Pro Tyr Asp Tyr Thr Glu Ser Asn Ser Ser Lys Thr Leu Thr Leu 50 55 60Asp Ile Ala Lys Trp Pro Ala Thr Lys Lys Pro Val Ser Glu Pro Ile65 70 75 80Ile Phe Asn Phe Gly Gly Pro Gly Val Asn Ser Phe Glu Gly Leu Gly 85 90 95Leu Tyr Gly Glu Glu Phe Gln Ala Ile Leu Gly Gly His Asn Asp Leu 100 105 110Ile Ala Phe Asn Asn Arg Gly Val Gly Asn Thr Ile Pro Phe Ser Cys 115 120 125Tyr Ser Asp Asp Ala Thr Arg Glu Leu Val Ala Leu Gln Ala Pro Asn 130 135 140Asp Gly Arg Ala Ser Ser Thr Ala Leu Gly Glu Ile Trp Ala Gln Asn145 150 155 160Ala Asn Ile Ala Gln Ala Cys Tyr Ala Thr Asn Asn Gln Thr Gly Ser 165 170 175Leu Ile Gly Thr Ser Phe Ala Ala Arg Asp Ile Met Gln Val Ala Asp 180 185 190Ala Leu Ser Gly Lys Asp Ser Leu Val Asn Tyr Trp Gly Phe Ser Tyr 195 200 205Gly Thr Thr Ile Gly Ala Val Leu Ala Ala Met Phe Pro Asp Arg Met 210 215 220Gly Asn Val Ala Leu Asp Gly Val Asp Asn Pro Arg Glu Ala Leu Tyr225 230 235 240Gly Tyr Asn Ala Gln Ala Val Val Asp Val Asp Lys Val Phe Glu Gly 245 250 255Phe Cys Thr Gly Cys Met Ala Ala Pro Asp Leu Cys Pro Ile Ala Lys 260 265 270Glu Tyr Thr Ser Ala Ala Asn Leu Glu Ala Ala Ile Tyr Leu Met Leu 275 280 285Glu Asn Leu Lys Tyr Asn Pro Ile Ala Ile Pro Glu Thr Gly Gly Ile 290 295 300Val Thr Trp Ser Asp Val Lys Ser Thr Ile Phe Glu Ala Met Tyr Leu305 310 315 320Pro Ser Ser Trp Pro Leu Thr Ser Glu Leu Leu Tyr Tyr Val Gln Thr 325 330 335Arg Asn Thr Thr Ile Leu Gly Asn Ser Glu Val Tyr Asp Thr Ile Lys 340 345 350Ser Tyr Gly Gln Ser Ala Ser Leu Thr Ser Ala Ser Asp Glu Val Gly 355 360 365Thr Ala Ile Thr Cys Ser Asp Lys His Arg Ser Ala Thr Ile Lys Glu 370 375 380Val Leu Pro Tyr Val Lys Ala Arg Gln Ala Leu Thr Lys Ile Gly Ser385 390 395 400Asp Gly Ser Asp Gly Asp Met Arg Cys Ala Gln Trp Asn Pro Lys Met 405 410 415Phe Ala Lys Glu Arg Tyr Ser Gly Asp Phe Glu Val Lys Thr Ala Asn 420 425 430Pro Val Leu Ile Leu Ser Asn Thr Tyr Asp Pro Ala Thr Pro Leu Pro 435 440 445Ala Ala Lys Asn Leu Thr Glu Thr Phe Glu Gly Ser Val Leu Leu Glu 450 455 460Gln Asn Gly Tyr Gly His Thr Thr Leu Ser Met Pro Ser Leu Cys Thr465 470 475 480Ala Lys Ala Val Arg Ala Tyr Phe Thr Asn Gly Thr Leu Pro Ala Asp 485 490 495Gly Thr Ile Cys Gln Val Asp Val Pro Leu Phe Thr Asn Leu Thr Tyr 500 505 510Lys Asp Val Trp Pro Lys Ser Phe Gln Arg Ser Val Glu Ser Arg Asp 515 520 525Asp Ala Thr Ile Leu Lys Ala Leu Met Ser Val Arg Asp Lys Met Ser 530 535 540Arg Arg Arg Met Cys Ile Tyr Leu Tyr Thr Asn Ser Ala Ser Trp Arg545 550 555 560Pro Glu Leu Pro119526PRTAspergillus niger 119Met Tyr Tyr Ser Leu Trp Val Ala Ala Leu Val Ala Ala Leu Pro Val1 5 10 15Ser Arg Ala Gln Phe Val Ala Pro Pro Thr Asp Leu Ile Pro Thr Lys 20 25 30Gly Tyr Leu Asp Ile Pro Val Arg Tyr Lys Gln Val Pro Thr Gly Ile 35 40 45Cys Glu Thr Asp Pro Ser Val Lys Ser Phe Ser Gly Tyr Val Asp Val 50 55 60Ala Glu His Glu His Ile Phe Phe Trp Phe Phe Glu Ala Arg Asn Gln65 70 75 80Asp Pro Thr Glu Ala Pro Leu Thr Val Trp Ile Asn Gly Gly Met Ser 85 90 95Asp Pro Gly Pro Gly Ser Ser Ser Met Ile Gly Leu Phe Gln Glu His 100 105 110Gly Pro Cys Gly Ile Asp Ala Asn Gly Ser Val Tyr Asn Asn Pro Tyr 115 120 125Ser Trp Asn Asn Ala Ser Asn Met Leu Tyr Ile Asp Gln Pro Val Gln 130 135 140Thr Gly Phe Ser Tyr Ser Ile Pro Val Pro Gly Tyr Val Asp Ser Ser145 150 155 160Thr Asp Asn Gly Phe Met Gly Ala Phe Pro Gln Tyr Ser Arg Glu Thr 165 170 175Phe His Phe Thr Thr Glu Ser Tyr Gly Gly His Tyr Gly Pro Val Phe 180 185 190Asn Glu Tyr Ile Glu Glu Gln Asn Ala His Leu Gln Pro Gly Ala Lys 195 200 205Lys Ile Gln Leu Gly Ser Val Met Ile Gly Asn Gly Trp Tyr Asp Pro 210 215 220Ile Ile Gln Tyr Gln Ala Tyr Tyr Asn Phe Thr Val Tyr Pro Gly Asn225 230 235 240Thr Tyr Asp Tyr Leu Pro Phe Asn Lys Ser Ile Ser Ser Leu Met Tyr 245 250 255Asn Asn Leu Tyr Gly Pro Gly Asn Cys Leu Asp Gln Leu Tyr Asp Cys 260 265 270Ala Ala Arg Gly Ile Asp Glu Ile Cys Ser Thr Ala Asp Asp Phe Cys 275 280 285Ala Asn Glu Val Glu Asn Val Tyr Asp Ile Tyr Ser Gly Arg Asp Glu 290 295 300Tyr Asp Phe Arg Glu Leu Thr Pro Asp Pro Phe Pro Tyr Glu Phe Tyr305 310 315 320Val Asp Tyr Leu Asn Lys Ala Ser Val Gln Ala Ala Ile Gly Ala Tyr 325 330 335Ile Asn Tyr Thr Glu Ser Asn Asn Ala Val Gly Leu Ala Phe Ser Ser 340 345 350Thr Gly Asp Asp Gly Arg Leu Met Asn Thr Ile Gln Asp Val Gly Lys 355 360 365Leu Leu Lys Gln Gly Val Thr Val Val Met Tyr Ala Gly Asp Ala Asp 370 375 380Tyr Asn Cys Asn Trp Leu Gly Gly Glu Ala Val Ser Leu Gln Val Lys385 390 395 400Ala Ala Asn Phe Ser Ser Ala Gly Tyr Thr Asn Ile Val Thr Ser Asp 405 410 415Gly Val Thr His Gly Gln Val Arg Gln Ala Gly Gln Phe Ala Phe Val 420 425 430Arg Val Tyr Glu Ser Gly His Glu Val Pro Phe Tyr Gln Pro Leu Leu 435 440 445Ala Leu Glu Met Phe Glu Arg Val Ile Gly Gly Lys Asp Val Ala Thr 450 455 460Gly Lys Ile Pro Ile Ser Ser Ser Leu Gln Thr Val Gly Thr Pro Lys465 470 475 480Ser Tyr Tyr Arg Glu Gly Asn Ser Thr Ile Gln Trp Glu Val Leu Asp 485 490 495Ser Leu Ala Thr Tyr Asn Thr Thr Thr Asn Ala Pro Asn Pro Val Ser 500 505 510Arg Arg Leu Lys Arg Met Gly Pro Ala Leu Arg Phe Gln Met 515 520

5251201156PRTAspergillus niger 120Met Ser Cys Val Trp Leu His Ile His Lys Arg Ser Leu Leu Ser Val1 5 10 15Ala Thr Asn Asn Ser Val Ala Arg Ala Ala Ala Ser Thr Ser Ala Ala 20 25 30Pro Pro Pro Pro Ser Ser Pro Pro Pro Gly Ser Asn Thr Tyr Ser Pro 35 40 45Leu Tyr Arg Pro Ile Thr Asn Pro Ile Gly Phe Thr Leu Ser Pro Ala 50 55 60Arg Ser Leu Val Ser Arg Asn Pro Lys Phe Pro Ala Tyr Arg Arg Ser65 70 75 80Ser Arg His Phe Ser Leu Cys Pro Ala Ala Ala Thr Pro Gly Val Thr 85 90 95Thr Ser Ile Cys Pro Gly Gln Ala Pro Val Arg Ser Leu Ser Ser Leu 100 105 110Ile Ile His Ser Thr Arg Pro Arg Ala Ile Arg Ile Arg Thr Asp Gln 115 120 125Met Asp Leu Asn Gly Asp Ala Gly Ala Lys Arg Lys Arg Ser Ser Ile 130 135 140Thr Thr Pro Ala Glu Arg Pro Val Lys His Leu Arg Pro Glu Ser Ser145 150 155 160Ala Leu Thr Pro Gly Asp Ser Thr Pro Ala Asn Gly Thr Val Tyr Asp 165 170 175Val Glu Asp Asp Glu Asp Ala Ser Arg Leu Leu Pro Val Gly Pro Ala 180 185 190Gln Ala Asp Ser Pro Glu Trp Gln Ala Thr Ile Glu Glu Val Val Lys 195 200 205Ser Val Val Ser Ile His Phe Cys Gln Thr Cys Ser Phe Asp Thr Glu 210 215 220Leu Ser Met Ser Ser Gln Ala Thr Gly Phe Val Val Asp Ala Glu Asn225 230 235 240Gly Tyr Ile Leu Thr Asn Arg His Val Val Cys Pro Gly Pro Phe Trp 245 250 255Gly Tyr Cys Ile Phe Asp Asn His Glu Glu Cys Asp Val Arg Pro Val 260 265 270Tyr Arg Asp Pro Val His Asp Phe Gly Ile Leu Lys Phe Asp Pro Lys 275 280 285Ala Ile Arg Tyr Met Lys Leu Arg Glu Leu Lys Leu Gln Pro Asp Ala 290 295 300Ala Lys Val Gly Ser Glu Ile Arg Val Val Gly Asn Asp Ala Gly Glu305 310 315 320Lys Leu Ser Ile Leu Ser Gly Val Ile Ser Arg Leu Asp Arg Asn Ala 325 330 335Pro Glu Tyr Gly Asp Gly Tyr Ser Asp Phe Asn Thr Asn Tyr Ile Gln 340 345 350Ala Ala Ala Ala Ala Ser Gly Gly Ser Ser Gly Ser Pro Val Val Asn 355 360 365Ile Asp Gly His Ala Ile Ala Leu Gln Ala Gly Gly Arg Ala Asp Gly 370 375 380Ala Ala Thr Asp Tyr Phe Leu Pro Leu Asp Arg Pro Leu Arg Ala Leu385 390 395 400Glu Cys Ile Arg Arg Gly Glu Pro Val Thr Arg Gly Thr Ile Gln Thr 405 410 415Gln Trp Ile Leu Lys Pro Phe Asp Glu Cys Arg Arg Leu Gly Leu Thr 420 425 430Pro Glu Trp Glu Ala Thr Val Arg Lys Ala Ala Pro Thr Glu Thr Ser 435 440 445Met Leu Val Ala Glu Ile Ile Leu Pro Glu Gly Pro Ala Asp Gly Lys 450 455 460Leu Glu Glu Gly Asp Val Leu Leu Gln Val Asn Gly Val Leu Leu Thr465 470 475 480Gln Phe Ile Arg Leu Asp Asp Ile Leu Asp Ser Ser Val Gly Gln Thr 485 490 495Val Arg Leu Leu Val Gln Arg Gly Gly Gln Asn Val Glu Ile Glu Cys 500 505 510Gln Val Gly Asp Leu His Ala Ile Thr Pro Asp Arg Phe Val Thr Val 515 520 525Ala Gly Gly Thr Phe His Asn Leu Ser Tyr Gln Gln Ser Arg Leu Tyr 530 535 540Ala Ile Ala Thr Arg Gly Val Tyr Val Cys Glu Ala Ala Gly Ser Phe545 550 555 560Lys Leu Glu Asn Thr Leu Ser Gly Trp Ile Ile Asp Ser Val Asp Lys 565 570 575Arg Pro Thr Arg Asn Leu Asp Glu Phe Val Glu Val Met Arg Thr Ile 580 585 590Pro Asp Arg Ser Arg Val Val Ile Ser Tyr Arg His Ile Arg Asp Leu 595 600 605His Thr Arg Gly Thr Ser Ile Val Tyr Ile Asp Arg His Trp His Pro 610 615 620Lys Met Arg Leu Ala Val Arg Asn Asp Asp Thr Gly Leu Trp Asp Phe625 630 635 640Ser Asp Leu Ala Asp Pro Ile Pro Ala Leu Pro Pro Val Pro Arg Lys 645 650 655Ala Asp Phe Ile Gln Leu Asp Gly Val Ser Gln Pro Ala Ala Ala Asp 660 665 670Ile Val Arg Ser Phe Val Arg Val Ser Cys Thr Met Pro Leu Lys Leu 675 680 685Asp Gly Tyr Pro Gln Ala Lys Lys Thr Gly Phe Gly Leu Val Val Asp 690 695 700Ala Glu Lys Gly Leu Val Val Val Ser Arg Ala Ile Val Pro Tyr Asp705 710 715 720Leu Cys Asp Ile Asn Val Thr Val Ala Asp Ser Ile Ile Val Asn Ala 725 730 735Lys Val Val Phe Leu His Pro Leu Gln Asn Tyr Ser Ile Ile Gln Tyr 740 745 750Asp Pro Ser Leu Val Gln Ala Pro Val Gln Ser Ala Lys Leu Ala Thr 755 760 765Asp Tyr Ile Lys Gln Gly Gln Asp Thr Ile Phe Val Gly Phe Asn Gln 770 775 780Asn Phe Arg Ile Val Val Ala Lys Thr Ala Val Thr Asp Ile Thr Thr785 790 795 800Val Ser Ile Pro Ala Asn Ala Ser Ala Pro Arg Tyr Arg Ala Ile Asn 805 810 815Leu Asp Ala Ile Thr Val Asp Thr Gly Leu Ser Gly Gln Cys Ser Asn 820 825 830Gly Val Leu Ile Gly Glu Asp Gly Val Val Gln Ala Leu Trp Leu Asn 835 840 845Tyr Leu Gly Glu Arg Thr Ser Asn Ser His Lys Asp Val Glu Tyr His 850 855 860Leu Gly Phe Ala Thr Pro Ser Leu Leu Pro Val Leu Ser Lys Val Gln865 870 875 880Gln Gly Glu Met Pro Glu Leu Arg Ile Leu Asn Met Glu Ser Tyr Val 885 890 895Val Gln Met Ser Gln Ala Arg Ile Met Gly Val Ser Glu Glu Trp Ile 900 905 910Glu Lys Val Thr Gln Ala Asn Pro Ser Arg His Gln Leu Phe Met Val 915 920 925Arg Lys Val Asp Cys Pro Pro Pro Gly Phe Asn Ser Ala Ala Asp Thr 930 935 940Phe Glu Glu Gly Asp Ile Ile Leu Thr Leu Asp Gly Gln Leu Ile Thr945 950 955 960Arg Val Ser Glu Leu Asp Ile Met Tyr Glu Lys Asp Thr Leu Glu Ala 965 970 975Leu Ile Val Arg Asn Gly Gln Glu Met Arg Ile Gln Val Pro Thr Val 980 985 990Pro Thr Glu Asp Leu Glu Thr Asp Arg Ala Val Val Phe Cys Gly Ala 995 1000 1005Val Leu Gln Lys Pro His His Ala Val Arg Gln Gln Ile Ser Lys 1010 1015 1020Leu His Ser Glu Val Tyr Val Ser Ala Arg Ser Arg Gly Ser Pro 1025 1030 1035Ser Tyr Gln Tyr Gly Leu Ala Pro Thr Asn Phe Ile Thr Ala Val 1040 1045 1050Asn Gly Val Pro Thr Pro Asn Leu Asp Arg Phe Ser Glu Glu Val 1055 1060 1065Ser Lys Ile Pro Asp Asn Thr Tyr Phe Arg Leu Arg Ala Val Thr 1070 1075 1080Phe Asp Asn Val Pro Trp Val Val Thr Val Lys Lys Asn Asp His 1085 1090 1095Tyr Phe Pro Met Ser Glu Tyr Ile Lys Asp Gln Ser Gln Pro Ser 1100 1105 1110Gly Trp Arg Thr Val Ser His Asp Lys Asp Lys Tyr Lys Asp Gly 1115 1120 1125Ile Ala Pro Asp Ala Ala Asn Leu Asn Pro Asp Ala Met Asp Glu 1130 1135 1140Gly Phe Asp Gly Val Ser Asp Ile Glu Pro Asp Leu Glu 1145 1150 1155121536PRTAspergillus niger 121Met Arg Val Leu Pro Ala Ala Met Leu Val Gly Ala Ala Thr Ala Ala1 5 10 15Val Pro Pro Phe Gln Gln Val Leu Gly Gly Asn Gly Ala Lys His Gly 20 25 30Ala Asp His Ala Ala Glu Val Pro Ala Asp His Ser Ala Asp Gly Phe 35 40 45Ser Lys Pro Leu His Ala Phe Gln Glu Glu Leu Lys Ser Leu Ser Asp 50 55 60Glu Ala Arg Lys Leu Trp Asp Glu Val Ala Ser Phe Phe Pro Glu Ser65 70 75 80Met Asp Gln Asn Pro Leu Phe Ser Leu Pro Lys Lys His Asn Arg Arg 85 90 95Pro Asp Ser His Trp Asp His Ile Val Asp Gly Lys Leu Glu Ala Tyr 100 105 110Asp Leu Arg Val Lys Lys Thr Asp Pro Gly Ser Leu Gly Ile Asp Pro 115 120 125Gly Val Lys Gln Tyr Thr Gly Tyr Leu Asp Asp Asn Glu Asn Asp Lys 130 135 140His Leu Phe Tyr Trp Phe Phe Glu Ser Arg Asn Asp Pro Glu Asn Asp145 150 155 160Pro Val Val Leu Trp Leu Asn Gly Gly Pro Gly Cys Ser Ser Leu Thr 165 170 175Gly Leu Phe Met Glu Leu Gly Pro Ser Ser Ile Asn Lys Lys Ile Gln 180 185 190Pro Val Tyr Asn Asp Tyr Ala Trp Asn Ser Asn Ala Ser Val Ile Phe 195 200 205Leu Asp Gln Pro Val Asn Val Gly Tyr Ser Tyr Ser Asn Ser Ala Val 210 215 220Ser Asp Thr Val Ala Ala Gly Lys Asp Val Tyr Ala Leu Leu Thr Leu225 230 235 240Phe Phe Lys Gln Phe Pro Glu Tyr Ala Lys Gln Asp Phe His Ile Ala 245 250 255Gly Glu Ser Tyr Ala Gly His Tyr Ile Pro Val Phe Ala Ser Glu Ile 260 265 270Leu Ser His Lys Lys Arg Asn Ile Asn Leu Gln Ser Val Leu Ile Gly 275 280 285Asn Gly Leu Thr Asp Gly Tyr Thr Gln Tyr Glu Tyr Tyr Arg Pro Met 290 295 300Ala Cys Gly Asp Gly Gly Tyr Pro Ala Val Leu Asp Glu Ser Ser Cys305 310 315 320Gln Ser Met Asp Asn Ala Leu Pro Arg Cys Gln Ser Met Ile Glu Ser 325 330 335Cys Tyr Ser Ser Glu Ser Ala Trp Val Cys Val Pro Ala Ser Ile Tyr 340 345 350Cys Asn Asn Ala Leu Leu Ala Pro Tyr Gln Arg Thr Gly Gln Asn Val 355 360 365Tyr Asp Val Arg Gly Lys Cys Glu Asp Ser Ser Asn Leu Cys Tyr Ser 370 375 380Ala Met Gly Tyr Val Ser Asp Tyr Leu Asn Lys Pro Glu Val Ile Glu385 390 395 400Ala Val Gly Ala Glu Val Asn Gly Tyr Asp Ser Cys Asn Phe Asp Ile 405 410 415Asn Arg Asn Phe Leu Phe His Gly Asp Trp Met Lys Pro Tyr His Arg 420 425 430Leu Val Pro Gly Leu Leu Glu Gln Ile Pro Val Leu Ile Tyr Ala Gly 435 440 445Asp Ala Asp Phe Ile Cys Asn Trp Leu Gly Asn Lys Ala Trp Thr Glu 450 455 460Ala Leu Glu Trp Pro Gly Gln Ala Glu Tyr Ala Ser Ala Glu Leu Glu465 470 475 480Asp Leu Val Ile Val Asp Asn Glu His Thr Gly Lys Lys Ile Gly Gln 485 490 495Val Lys Ser His Gly Asn Phe Thr Phe Met Arg Leu Tyr Gly Gly Gly 500 505 510His Met Val Pro Met Asp Gln Pro Glu Ser Ser Leu Glu Phe Phe Asn 515 520 525Arg Trp Leu Gly Gly Glu Trp Phe 530 535122279PRTAspergillus niger 122Met Lys Phe Thr Asn Tyr Leu Leu Thr Thr Ala Thr Leu Ala Ser Ser1 5 10 15Val Leu Ala Ala Pro Ala Pro Arg Thr Gly Leu Glu Asp Arg Leu Arg 20 25 30Ala Arg Ser Leu Gln Arg Gln Ser His Pro Leu Ala Pro Ile Pro Leu 35 40 45Asp Thr Ser Thr Lys Glu Asn Ser Arg Leu Leu Glu Ala Asp Glu Asn 50 55 60Thr Thr His Val Thr Tyr Ser Ser Asn Trp Ala Gly Ala Val Arg Glu65 70 75 80Gln Pro Pro Pro Gln Gly Thr Tyr Ser Ala Val Ser Ala Thr Phe Arg 85 90 95Val Pro Glu Pro Thr Ala Gln Gly Gly Ser Gly Thr Gln Ala Gly Ser 100 105 110Ala Trp Val Gly Ile Asp Gly Asp Thr Tyr Ser Asn Ala Ile Leu Gln 115 120 125Thr Gly Val Asp Phe Tyr Val Glu Asn Gly Gln Thr Tyr Asn Asp Ala 130 135 140Trp Tyr Glu Trp Tyr Pro Asp Tyr Ala Tyr Asp Phe Asp Leu Asp Val145 150 155 160Ser Thr Gly Asp Thr Ile Val Ala Lys Val Glu Ala Ile Ser Pro Ser 165 170 175Gln Gly Val Ala Thr Ile Glu Asn Ile Ser Thr Gly Lys Lys Ala Thr 180 185 190Gln Thr Ile Arg Ala Pro Ala Ala Thr Ala Thr Leu Ala Gly Gln Asn 195 200 205Ala Asp Trp Ile Val Glu Asp Phe Gln Ser Gly Asp Ser Met Val Asp 210 215 220Leu Ala Gly Phe Gly Glu Ile Ser Phe Trp Gly Val Gln Ala Gln Gly225 230 235 240Gly Gly Ser Thr Trp Gly Val Asp Asp Ala Thr Ile Val Glu Leu Lys 245 250 255Gln Gly Asn Glu Val Leu Thr Asp Val Glu Val Gln Ser Asp Ser Ala 260 265 270Phe Thr Val Lys Tyr Thr Ser 275123573PRTAspergillus niger 123Met Ile Tyr Val Asn Tyr Ile Leu Gly Leu Leu Ser Leu Leu His Thr1 5 10 15Ala Val Ala Thr Ala Pro Asp Tyr Val Val Val Asp Gln Leu Asn Ser 20 25 30Ile Pro Asp Gly Trp Thr Lys Gly Ala Ala Pro Pro Pro Phe Thr Pro 35 40 45Met Lys Phe Trp Leu Ser Met His His Glu Tyr Lys Ala Asp Phe Glu 50 55 60Gln Lys Val Ile Asp Ile Ser Thr Pro Gly His Arg Asp Tyr Gly Arg65 70 75 80His Met Lys Arg Asn Asp Val Met Ala Phe Met Arg Pro Ser Asp Gln 85 90 95Val Ser Lys Ile Ile Phe Ser Trp Leu Glu Ser Glu His Val Pro Pro 100 105 110Asn Ala Ile Glu Asp Arg Gly Asp Trp Val Ala Phe Thr Val Pro Leu 115 120 125Ala Gln Ala Gln Ser Met Met Lys Thr Asp Phe Tyr Asn Phe His His 130 135 140Leu Glu Thr Asn Thr Thr Gln Ile Arg Thr Leu Lys Tyr Ser Val Pro145 150 155 160Glu Gln Val Asp Ala His Leu Gln Met Ile Gln Pro Thr Thr Arg Phe 165 170 175Gly Arg Pro Lys Thr Gln Thr Ser Leu Pro Ser Leu Met Pro Val Ser 180 185 190Val Asn Ile Asp Glu Ile Ser Glu Asp Cys Leu Thr Gly Val Thr Pro 195 200 205Ile Cys Leu Arg Gln Leu Tyr Gly Leu Pro Ser Thr Lys Ala Ser Pro 210 215 220Asp Ser Arg Asn Val Leu Gly Ile Ser Gly Tyr Leu Asp Gln Tyr Ala225 230 235 240Arg Tyr Ser Asp Leu Asp Glu Phe Leu Ala Val Tyr Ser Pro Asn Ser 245 250 255Val Asp Ala Asp Phe Ser Val Val Ser Ile Asn Gly Gly Gln Asn Pro 260 265 270Gln Asn Ser Gln Glu Gly Ser Thr Glu Ala Ser Leu Asp Ile Gln Tyr 275 280 285Ala Leu Ser Met Ala Phe Asp Ala Asn Ala Thr Phe Tyr Thr Thr Ala 290 295 300Gly Arg Ala Pro Ser Pro Tyr Leu Glu Gln Leu Gln Tyr Leu Val Gly305 310 315 320Leu Pro Asp Glu Asp Leu Pro Ala Val Leu Ser Thr Ser Tyr Gly Glu 325 330 335Asp Glu Gln Ser Leu Pro Glu Glu Tyr Thr Glu Ala Thr Cys Asn Leu 340 345 350Phe Ala Gln Leu Gly Ala Arg Gly Val Ser Val Ile Phe Ser Ser Gly 355 360 365Asp Ser Gly Val Gly Gly Ser Cys Val Ser Asn Asp Gly Ser Gln Arg 370 375 380Thr Arg Phe Gln Pro Ile Phe Pro Ala Ser Cys Pro Phe Val Thr Ser385 390 395 400Val Gly Gly Thr Glu Gly Val Gly Pro Glu Lys Ala Val Asp Phe Ser 405 410 415Ser Gly Gly Phe Ser Glu Arg Phe Ala Arg Pro Ser Tyr Gln Asn Ala 420 425 430Ser Val Glu Ala Tyr Leu Ala Arg Leu Gly Asp Lys Trp Asp Gly Leu 435 440 445Tyr Asn Pro Asp Gly Arg Gly Ile Pro Asp Val Ser Ala Gln Ala Ser 450 455 460Asn Tyr Val Ile Arg Asp His Gly Gln Trp Leu Gln Thr Ala Gly Thr465 470 475 480Ser Ala Ala Ala Pro Val Phe

Ala Ala Val Ile Ser Arg Leu Asn Ala 485 490 495Ala Arg Leu Glu Gln Gly Lys Pro Thr Leu Gly Phe Leu Asn Pro Trp 500 505 510Leu Tyr Ser Leu Asp Gln Gln Gly Phe Thr Asp Ile Val Asp Gly Gly 515 520 525Ser Val Gly Cys Asp Gly Ser Asn Gly Gly Ala Leu Val Pro Tyr Ala 530 535 540Ser Trp Asn Ala Thr Lys Gly Trp Asp Pro Val Thr Gly Leu Gly Thr545 550 555 560Pro Leu Tyr Gln Thr Leu Glu Gln Leu Ala Gln Ser Ala 565 570124585PRTAspergillus niger 124Met Arg Ser Ser Gly Leu Tyr Thr Ala Leu Leu Cys Ser Leu Ala Ala1 5 10 15Ser Thr Asn Ala Ile Val His Glu Lys Leu Ala Ala Val Pro Ser Gly 20 25 30Trp His His Val Glu Asp Ala Gly Ser Asp His Gln Ile Ser Leu Ser 35 40 45Ile Ala Leu Ala Arg Lys Asn Leu Asp Gln Leu Glu Ser Lys Leu Lys 50 55 60Asp Leu Ser Thr Pro Gly Glu Ser Gln Tyr Gly Gln Trp Leu Asp Gln65 70 75 80Glu Asp Val Asp Thr Leu Phe Pro Val Ala Ser Asp Lys Ala Val Ile 85 90 95Asn Trp Leu Arg Ser Ala Asn Ile Thr His Ile Ser Arg Gln Gly Ser 100 105 110Leu Val Asn Phe Ala Thr Thr Val Asp Lys Val Asn Lys Leu Leu Asn 115 120 125Ala Thr Phe Ala Tyr Tyr Gln Ser Gly Ser Ser Gln Arg Leu Arg Thr 130 135 140Thr Glu Tyr Ser Ile Pro Asp Asp Leu Val Asp Ser Ile Asp Leu Ile145 150 155 160Ser Pro Thr Thr Phe Phe Gly Lys Glu Lys Thr Thr Ala Gly Leu Asn 165 170 175Gln Arg Ala Gln Lys Ile Asp Thr His Val Ala Lys Arg Ser Asn Ser 180 185 190Ser Ser Cys Ala Asp Val Ile Thr Leu Ser Cys Leu Lys Glu Met Tyr 195 200 205Asn Phe Gly Asn Tyr Thr Pro Ser Ala Ser Ser Gly Ser Lys Leu Gly 210 215 220Phe Gly Ser Phe Leu Asn Glu Ser Ala Ser Tyr Ser Asp Leu Ala Lys225 230 235 240Phe Glu Lys Leu Phe Asn Leu Pro Ser Gln Ser Phe Ser Val Glu Leu 245 250 255Val Asn Gly Gly Val Asn Asp Gln Asn Gln Ser Thr Ala Ser Leu Thr 260 265 270Glu Ala Asp Leu Asp Val Glu Leu Leu Val Gly Val Ala His Pro Leu 275 280 285Pro Val Thr Glu Phe Ile Thr Ser Gly Glu Pro Ala Ala Asp Asn Glu 290 295 300Asn Glu Pro Tyr Leu Gln Tyr Tyr Glu Tyr Leu Leu Ser Lys Pro Asn305 310 315 320Ser Ala Leu Pro Gln Val Ile Ser Asn Ser Tyr Gly Asp Asp Glu Gln 325 330 335Thr Val Pro Glu Tyr Tyr Ala Lys Arg Val Cys Asn Leu Ile Gly Leu 340 345 350Val Gly Leu Arg Gly Ile Ser Val Leu Glu Ser Ser Gly Asp Glu Gly 355 360 365Ile Gly Ser Gly Cys Arg Thr Thr Asp Gly Thr Asn Arg Thr Gln Phe 370 375 380Asn Pro Ile Phe Pro Ala Thr Cys Pro Tyr Val Thr Ala Val Gly Gly385 390 395 400Thr Met Ser Tyr Ala Pro Glu Ile Ala Trp Glu Ala Ser Ser Gly Gly 405 410 415Phe Ser Asn Tyr Phe Glu Arg Ala Trp Phe Gln Lys Glu Ala Val Gln 420 425 430Asn Tyr Leu Ala His His Ile Thr Asn Glu Thr Lys Gln Tyr Tyr Ser 435 440 445Gln Phe Ala Asn Phe Ser Gly Arg Gly Phe Pro Asp Val Ala Ala His 450 455 460Ser Phe Glu Pro Ser Tyr Glu Val Ile Phe Tyr Gly Ala Arg Tyr Gly465 470 475 480Ser Gly Gly Thr Ser Ala Ala Cys Pro Leu Phe Ser Ala Leu Val Gly 485 490 495Met Leu Asn Asp Ala Arg Leu Arg Ala Gly Lys Ser Thr Leu Gly Phe 500 505 510Leu Asn Pro Leu Leu Tyr Ser Lys Gly Tyr Arg Ala Leu Thr Asp Val 515 520 525Thr Gly Gly Gln Ser Ile Gly Cys Asn Gly Ile Asp Pro Gln Asn Asp 530 535 540Glu Thr Val Ala Gly Ala Gly Ile Ile Pro Trp Ala His Trp Asn Ala545 550 555 560Thr Val Gly Trp Asp Pro Val Thr Gly Leu Gly Leu Pro Asp Phe Glu 565 570 575Lys Leu Arg Gln Leu Val Leu Ser Leu 580 585125265PRTAspergillus niger 125Met Lys Thr Thr Ala Leu Leu Thr Ala Gly Leu Leu Ala Thr Thr Ala1 5 10 15Met Ala Ala Pro Leu Thr Ala Lys Arg Gln Ala Ala Arg Ala Lys Arg 20 25 30Ser Thr Asn Arg Gln Ser Asn Pro Pro Phe Lys Pro Gly Thr Asn Glu 35 40 45Val Leu Ala Leu Asn Gly Thr Lys Asn Val Glu Tyr Ser Ser Asn Trp 50 55 60Ala Gly Ala Val Leu Ile Gly Thr Gly Tyr Thr Ala Val Thr Ala Glu65 70 75 80Phe Val Val Pro Thr Pro Ser Val Pro Ser Gly Gly Ser Ser Arg Glu 85 90 95Glu Tyr Cys Ala Ser Ala Trp Val Gly Ile Asp Gly Asp Thr Cys Asp 100 105 110Thr Ala Ile Leu Gln Thr Gly Val Asp Phe Cys Val Gln Gly Ser Glu 115 120 125Val Ser Phe Asp Ala Trp Tyr Glu Trp Tyr Pro Asp Tyr Ala Tyr Asp 130 135 140Phe Ser Gly Ile Ser Ile Ser Ala Gly Asp Thr Ile Lys Val Thr Val145 150 155 160Asp Ala Ser Ser Asp Thr Thr Gly Thr Ala Thr Ile Glu Asn Val Ser 165 170 175Thr Gly Thr Thr Val Thr His Ser Phe Thr Gly Gly Val Asp Gly Asp 180 185 190Leu Cys Glu Tyr Asn Ala Glu Trp Ile Val Glu Asp Phe Glu Glu Asp 195 200 205Asp Ser Leu Val Pro Phe Ala Asp Phe Gly Thr Val Thr Phe Thr Ser 210 215 220Cys Ser Ala Thr Lys Asp Gly Ser Ser Val Gly Pro Glu Asp Ala Thr225 230 235 240Ile Ile Asp Ile Glu Gln Asn Glu Val Leu Thr Ser Val Ser Val Ser 245 250 255Ser Ser Glu Val Val Val Lys Tyr Val 260 265126580PRTAspergillus niger 126Met Val Ala Phe Ser Arg Ile Ser Ala Gly Phe Ala Leu Ala Ala Pro1 5 10 15Ala Leu Ala Ser Val Val Leu Glu Thr Val Lys Ser Val Pro Ser Asp 20 25 30Trp Lys Leu Val Glu Ala Ala Asp Thr Ser Ser Thr Ile Ser Leu Ser 35 40 45Val Ala Leu Ala Arg Gln Asn Leu Asp Gln Leu Glu Glu Lys Leu Leu 50 55 60Ala Val Ser Thr Pro Gly Lys Asp Thr Tyr Gly Gln Phe Leu Asp Leu65 70 75 80Asp Asp Ile Asn Glu Gln Phe Pro Leu Ala Asp Asp Ala Ala Val Val 85 90 95Ala Trp Leu Lys Lys Ala Gly Val Thr Gln Ile His Lys Glu Gly Gly 100 105 110Leu Leu Asn Phe Ala Thr Thr Val Gly Thr Ala Asn Gln Leu Leu Asn 115 120 125Thr Thr Phe Ser Val Tyr Lys Ser Gly Ser Thr Gln Lys Leu Arg Thr 130 135 140Thr Gln Tyr Ser Val Pro Asp Glu Leu Thr Gly Ser Ile Asp Leu Ile145 150 155 160Ser Pro Thr Val Phe Phe Gly Lys Ser Asn Ala Ala Arg Ser Ala Ala 165 170 175Val Arg Ala Ser Gln Thr Thr Lys Glu Thr Ser Arg Lys Lys Ser Ser 180 185 190Asn Val Cys Glu Tyr Ile Thr Pro Asp Cys Leu Lys Glu Gln Tyr Ser 195 200 205Ile Asp Tyr Thr Pro Glu Ala Ser Ser Gly Ser Arg Val Gly Phe Gly 210 215 220Ser Phe Leu Asn Glu Ser Ala Leu Tyr Ser Asp Leu Asp Leu Phe Thr225 230 235 240Gln Tyr Phe Asp Ile Pro Gln Gln Ser Phe Thr Val Glu Thr Ile Asn 245 250 255Gly Gly Ile Asn Asn Gln Glu Asn Asp Pro Asp Gly Glu Ala Asp Leu 260 265 270Asp Val Gln Asn Ile Val Gly Ile Ser His Pro Leu Pro Val Thr Glu 275 280 285Tyr Ile Thr Gly Gly Ser Pro Pro Phe Ile Pro Asp Val Glu Thr Thr 290 295 300Thr Asp Glu Asn Glu Pro Tyr Leu Gln Tyr Tyr Glu Tyr Leu Leu Ala305 310 315 320Lys Thr Asn Asp Glu Leu Pro Leu Val Ile Ser Asn Ser Tyr Gly Asp 325 330 335Asp Glu Asp Thr Val Pro Ile Ala Tyr Ala Thr Arg Val Cys Asn Leu 340 345 350Ile Gly Leu Met Gly Thr Arg Gly Ile Ser Ile Leu Glu Ser Ser Gly 355 360 365Asp Ser Gly Val Gly Gly Ala Cys Met Ser Asn Asp Gly Thr Asp Lys 370 375 380Thr Glu Phe Thr Pro Met Phe Pro Gly Thr Cys Pro Tyr Ile Thr Ala385 390 395 400Val Gly Gly Thr Gln Asp Val Pro Glu Val Ala Trp Val Asp Ser Ser 405 410 415Gly Gly Phe Ser Asn Tyr Phe Ser Gln Pro Ser Tyr Gln Ser Asp Gln 420 425 430Val Glu Thr Tyr Leu Asp Lys Tyr Ile Ser Ala Ser Thr Lys Lys Tyr 435 440 445Tyr Glu Gln Tyr Thr Asn Phe Ser Gly Arg Ala Phe Pro Asp Val Ser 450 455 460Ala Phe Ala Gly Ser Pro Tyr Tyr Glu Thr Tyr Ile Asp Gly Gln Leu465 470 475 480Gly Leu Val Ala Gly Thr Ser Gly Ala Ser Pro Val Phe Ala Gly Ile 485 490 495Val Ala Leu Leu Asn Asp Ala Arg Leu Arg Ala Asn Lys Thr Ser Leu 500 505 510Gly Phe Leu Asn Pro Trp Leu Tyr Ser Ser Gly Tyr Lys Ser Leu Asn 515 520 525Asp Ile Thr Ser Gly Glu Ala Val Gly Cys Gln Gly Asp Val Glu Gly 530 535 540Ala Gly Val Ile Pro Trp Ala Ser Trp Asn Ala Thr Thr Gly Trp Asp545 550 555 560Pro Ala Thr Gly Leu Gly Thr Pro Asn Phe Ala Lys Leu Lys Glu Ala 565 570 575Val Leu Ala Leu 580127631PRTAspergillus niger 127Met His Gly Leu Arg Leu Val Cys Ser Ile Gly Thr Leu Pro Leu Val1 5 10 15Ile Leu Ala Tyr Pro Ala Ala Ser Leu His Thr Thr Ser Ala Ala Val 20 25 30Asp Leu Asp Ser Leu Arg Leu Thr Ser Asn Ser Glu Tyr Val Asn Ser 35 40 45Val His Val Asp Thr Asn Arg Ser Val Ala Val Ser Ala Glu Glu His 50 55 60Tyr Thr Asp Thr Ala Ala Arg Leu Val Gln Asn Ile Val Pro Gly Ala65 70 75 80Ser Phe Arg Leu Ile Asp Asp His Phe Val Gly Asp Asn Gly Val Ala 85 90 95His Val Tyr Phe Arg Gln Thr Leu His Gly Ile Asp Ile Asp Asn Ala 100 105 110Asp Phe Asn Val Asn Ile Gly Lys Asp Gly Leu Val Leu Ser Phe Gly 115 120 125His Ser Phe Phe Thr Gly Ala Leu Pro Ser Ser His Leu Asp Asn Thr 130 135 140Asn Val Leu Ser Pro Glu Ala Ala Leu Arg Gly Ala Arg Asp Ala Ile145 150 155 160Gln Leu Pro Leu Thr Ile Asp Asn Val Ser Thr Glu Ala Ala Glu Gly 165 170 175Arg Asn Glu Tyr Ile Phe Arg Glu Ala Val Gly Ala Val Ser Asp Pro 180 185 190Lys Ala Lys Leu Val Tyr Leu Val Lys Pro Glu Gly Thr Leu Ala Leu 195 200 205Thr Trp Arg Ile Glu Thr Asp Met Tyr Glu His Trp Leu Leu Thr Tyr 210 215 220Ile Asp Ala Glu Thr Thr Thr Val His Gly Val Val Asp Tyr Val Ala225 230 235 240Asp Ala Thr Tyr Gln Val Tyr Pro Trp Gly Thr Asn Asp Pro Ala Glu 245 250 255Gly His Arg Thr Ile Val Thr Asp Pro Trp Asp Leu Ser Ala Ser Ala 260 265 270Tyr Thr Trp Ile Ser Asp Gly Arg Asp Asn Tyr Thr Thr Thr Arg Gly 275 280 285Asn Asn Ala Ile Ala His Trp Asn Pro Thr Gly Gly Gly Ser Tyr Leu 290 295 300Tyr Asn Leu Arg Pro Ser Asp Pro Asn Leu Asn Phe Gln Trp Pro Tyr305 310 315 320Ser Pro Asn Met Ser Pro Pro Arg Ser Tyr Ile Asn Ala Ser Ile Val 325 330 335Gln Leu Phe Tyr Thr Ala Asn Ala Tyr His Asp Leu Leu Tyr Thr Leu 340 345 350Gly Phe Thr Glu Ser Ala Gly Asn Phe Gln Trp Asn Asn Ser Ala His 355 360 365Gly Gly Arg Asp Lys Asp Tyr Val Ile Leu Asn Ala Gln Asp Gly Ser 370 375 380Gly Phe Ser Asn Ala Asn Phe Ala Thr Pro Pro Asp Gly Ile Pro Gly385 390 395 400Arg Met Arg Met Tyr Ile Trp Ile Glu Ser Thr Pro Ser Arg Asp Gly 405 410 415Ser Phe Asp Ala Gly Ile Val Ile His Glu Tyr Thr His Gly Val Ser 420 425 430Asn Arg Leu Thr Gly Gly Ser His Asn Ala Gly Cys Leu Ser Ala Leu 435 440 445Glu Ser Gly Gly Met Gly Glu Gly Trp Gly Asp Phe Met Ala Thr Ala 450 455 460Ile Arg Ile Lys Pro Asn Asp Thr Arg Thr Thr Ser Tyr Thr Met Gly465 470 475 480Ala Trp Ala Asp Asn Asp Lys Cys Gly Val Arg Asp Tyr Pro Tyr Ser 485 490 495Thr Ser Phe Thr Glu Asn Pro Leu Asn Tyr Thr Ser Val Asn Thr Met 500 505 510Asn Gly Val His Ala Ile Gly Thr Val Trp Ala Thr Met Leu Tyr Glu 515 520 525Val Leu Trp Asn Leu Ile Asp Lys Tyr Gly Lys Asn Asp Gly Ser Arg 530 535 540Pro Val Phe Arg Asn Gly Val Pro Thr Asp Gly Lys Tyr Leu Met Met545 550 555 560Lys Leu Val Val Asp Gly Met Ala Leu Gln Pro Cys Asn Pro Asn Phe 565 570 575Val Gln Ala Arg Asp Ala Ile Leu Asp Ala Asp Ile Val Leu Thr Gly 580 585 590Gly Lys Asn Arg Cys Glu Ile Trp Arg Gly Phe Ala Lys Arg Gly Leu 595 600 605Gly Gln Gly Ala Ala His Ser Ser Leu Asn Trp Met Arg Arg Gly Ser 610 615 620Thr Leu Leu Pro Thr Gly Cys625 630128394PRTAspergillus niger 128Met Val Val Phe Ser Lys Thr Ala Ala Leu Val Leu Gly Leu Ser Ser1 5 10 15Ala Val Ser Ala Ala Pro Ala Pro Thr Arg Lys Gly Phe Thr Ile Asn 20 25 30Gln Ile Ala Arg Pro Ala Asn Lys Thr Arg Thr Ile Asn Leu Pro Gly 35 40 45Met Tyr Ala Arg Ser Leu Ala Lys Phe Gly Gly Thr Val Pro Gln Ser 50 55 60Val Lys Glu Ala Ala Ser Lys Gly Ser Ala Val Thr Thr Pro Gln Asn65 70 75 80Asn Asp Glu Glu Tyr Leu Thr Pro Val Thr Val Gly Lys Ser Thr Leu 85 90 95His Leu Asp Phe Asp Thr Gly Ser Ala Asp Leu Trp Val Phe Ser Asp 100 105 110Glu Leu Pro Ser Ser Glu Gln Thr Gly His Asp Leu Tyr Thr Pro Ser 115 120 125Ser Ser Ala Thr Lys Leu Ser Gly Tyr Thr Trp Asp Ile Ser Tyr Gly 130 135 140Asp Gly Ser Ser Ala Ser Gly Asp Val Tyr Arg Asp Thr Val Thr Val145 150 155 160Gly Gly Val Thr Thr Asn Lys Gln Ala Val Glu Ala Ala Ser Lys Ile 165 170 175Ser Ser Glu Phe Val Gln Asn Thr Ala Asn Asp Gly Leu Leu Gly Leu 180 185 190Ala Phe Ser Ser Ile Asn Thr Val Gln Pro Lys Ala Gln Thr Thr Phe 195 200 205Phe Asp Thr Val Lys Ser Gln Leu Asp Ser Pro Leu Phe Ala Val Gln 210 215 220Leu Lys His Asp Ala Pro Gly Val Tyr Asp Phe Gly Tyr Ile Asp Asp225 230 235 240Ser Lys Tyr Thr Gly Ser Ile Thr Tyr Thr Asp Ala Asp Ser Ser Gln 245 250 255Gly Tyr Trp Gly Phe Ser Thr Asp Gly Tyr Ser Ile Gly Asp Gly Ser 260 265 270Ser Ser Ser Ser Gly Phe Ser Ala Ile Ala Asp Thr Gly Thr Thr Leu 275 280 285Ile Leu Leu Asp Asp Glu Ile Val Ser Ala Tyr Tyr Glu Gln Val Ser 290 295

300Gly Ala Gln Glu Ser Glu Glu Ala Gly Gly Tyr Val Phe Ser Cys Ser305 310 315 320Thr Asn Pro Pro Asp Phe Thr Val Val Ile Gly Asp Tyr Lys Ala Val 325 330 335Val Pro Gly Lys Tyr Ile Asn Tyr Ala Pro Ile Ser Thr Gly Ser Ser 340 345 350Thr Cys Phe Gly Gly Ile Gln Ser Asn Ser Gly Leu Gly Leu Ser Ile 355 360 365Leu Gly Asp Val Phe Leu Lys Ser Gln Tyr Val Val Phe Asn Ser Glu 370 375 380Gly Pro Lys Leu Gly Phe Ala Ala Gln Ala385 390129398PRTAspergillus niger 129Met Lys Ser Ala Ser Leu Leu Thr Ala Ser Val Leu Leu Gly Cys Ala1 5 10 15Ser Ala Glu Val His Lys Leu Lys Leu Asn Lys Val Pro Leu Glu Glu 20 25 30Gln Leu Tyr Thr His Asn Ile Asp Ala His Val Arg Ala Leu Gly Gln 35 40 45Lys Tyr Met Gly Ile Arg Pro Ser Ile His Lys Glu Leu Val Glu Glu 50 55 60Asn Pro Ile Asn Asp Met Ser Arg His Asp Val Leu Val Asp Asn Phe65 70 75 80Leu Asn Ala Gln Tyr Phe Ser Glu Ile Glu Leu Gly Thr Pro Pro Gln 85 90 95Lys Phe Lys Val Val Leu Asp Thr Gly Ser Ser Asn Leu Trp Val Pro 100 105 110Ser Ser Glu Cys Ser Ser Ile Ala Cys Tyr Leu His Asn Lys Tyr Asp 115 120 125Ser Ser Ala Ser Ser Thr Tyr His Lys Asn Gly Ser Glu Phe Ala Ile 130 135 140Lys Tyr Gly Ser Gly Ser Leu Ser Gly Phe Ile Ser Gln Asp Thr Leu145 150 155 160Lys Ile Gly Asp Leu Lys Val Lys Gly Gln Asp Phe Ala Glu Ala Thr 165 170 175Asn Glu Pro Gly Leu Ala Phe Ala Phe Gly Arg Phe Asp Gly Ile Leu 180 185 190Gly Leu Gly Tyr Asp Thr Ile Ser Val Asn Lys Ile Val Pro Pro Phe 195 200 205Tyr Asn Met Leu Asp Gln Gly Leu Leu Asp Glu Pro Val Phe Ala Phe 210 215 220Tyr Leu Gly Asp Thr Asn Lys Glu Gly Asp Glu Ser Val Ala Thr Phe225 230 235 240Gly Gly Val Asp Lys Asp His Tyr Thr Gly Glu Leu Ile Lys Ile Pro 245 250 255Leu Arg Arg Lys Ala Tyr Trp Glu Val Glu Leu Asp Ala Ile Ala Leu 260 265 270Gly Asp Asp Val Ala Glu Met Glu Asn Thr Gly Val Ile Leu Asp Thr 275 280 285Gly Thr Ser Leu Ile Ala Leu Pro Ala Asp Leu Ala Glu Met Ile Asn 290 295 300Ala Gln Ile Gly Ala Lys Lys Gly Trp Thr Gly Gln Tyr Thr Val Asp305 310 315 320Cys Asp Lys Arg Ser Ser Leu Pro Asp Val Thr Phe Thr Leu Ala Gly 325 330 335His Asn Phe Thr Ile Ser Ser Tyr Asp Tyr Thr Leu Glu Val Gln Gly 340 345 350Ser Cys Val Ser Ala Phe Met Gly Met Asp Phe Pro Glu Pro Val Gly 355 360 365Pro Leu Ala Ile Leu Gly Asp Ala Phe Leu Arg Lys Trp Tyr Ser Val 370 375 380Tyr Asp Leu Gly Asn Ser Ala Val Gly Leu Ala Lys Ala Lys385 390 395130393PRTAspergillus niger 130Met Arg Lys Tyr Arg Phe His Pro Thr Lys Pro Gly Pro Tyr Thr Leu1 5 10 15Ser Ser Ser Ile Gln Gln Thr Gly Arg Pro Tyr Thr Glu Lys Pro Ile 20 25 30Gly Gly Arg Ala His Ile Arg Gln Leu Val Arg Lys Lys Ser Thr Thr 35 40 45Ser Asp Glu Val Gly Glu Val Pro Ala Glu Asp Val Gln Asn Asp Ser 50 55 60Met Tyr Leu Ala Thr Val Gly Ile Gly Thr Pro Ala Gln Asn Leu Lys65 70 75 80Leu Asp Phe Asp Thr Gly Ser Ala Asp Leu Trp Val Trp Ser Asn Lys 85 90 95Leu Pro Ser Thr Leu Leu Ser Glu Asn Lys Thr His Ala Ile Phe Asp 100 105 110Ser Ser Lys Ser Ser Thr Phe Lys Thr Leu Glu Gly Glu Ser Trp Gln 115 120 125Ile Ser Tyr Gly Asp Gly Ser Ser Ala Ser Gly Ser Val Gly Thr Asp 130 135 140Asp Val Asn Ile Gly Gly Val Val Val Lys Asn Gln Ala Val Glu Leu145 150 155 160Ala Glu Lys Met Ser Ser Thr Phe Ala Gln Gly Glu Gly Asp Gly Leu 165 170 175Leu Gly Leu Ala Phe Ser Asn Ile Asn Thr Val Gln Pro Lys Ser Val 180 185 190Lys Thr Pro Val Glu Asn Met Ile Leu Gln Asp Asp Ile Pro Lys Ser 195 200 205Ala Glu Leu Phe Thr Ala Lys Leu Asp Thr Trp Arg Asp Thr Asp Asp 210 215 220Glu Ser Phe Tyr Thr Phe Gly Phe Ile Asp Gln Asp Leu Val Lys Thr225 230 235 240Ala Gly Glu Glu Val Tyr Tyr Thr Pro Val Asp Asn Ser Gln Gly Phe 245 250 255Trp Leu Phe Asn Ser Thr Ser Ala Thr Val Asn Gly Lys Thr Ile Asn 260 265 270Arg Ser Gly Asn Thr Ala Ile Ala Asp Thr Gly Thr Thr Leu Ala Leu 275 280 285Val Asp Asp Asp Thr Cys Glu Ala Ile Tyr Ser Ala Ile Asp Gly Ala 290 295 300Tyr Tyr Asp Gln Glu Val Gln Gly Trp Ile Tyr Pro Thr Asp Thr Ala305 310 315 320Gln Asp Lys Leu Pro Thr Val Ser Phe Ala Val Gly Glu Lys Gln Phe 325 330 335Val Val Gln Lys Glu Asp Leu Ala Phe Ser Glu Ala Lys Thr Gly Tyr 340 345 350Val Tyr Gly Gly Ile Gln Ser Arg Gly Asp Met Thr Met Asp Ile Leu 355 360 365Gly Asp Thr Phe Leu Lys Ser Ile Tyr Ala Val Ser Ala Leu Leu Leu 370 375 380Ala Leu Arg Gly Asp Ile Glu Ala His385 390131282PRTAspergillus niger 131Met Lys Phe Ser Thr Ile Leu Thr Gly Ser Leu Phe Ala Thr Ala Ala1 5 10 15Leu Ala Ala Pro Leu Thr Glu Lys Arg Arg Ala Arg Lys Glu Ala Arg 20 25 30Ala Ala Gly Lys Arg His Ser Asn Pro Pro Tyr Ile Pro Gly Ser Asp 35 40 45Lys Glu Ile Leu Lys Leu Asn Gly Thr Ser Asn Glu Asp Tyr Ser Ser 50 55 60Asn Trp Ala Gly Ala Val Leu Ile Gly Asp Gly Tyr Thr Lys Val Thr65 70 75 80Gly Glu Phe Thr Val Pro Ser Val Ser Ala Gly Ser Ser Ser Ser Ser 85 90 95Gly Tyr Gly Gly Gly Tyr Gly Tyr Tyr Lys Asn Lys Arg Gln Ser Glu 100 105 110Glu Tyr Cys Ala Ser Ala Trp Val Gly Ile Asp Gly Asp Thr Cys Glu 115 120 125Thr Ala Ile Leu Gln Thr Gly Val Asp Phe Cys Tyr Glu Asp Gly Gln 130 135 140Thr Ser Tyr Asp Ala Trp Tyr Glu Trp Tyr Pro Asp Tyr Ala Tyr Asp145 150 155 160Phe Asn Asp Ile Thr Ile Ser Glu Gly Asp Thr Ile Lys Val Thr Val 165 170 175Glu Ala Thr Ser Lys Ser Ser Gly Ser Ala Thr Val Glu Asn Leu Thr 180 185 190Thr Gly Gln Ser Val Thr His Thr Phe Ser Gly Asn Val Glu Gly Asp 195 200 205Leu Cys Glu Thr Asn Ala Glu Trp Ile Val Glu Asp Phe Glu Ser Gly 210 215 220Asp Ser Leu Val Ala Phe Ala Asp Phe Gly Ser Val Thr Phe Thr Asn225 230 235 240Ala Glu Ala Thr Ser Asp Gly Ser Thr Val Gly Pro Ser Asp Ala Thr 245 250 255Val Met Asp Ile Glu Gln Asp Gly Thr Val Leu Thr Glu Thr Ser Val 260 265 270Ser Gly Asp Ser Val Thr Val Thr Tyr Val 275 280132273PRTAspergillus niger 132Met Gly Asp Tyr Gly Pro Gly Val Ser Ser Leu Thr Ala Gln Leu Pro1 5 10 15Gly Asn Pro Pro Val Ser Glu Thr Asp Gln Asp Glu Ile Ser Val Leu 20 25 30Val Thr Gly Phe Gly Pro Phe Lys Ser Asn Leu Val Asn Ala Ser Tyr 35 40 45Leu Ile Ala Ser Ser Leu Pro Pro Ser Phe Thr Phe Ser Pro Ala Ser 50 55 60Ser Asp Gly Ser Asp Ala Val Pro Arg Arg Val Ser Ile Asn Val His65 70 75 80Pro Ser Pro Ile Pro Val Ala Tyr Ser Ser Val Arg Thr Thr Leu Pro 85 90 95Val Ile Leu Asp Asp Tyr Ala Lys Thr His Gly Gly Arg Arg Pro Asp 100 105 110Ile Val Ile His Ile Gly Ile Ala Ala Met Arg Asn Tyr Tyr Ser Val 115 120 125Glu Thr Gln Ala His Arg Asp Gly Tyr Leu Met Ser Asp Ile Lys Gly 130 135 140Arg Ser Gly Tyr Glu Asp Gly Glu Lys Leu Trp Arg Glu Leu Asp Leu145 150 155 160Pro Leu Val Leu Arg Ala Gly Pro Ser Glu Gly His Ala Ser Glu Lys 165 170 175Lys His Leu Ser Pro Arg Pro Pro Asp Glu Asp Phe Leu Ala Ala Trp 180 185 190Lys Thr Phe Cys Pro Pro Glu Thr Asp Ala Arg Ile Ser Thr Asp Ala 195 200 205Gly Arg Tyr Leu Cys Glu Phe Ile Leu Tyr Thr Ser Leu Ala Leu Ala 210 215 220Tyr Gln Ala Gly Glu Asp Arg Asn Val Thr Phe Phe His Val Pro Ala225 230 235 240Ser Cys Leu Asp Glu Asp Ile Glu Thr Gly Lys Glu Val Ala Val Ala 245 250 255Leu Ile Lys Ala Leu Val Thr Ser Trp Ser Glu Gln Gln His Ser Val 260 265 270Pro133542PRTAspergillus niger 133Met Gly Ser Arg Gln Gly Lys Ala Pro Phe Gly Trp Gly Thr Gln Ser1 5 10 15Leu Ala His Phe Gly Ile Asn Pro Asp Leu Gly Leu His Asn Gln Gln 20 25 30Asn Leu Asn Ser Leu Ile Ser His Ser Ala Met Ala Thr Ala Leu Glu 35 40 45Thr Glu Tyr Ala Thr Ile Pro Ile Asp His Asn Asn Ala Ser Ala Gly 50 55 60Thr Tyr Gln Asn Arg Phe Trp Val Ser Asp Glu Phe Tyr Gln Pro Gly65 70 75 80Asn Pro Ile Phe Val Tyr Asp Thr Gly Glu Ser Asp Gly Gly Ser Ile 85 90 95Ala Gln Ser Tyr Leu Thr Ser Thr Leu Ser Phe Phe Arg Glu Phe Leu 100 105 110Ile Glu Phe Asn Ala Met Gly Ile Ala Trp Glu His Arg Tyr Tyr Gly 115 120 125Asn Ser Thr Pro Ala Pro Val Ser Tyr Glu Thr Pro Pro Glu Ala Trp 130 135 140Gln Tyr Leu Thr Thr Lys Gln Ala Leu Ala Asp Leu Pro Tyr Phe Ala145 150 155 160Ser Asn Phe Ser Arg Glu Lys Tyr Pro Asp Met Asp Leu Thr Pro Gln 165 170 175Gly Thr Pro Trp Ile Met Val Gly Gly Ser Tyr Ala Gly Ile Arg Ala 180 185 190Ala Leu Thr Arg Lys Glu Tyr Pro Glu Thr Ile Phe Ala Ala Phe Ser 195 200 205Ser Ser Ser Pro Val Glu Ala Gln Val Asn Met Ser Ala Tyr Tyr Asp 210 215 220Gln Val Tyr Arg Gly Met Val Ala Ser Gly Trp Thr Asn Cys Ser Ala225 230 235 240Asp Ile His Ala Ala Leu Glu Tyr Ile Asp Asp Gln Leu Ser Asp Glu 245 250 255Asp Thr Ala Thr Ser Val Lys Gln Leu Phe Phe Gly Ser Gly Ala Glu 260 265 270Thr Asn Ser Asn Gly Asp Phe Thr Ala Ala Leu Thr Ala Ile Tyr Gly 275 280 285Tyr Phe Gln Ser Tyr Gly Met Ala Gly Gly Ile Gly Gly Leu Gly Ala 290 295 300Phe Cys Glu Tyr Leu Glu Ile Asp Pro Lys Thr Asn Gly Thr Thr Gly305 310 315 320Pro Asp Gly Leu Ala Pro Thr Tyr Gly Gly Gln Tyr Val Ala Glu Arg 325 330 335Trp Ala Ala Trp Pro Thr Phe Leu Glu Leu Val Asn Leu Asn Met Gly 340 345 350Thr Asn Cys Gly Pro Gln Asp Ala Ser Gln Pro Ile Asp Cys Asp Phe 355 360 365Ser Lys Pro Tyr Gly Asp Pro Ser Ala Ile Thr Trp Thr Trp Gln Tyr 370 375 380Cys Ser Glu Trp Gly Phe Phe Gln Ala Asn Asn Asp Gly Pro His Ser385 390 395 400Leu Ala Ser Arg Tyr Gln Ser Val Glu Tyr Gln Gln Glu Val Cys Asn 405 410 415Arg Gln Phe Pro Asp Ala Val Asp Lys Gly Leu Leu Pro Pro Ser Pro 420 425 430Arg Ala Asp Asp Val Asn Gln Glu Phe Gly Gly Trp Thr Ile Arg Pro 435 440 445Ser Asn Val Tyr Phe Ser Gly Gly Glu Phe Asp Pro Trp Arg Ser Leu 450 455 460Ser Ile Leu Ser Thr Glu Asp Phe Ala Pro Gln Gly Val Glu Phe Thr465 470 475 480Ser Ala Ile Pro Ala Cys Gly Val Gln Thr Asn Glu Asp Thr Val Phe 485 490 495Gly Tyr Val Met Gln Asn Ser Glu His Cys Phe Asp Phe Gln Ala Thr 500 505 510Pro Thr Val Gly Lys Leu Ser Arg Gly Ile Phe Thr Ser Ala Leu Leu 515 520 525Gln Trp Leu Glu Cys Phe Gly Gln Asn Ser Ser Gln Ser Arg 530 535 540134391PRTAspergillus niger 134Met Lys Leu Ser Ile Ala Leu Ala Leu Gly Ala Thr Ala Ser Thr Gly1 5 10 15Val Leu Ala Ala Val Val Pro Gln Gln Glu Pro Leu Ile Thr Pro Gln 20 25 30Asp Pro Pro Thr His His His Gln Glu Lys Phe Leu Ile Glu Leu Ala 35 40 45Pro Tyr Gln Thr Arg Trp Val Thr Glu Glu Glu Lys Trp Asp Leu Lys 50 55 60Leu Asp Gly Val Asn Phe Ile Asp Ile Thr Glu Glu Arg Asn Thr Gly65 70 75 80Phe Tyr Pro Thr Leu His Ala Gly Ser Tyr Val His Tyr Pro Pro Thr 85 90 95Met Lys His Ala Glu Lys Val Val Pro Leu Leu Arg Gly Leu Ser Lys 100 105 110Asp Asn Met Glu Gln Asn Leu Asn Lys Phe Thr Ser Phe His Thr Arg 115 120 125Tyr Tyr Arg Ser Ser Thr Gly Ile Glu Ser Ala Lys Trp Leu Tyr Ser 130 135 140Arg Val Ser Asp Val Ile Glu Gln Ser Gly Ala Ala Glu Tyr Gly Ala145 150 155 160Thr Val Glu Gln Phe Ala His Ser Trp Gly Gln Phe Ser Ile Ile Ala 165 170 175Arg Ile Pro Gly Gln Thr Asn Lys Thr Val Val Leu Gly Ala His Gln 180 185 190Asp Ser Ile Asn Leu Phe Leu Pro Ser Ile Leu Ala Ala Pro Gly Ala 195 200 205Asp Asp Asp Gly Ser Gly Thr Val Thr Ile Leu Glu Ala Leu Arg Gly 210 215 220Leu Leu Gln Ser Asp Ala Ile Val Arg Gly Asn Ala Ser Asn Thr Ile225 230 235 240Glu Phe His Trp Tyr Ser Ala Glu Glu Gly Gly Met Leu Gly Ser Gln 245 250 255Ala Ile Phe Ser Gln Tyr Lys Arg Asp Lys Arg Asp Ile Lys Ala Met 260 265 270Leu Gln Gln Asp Met Thr Gly Tyr Thr Gln Gly Ala Leu Asp Ala Gly 275 280 285Arg Gln Glu Ala Ile Gly Ile Met Val Asp Tyr Val Asp Glu Gly Leu 290 295 300Thr Gln Phe Leu Lys Asp Val Thr Thr Glu Tyr Cys Gly Ile Gly Tyr305 310 315 320Ile Glu Thr Arg Cys Gly Tyr Ala Cys Ser Asp His Thr Ser Ala Ser 325 330 335Lys Tyr Gly Tyr Pro Ala Ala Met Ala Thr Glu Ser Glu Met Glu Asn 340 345 350Ser Asn Lys Arg Ile His Thr Thr Asp Asp Ser Ile Arg Tyr Leu Ser 355 360 365Phe Asp His Met Leu Glu His Ala Arg Leu Thr Leu Gly Phe Ala Tyr 370 375 380Glu Leu Ala Phe Ala Gln Phe385 390135442PRTAspergillus niger 135Met Arg Thr Thr Thr Ser Phe Ala Arg Leu Ala Leu Ala Val Ala Ser1 5 10 15Val Gly Ile Val Phe Ala Ser Pro Thr Lys Asn Asn Asp Gly Lys Leu 20 25 30Val Tyr Gly Ser Pro Glu Ser Val Gly Met Ile Ser Ala Pro Leu His 35 40 45Gln Met Val Gln Asn Val Ser Ala Tyr Thr His Ala Ala Asn Tyr Ser 50 55 60Lys Phe Ser Tyr Asp Lys Val His Pro Ile Glu Pro Gly Ser Val Thr65 70 75 80Leu Val Ala Leu Asp Gly Val Ile

Val Ser Glu Phe Ala Leu Gly Lys 85 90 95Arg Asn Leu Tyr Ala Asp Val Asn Gly Thr Asn Leu Pro Arg Tyr Leu 100 105 110Gln Glu Asp Thr Thr Leu Asp Thr Val Tyr Asp Met Ala Ser Leu Thr 115 120 125Lys Leu Phe Thr Thr Val Ala Ala Leu Arg Glu Leu Asp Ala Gly Arg 130 135 140Ile Ala Leu Asn Val Thr Val Ala Thr Tyr Ile Pro Asp Phe Ala Thr145 150 155 160Asn Gly Lys Glu Asn Ile Thr Ile Leu Glu Leu Phe Thr His Thr Ser 165 170 175Gly Phe Ala Ser Asp Pro Ser Pro Pro Leu Phe Ser Ala Tyr Tyr Thr 180 185 190Thr Tyr Asp Glu Arg Ile Lys Ala Ile Leu Thr Gln Lys Ile Ile Asn 195 200 205Thr Pro Gly Ser Thr Tyr Leu Tyr Leu Asp Leu Asn Phe Met Ser Leu 210 215 220Gly Leu Val Ile Glu Thr Val Thr Gly Arg Ala Leu Asp Asp Leu Ile225 230 235 240Tyr Asp Phe Thr Arg Pro Leu Glu Met Thr Ser Thr Phe Phe Asn Arg 245 250 255Gly Asn Ile Glu Gly Ser Thr Pro Gln Ser Pro Asn Tyr Asp Arg Thr 260 265 270Ala Val Gln Glu Phe Gln Ile Ala Ala Leu Gly Pro Ser Glu Pro Gln 275 280 285Arg Pro Gln Pro Val Arg Gly Thr Val His Asp Glu Asn Ala Trp Ser 290 295 300Leu Asp Gly Val Ser Gly His Ala Gly Leu Phe Ser Thr Val Arg Asp305 310 315 320Thr Ala Thr Phe Cys Gln Met Ile Leu Asn Asn Gly Thr Tyr Ala Gly 325 330 335Gln Arg Ile Leu Ser Arg Thr Ala Val Asp Met Ile Phe Thr Asn Phe 340 345 350Asn Ala Arg Phe Pro Gly Asp Ala Arg Ser Leu Gly Phe Glu Leu Asp 355 360 365Gln Tyr Ser Thr Ala Gly Pro Met Ala Ser Leu Gln Thr Ala Ser His 370 375 380Thr Gly Phe Thr Gly Thr Thr Leu Val Met Asp Arg Thr Tyr Asn Ala385 390 395 400Phe Trp Leu His Phe Ser Asn Arg Val His Pro Ser Arg Ala Trp Ser 405 410 415Ser Asn Thr Ile Val Arg Glu Ala Ile Gly Tyr Trp Val Gly Lys Ser 420 425 430Leu Gly Leu Asp Val Ala Phe Ala Leu Leu 435 440136612PRTAspergillus niger 136Met Ala Ser Trp Leu Leu Ser Thr Leu Leu Phe Leu Ser Pro Ser Leu1 5 10 15Val Ser Ala Lys Ser Ala Ala Asp Tyr Tyr Val His Ser Leu Pro Gly 20 25 30Ala Pro Glu Gly Pro Leu Leu Lys Met His Ala Gly His Ile Glu Val 35 40 45Asp Pro Gln Asn Asn Gly Asn Leu Phe Phe Trp His Tyr Gln Asn Arg 50 55 60His Ile Ala Asn Arg Gln Arg Thr Val Ile Trp Leu Asn Gly Gly Pro65 70 75 80Gly Cys Ser Ser Met Asp Gly Ala Leu Met Glu Val Gly Pro Tyr Arg 85 90 95Leu Lys Asp Asn Glu Thr Leu Thr Tyr Asn Glu Gly Ser Trp Asp Glu 100 105 110Phe Ala Asn Leu Leu Phe Val Asp Gln Pro Val Gly Thr Gly Phe Ser 115 120 125Tyr Val Asn Thr Asp Ser Tyr Leu His Glu Leu Asp Glu Met Ser Ala 130 135 140Gln Phe Ile Val Phe Leu Glu Glu Trp Phe Arg Leu Phe Pro Glu Tyr145 150 155 160Glu Arg Asp Asp Ile Tyr Ile Ala Gly Glu Ser Tyr Ala Gly Gln His 165 170 175Ile Pro Tyr Ile Ala Lys Ala Ile Gln Glu Arg Asn Lys Asn Val Gln 180 185 190Gly Lys Thr Ile Ala Ser Trp Asn Leu Lys Gly Leu Leu Ile Gly Asn 195 200 205Gly Trp Ile Ser Pro Asn Glu Gln Tyr Met Ser Tyr Leu Pro Tyr Ala 210 215 220Tyr Glu Glu Gly Leu Ile Lys Glu Gly Ser Arg Thr Ala Lys Glu Leu225 230 235 240Glu Val Leu Gln Ser Val Cys Lys Ser Arg Leu Glu Thr Gly Lys Asn 245 250 255Lys Val His Leu Asn Asp Cys Glu Lys Val Met Asn Ala Leu Leu Asp 260 265 270Lys Thr Val Glu Asp Asn Lys Cys Leu Asn Met Tyr Asp Ile Arg Leu 275 280 285Arg Asp Thr Thr Asp Ala Cys Gly Met Asn Trp Pro Thr Asp Leu Glu 290 295 300Asp Val Lys Pro Tyr Leu Gln Arg Glu Asp Val Val Lys Ala Leu Asn305 310 315 320Ile Asn Pro Glu Lys Lys Ser Gly Trp Val Glu Cys Ser Gly Ala Val 325 330 335Ser Ser Ala Phe Asn Pro Gln Lys Ser Pro Pro Ser Val Gln Leu Leu 340 345 350Pro Gly Leu Leu Glu Ser Gly Leu Gln Ile Leu Leu Phe Ser Gly Asp 355 360 365Lys Asp Leu Ile Cys Asn His Val Gly Thr Glu Gln Leu Ile Asn Asn 370 375 380Met Lys Trp Asn Gly Gly Thr Gly Phe Glu Thr Ser Pro Gly Val Trp385 390 395 400Ala Pro Arg His Asp Trp Ser Phe Glu Gly Glu Pro Ala Gly Ile Tyr 405 410 415Gln Tyr Ala Arg Asn Leu Thr Tyr Val Leu Ile Tyr Asn Ala Ser His 420 425 430Met Val Pro Tyr Asp Leu Pro Arg Gln Ser Arg Asp Met Leu Asp Arg 435 440 445Phe Met Asn Val Asp Ile Ala Ser Ile Gly Gly Ser Pro Ala Asp Ser 450 455 460Arg Ile Asp Gly Glu Lys Leu Pro Gln Thr Ser Val Gly Gly His Pro465 470 475 480Asn Ser Thr Ala Ala Glu Glu Gln Glu Lys Glu Arg Ile Lys Glu Thr 485 490 495Glu Trp Lys Ala Tyr Ala Lys Ser Gly Glu Ala Val Leu Leu Val Val 500 505 510Ile Ile Gly Val Leu Val Trp Gly Phe Phe Ile Trp Arg Ser Arg Arg 515 520 525Arg His Gln Gly Tyr Arg Gly Val Trp His Lys Asp Met Ser Gly Ser 530 535 540Ser Val Leu Glu Arg Phe His Asn Lys Arg Thr Gly Gly Ala Asp Val545 550 555 560Glu Ala Gly Asp Phe Asp Glu Ala Glu Leu Asp Asp Leu His Ser Pro 565 570 575Asp Leu Glu Arg Glu His Tyr Ala Val Gly Glu Asp Ser Asp Glu Asp 580 585 590Asp Ile Ser Arg Gln His Ser Gln Gln Ala Ser Arg Ala Gly Gly Ser 595 600 605His Asn Leu Ser 610137531PRTAspergillus niger 137Met Phe Leu Ile Ser Pro Ala Val Thr Val Ala Ala Ala Leu Leu Leu1 5 10 15Ile Asn Gly Ala Gly Ala Thr Gln Ser Glu Arg Ser Arg Ala Ala Ala 20 25 30His Phe Ser Lys Arg His Pro Thr Tyr Arg Ala Ala Thr Arg Ala Gln 35 40 45Ser Ser Asn Thr Ser Asp Tyr Arg Phe Phe Asn Asn Arg Thr Lys Pro 50 55 60His Leu Val Glu Ser Leu Pro Asp Val His Phe Asp Val Gly Glu Met65 70 75 80Tyr Ser Gly Ser Ile Pro Ile Asp Asp Ser Asn Asn Gly Ser Arg Ser 85 90 95Leu Phe Tyr Ile Phe Gln Pro Lys Ile Gly Glu Pro Ser Asp Asp Leu 100 105 110Thr Ile Tyr Leu Asn Gly Gly Pro Gly Cys Ser Ser Glu Gln Gly Phe 115 120 125Phe Gln Glu Asn Gly Arg Phe Thr Trp Gln Pro Gly Thr Tyr Ala Pro 130 135 140Val Ile Asn Glu Tyr Ser Trp Val Asn Leu Thr Asn Met Leu Trp Val145 150 155 160Asp Gln Pro Val Gly Thr Gly Phe Ser Val Gly Asn Val Thr Ala Thr 165 170 175Asn Glu Glu Glu Ile Ala Ala Asp Phe Leu Asp Phe Phe Glu Lys Phe 180 185 190Glu Asp Leu Tyr Gly Ile Lys Asn Phe Arg Ile Phe Met Thr Gly Glu 195 200 205Ser Tyr Ala Gly Arg Tyr Val Pro Tyr Ile Ser Ser Ala Met Leu Asp 210 215 220Lys Asn Asp Thr Thr Arg Phe Asn Leu Ser Gly Ala Leu Leu Tyr Asp225 230 235 240Ala Cys Ile Gly Gln Trp Asp Tyr Ile Gln Ala Glu Leu Pro Ala Tyr 245 250 255Pro Phe Val Lys Gln His Ala Ser Leu Phe Asn Phe Asn Gln Ser Tyr 260 265 270Met Asn Glu Leu Glu Thr Thr Tyr Glu Glu Cys Gly Tyr Lys Ala Tyr 275 280 285Phe Asp Glu Tyr Phe Ala Phe Pro Pro Ser Gly Ile Gln Pro Pro Lys 290 295 300Tyr Met Asn Tyr Ser Glu Cys Asp Ile Tyr Asn Met Ile Tyr Tyr Glu305 310 315 320Ala Tyr Asn Pro Asn Pro Cys Phe Asn Pro Tyr Arg Val Ile Asp Glu 325 330 335Cys Pro Leu Leu Trp Asp Val Leu Gly Trp Pro Thr Asp Leu Ala Tyr 340 345 350Glu Pro Ala Pro Thr Thr Tyr Phe Asn Arg Ile Asp Val Lys Lys Ala 355 360 365Leu His Ala Pro Met Asp Val Glu Trp Glu Leu Cys Ser Tyr Asp Leu 370 375 380Val Phe Ala Gly Gly Asp Ala Asp Pro Gly Pro Glu Gln Gln Gly Asp385 390 395 400Asp Ser Pro Asn Pro Thr Glu Gly Val Leu Pro Arg Val Ile Glu Ala 405 410 415Thr Asn Arg Val Leu Ile Ala Asn Gly Asp Trp Asp Tyr Leu Ile Ile 420 425 430Thr Asn Gly Thr Leu Leu Ala Ile Gln Asn Met Thr Trp Asn Gly Gln 435 440 445Leu Gly Phe Gln Ser Ala Pro Ala Thr Pro Ile Asp Ile Gln Met Pro 450 455 460Asp Leu Gln Trp Val Glu Ile Phe Glu Ala Gln Glu Gly Tyr Gly Gly465 470 475 480Leu Asp Gly Pro Gln Gly Val Met Gly Val Gln His Tyr Glu Arg Gly 485 490 495Leu Met Trp Ala Glu Thr Tyr Gln Ser Gly His Lys Gln Ala Gln Asp 500 505 510Gln Gly Arg Val Ser Tyr Arg His Leu Gln Trp Leu Leu Gly Gln Val 515 520 525Glu Ile Leu 530138531PRTAspergillus niger 138Met Leu Phe Arg Ser Leu Leu Ser Thr Ala Val Leu Ala Val Ser Leu1 5 10 15Cys Thr Asp Asn Ala Ser Ala Ala Lys His Gly Arg Phe Gly Gln Lys 20 25 30Ala Arg Asp Ala Met Asn Ile Ala Lys Arg Ser Ala Asn Ala Val Lys 35 40 45His Ser Leu Lys Ile Pro Val Glu Asp Tyr Gln Phe Leu Asn Asn Lys 50 55 60Thr Lys Pro Tyr Arg Val Glu Ser Leu Pro Asp Val His Phe Asp Leu65 70 75 80Gly Glu Met Tyr Ser Gly Leu Val Pro Ile Glu Lys Gly Asn Val Ser 85 90 95Arg Ser Leu Phe Phe Val Phe Gln Pro Thr Ile Gly Glu Pro Val Asp 100 105 110Glu Ile Thr Ile Trp Leu Asn Gly Gly Pro Gly Cys Ser Ser Leu Glu 115 120 125Ala Phe Leu Gln Glu Asn Gly Arg Phe Val Trp Gln Pro Gly Thr Tyr 130 135 140Gln Pro Val Glu Asn Pro Tyr Ser Trp Val Asn Leu Thr Asn Val Leu145 150 155 160Trp Val Asp Gln Pro Val Gly Thr Gly Phe Ser Leu Gly Val Pro Thr 165 170 175Ala Thr Ser Glu Glu Glu Ile Ala Glu Asp Phe Val Lys Phe Phe Lys 180 185 190Asn Trp Gln Gln Ile Phe Gly Ile Lys Asn Phe Lys Ile Tyr Val Thr 195 200 205Gly Glu Ser Tyr Ala Gly Arg Tyr Val Pro Tyr Ile Ser Ala Ala Phe 210 215 220Leu Asp Gln Asn Asp Thr Glu His Phe Asn Leu Lys Gly Ala Leu Ala225 230 235 240Tyr Asp Pro Cys Ile Gly Gln Phe Asp Tyr Val Gln Glu Glu Ala Pro 245 250 255Val Val Pro Phe Val Gln Lys Asn Asn Ala Leu Phe Asn Phe Asn Ala 260 265 270Ser Phe Leu Ala Glu Leu Glu Ser Ile His Glu Gln Cys Gly Tyr Lys 275 280 285Asp Phe Ile Asp Gln Tyr Leu Val Phe Pro Ala Ser Gly Val Gln Pro 290 295 300Pro Lys Ala Met Asn Trp Ser Asp Pro Thr Cys Asp Val Tyr Asp Ile305 310 315 320Val Asn Asn Ala Val Leu Asp Pro Asn Pro Cys Phe Asn Pro Tyr Glu 325 330 335Ile Asn Glu Met Cys Pro Ile Leu Trp Asp Val Leu Gly Phe Pro Thr 340 345 350Glu Val Asp Tyr Leu Pro Ala Gly Ala Ser Ile Tyr Phe Asp Arg Ala 355 360 365Asp Val Lys Arg Ala Met His Ala Pro Asn Ile Thr Trp Ser Glu Cys 370 375 380Ser Val Glu Ser Val Phe Val Gly Gly Asp Gly Gly Pro Glu Gln Glu385 390 395 400Gly Asp Tyr Ser Ala Asn Pro Ile Glu His Val Leu Pro Gln Val Ile 405 410 415Glu Gly Thr Asn Arg Val Leu Ile Gly Asn Gly Asp Tyr Asp Met Val 420 425 430Ile Leu Thr Asn Gly Thr Leu Leu Ser Ile Gln Asn Met Thr Trp Asn 435 440 445Gly Lys Leu Gly Phe Asp Thr Ala Pro Ser Thr Pro Ile Asn Ile Asp 450 455 460Ile Pro Asp Leu Met Tyr Asn Glu Val Phe Ile Glu Asn Gly Tyr Asp465 470 475 480Pro Gln Gly Gly Gln Gly Val Met Gly Ile Gln His Tyr Glu Arg Gly 485 490 495Leu Met Trp Ala Glu Thr Phe Gln Ser Gly His Met Gln Pro Gln Phe 500 505 510Gln Pro Arg Val Ser Tyr Arg His Leu Glu Trp Leu Leu Gly Arg Arg 515 520 525Asp Thr Leu 530139492PRTAspergillus niger 139Met Lys Gly Ala Ala Leu Ile Pro Leu Ala Ala Gly Ile Pro Phe Ala1 5 10 15His Gly Leu Ser Leu His Lys Arg Asp Gly Pro Ala Val Val Arg Met 20 25 30Pro Ile Glu Arg Arg Ser Ala Gln Ser Leu Gln Lys Arg Asp Ser Thr 35 40 45Val Gly Val Thr Leu Gln Asn Trp Asp Ala Thr Tyr Tyr Ala Val Asn 50 55 60Leu Thr Leu Gly Thr Pro Ala Gln Lys Val Ser Leu Ala Leu Asp Thr65 70 75 80Gly Ser Ser Asp Leu Trp Val Asn Thr Gly Asn Ser Thr Tyr Cys Ser 85 90 95Ile Asp Asn Leu Cys Thr Pro Tyr Gly Leu Tyr Asn Ala Ser Glu Ser 100 105 110Ser Thr Val Lys Thr Val Gly Thr His Leu Asn Asp Thr Tyr Ala Asp 115 120 125Gly Thr Asn Leu Tyr Gly Pro Tyr Val Thr Asp Lys Leu Thr Ile Gly 130 135 140Asn Thr Thr Ile Asp Asn Met Gln Phe Gly Ile Ala Glu Ser Thr Thr145 150 155 160Ser Lys Arg Gly Ile Ala Gly Val Gly Tyr Lys Ile Ser Thr Tyr Gln 165 170 175Ala Glu His Asp Asp Lys Val Tyr Ala Asn Leu Pro Gln Ala Leu Val 180 185 190Asp Ser Gly Ala Ile Lys Ser Ala Ala Tyr Ser Ile Trp Leu Asp Ser 195 200 205Leu Glu Ala Ser Thr Gly Ser Leu Leu Phe Gly Gly Val Asn Thr Ala 210 215 220Lys Tyr Lys Gly Asp Leu Gln Thr Leu Pro Ile Ile Pro Val Tyr Gly225 230 235 240Lys Tyr Tyr Ser Leu Ala Ile Ala Leu Thr Glu Leu Ser Val Ala Thr 245 250 255Asp Ser Asn Ser Ser Ser Phe Thr Asp Ser Leu Pro Leu Ser Val Ser 260 265 270Leu Asp Thr Gly Thr Thr Met Thr Ala Leu Pro Ser Asp Leu Val Asn 275 280 285Lys Val Tyr Asp Ala Leu Asn Ala Thr Tyr Asp Lys Thr Tyr Asp Met 290 295 300Ala Tyr Ile Asp Cys Asp Thr Arg Glu Ala Asp Tyr Asn Val Thr Tyr305 310 315 320Ser Phe Ser Gly Ala Thr Ile Thr Val Ser Met Ser Glu Leu Ile Ile 325 330 335Pro Ala Thr Glu Pro Gly Trp Pro Asp Asn Thr Cys Val Leu Gly Leu 340 345 350Val Pro Ser Gln Pro Gly Val Asn Leu Leu Gly Asp Thr Phe Leu Arg 355 360 365Ser Ala Tyr Val Val Tyr Asp Leu Glu Asn Asn Glu Ile Ser Leu Ala 370 375 380Asn Thr Asn Phe Asn Pro Gly Asp Asp Asp Ile Leu Glu Ile Gly Thr385 390 395 400Gly Thr Ser Ala Val Pro Gly Ala Thr Pro Val Pro Ser Ala Val Ser 405 410 415Ser Ala Thr Gly Asn Gly Leu Ile Ser Ser Gly Thr Ala Val Pro Thr 420

425 430Leu Ser Gly Val Thr Ile Thr Ala Thr Ala Thr Ala Thr Gly Ser Thr 435 440 445Gly Thr Gly Ser Ser Gly Gly Ser Ser Ala Glu Ala Thr Ser Thr Ser 450 455 460Ser Glu Gly Ala Ala Ala Gln Ala Thr Ser Asn Pro Met Asn Leu Leu465 470 475 480Pro Gly Leu Ala Gly Ile Gly Leu Leu Leu Ala Leu 485 490140611PRTAspergillus niger 140Met Leu Ser Ser Leu Leu Ser Gln Gly Ala Ala Val Ser Leu Ala Val1 5 10 15Leu Ser Leu Leu Pro Ser Pro Val Ala Ala Glu Ile Phe Glu Lys Leu 20 25 30Ser Gly Val Pro Asn Gly Trp Arg Tyr Ala Asn Asn Pro Gln Gly Asn 35 40 45Glu Val Ile Arg Leu Gln Ile Ala Leu Gln Gln His Asp Val Ala Gly 50 55 60Phe Glu Gln Ala Val Met Asp Met Ser Thr Pro Gly His Ala Asp Tyr65 70 75 80Gly Lys His Phe Arg Thr His Asp Glu Met Lys Arg Met Leu Leu Pro 85 90 95Ser Glu Thr Ala Val Asp Ser Val Arg Asp Trp Leu Glu Ser Ala Gly 100 105 110Val His Asn Ile Gln Val Asp Ala Asp Trp Val Lys Phe His Thr Thr 115 120 125Val Asn Lys Ala Asn Ala Leu Leu Asp Ala Asp Phe Lys Trp Tyr Val 130 135 140Ser Asp Ala Lys His Ile Arg Arg Leu Arg Thr Leu Gln Tyr Ser Ile145 150 155 160Pro Asp Ala Leu Val Ser His Ile Asn Met Ile Gln Pro Thr Thr Arg 165 170 175Phe Gly Gln Ile Gln Pro Asn Arg Ala Thr Met Arg Ser Lys Pro Lys 180 185 190His Ala Asp Glu Thr Phe Leu Thr Ala Ala Thr Leu Ala Gln Asn Thr 195 200 205Ser His Cys Asp Ser Ile Ile Thr Pro His Cys Leu Lys Gln Leu Tyr 210 215 220Asn Ile Gly Asp Tyr Gln Ala Asp Pro Lys Ser Gly Ser Lys Ile Gly225 230 235 240Phe Ala Ser Tyr Leu Glu Glu Tyr Ala Arg Tyr Ala Asp Leu Glu Arg 245 250 255Phe Glu Gln His Leu Ala Pro Asn Ala Ile Gly Gln Asn Phe Ser Val 260 265 270Val Gln Phe Asn Gly Gly Leu Asn Asp Gln Leu Ser Ser Ser Asp Ser 275 280 285Gly Glu Ala Asn Leu Asp Leu Gln Tyr Ile Leu Gly Val Ser Ala Pro 290 295 300Val Pro Ile Thr Glu Tyr Ser Thr Gly Gly Arg Gly Glu Leu Val Pro305 310 315 320Asp Leu Ser Ser Pro Asp Pro Asn Asp Asn Ser Asn Glu Pro Tyr Leu 325 330 335Asp Phe Leu Gln Gly Ile Leu Lys Leu Asn Asn Ser Asp Leu Pro Gln 340 345 350Val Ile Ser Thr Ser Tyr Gly Glu Asp Glu Gln Thr Ile Pro Val Pro 355 360 365Tyr Ala Arg Thr Val Cys Asn Leu Tyr Ala Gln Leu Gly Ser Arg Gly 370 375 380Val Ser Val Ile Phe Ser Ser Gly Asp Ser Gly Val Gly Ala Ala Cys385 390 395 400Leu Thr Asn Asp Gly Thr Asn Arg Thr His Phe Pro Pro Gln Phe Pro 405 410 415Ala Ser Cys Pro Trp Val Thr Ser Val Gly Ala Thr Ser Lys Thr Ser 420 425 430Pro Glu Gln Ala Val Ser Phe Ser Ser Gly Gly Phe Ser Asp Leu Trp 435 440 445Pro Arg Pro Ser Tyr Gln His Ala Ala Val Gln Thr Tyr Leu Thr Lys 450 455 460His Leu Gly Asn Lys Phe Ser Gly Leu Phe Asn Ala Ser Gly Arg Ala465 470 475 480Phe Pro Asp Val Ser Ala Gln Gly Val Asn Tyr Ala Val Tyr Asp Lys 485 490 495Gly Met Leu Gly Gln Phe Asp Gly Thr Ser Cys Ser Ala Pro Thr Phe 500 505 510Ser Gly Val Ile Ala Leu Leu Asn Asp Ala Arg Leu Arg Ala Gly Leu 515 520 525Pro Val Met Gly Phe Leu Asn Pro Phe Leu Tyr Gly Val Gly Ser Glu 530 535 540Lys Gly Ala Leu Asn Asp Ile Val Asn Gly Gly Ser Val Gly Cys Asp545 550 555 560Gly Arg Asn Arg Phe Gly Gly Thr Pro Asn Gly Ser Pro Val Val Pro 565 570 575Phe Ala Ser Trp Asn Ala Thr Thr Gly Trp Asp Pro Val Ser Gly Leu 580 585 590Gly Thr Pro Asp Phe Ala Lys Leu Lys Gly Val Ala Leu Gly Glu Glu 595 600 605Gly Gly Asn 610141478PRTAspergillus niger 141Met Trp Leu Phe Leu Val Cys Ser Ile Leu Leu Pro Leu Gly Val Val1 5 10 15Asn Ala Gln Ser Gln Tyr Phe Asn Asn Lys Thr Lys Glu Phe Val Val 20 25 30Asn Gly Ser Ala Ile Pro Phe Val Asp Phe Asp Ile Gly Glu Ser Tyr 35 40 45Ala Gly Tyr Leu Pro Asn Thr Pro Ser Gly Ile Ser Ser Leu Tyr Phe 50 55 60Trp Phe Phe Pro Ser Ser Asp Pro Asp Ala Ser Asp Glu Ile Thr Val65 70 75 80Trp Leu Asn Gly Gly Pro Gly Cys Ser Ser Leu Ala Gly Ile Met Leu 85 90 95Glu Asn Gly Pro Phe Leu Trp Gln Pro Gly Thr Tyr Arg Pro Val Arg 100 105 110Asn Pro Tyr Ala Trp Asn Asn Leu Thr Asn Met Val Tyr Ile Asp Gln 115 120 125Pro Ala Gly Thr Gly Phe Ser Leu Gly Pro Ser Thr Val Val Ser Glu 130 135 140Phe Asp Val Ala Arg Gln Phe Met Asp Phe Trp Arg Arg Phe Met Lys145 150 155 160Thr Phe Asp Leu Gln Asn Arg Lys Ile Tyr Leu Thr Gly Glu Ser Tyr 165 170 175Ala Gly Gln Tyr Ile Pro Tyr Ile Ala Ser Gln Met Leu Asp Gln Asp 180 185 190Asp Asp Glu Tyr Phe Arg Val Ala Gly Ile Gln Ile Asn Asp Pro Tyr 195 200 205Ile Asn Glu Leu Pro Val Leu Gln Asp Val Ala Thr Val Asn Gln His 210 215 220Arg Ser Leu Phe Pro Phe Asn Asp Thr Phe Met Ser Gln Ile Thr Lys225 230 235 240Leu Ser Asp Asp Cys Gly Tyr Thr Ser Phe Leu Asp Asp Ala Leu Thr 245 250 255Phe Pro Pro Arg Ser Gln Phe Pro Ser Val Pro Tyr Asn Ala Ser Cys 260 265 270Asn Ile Trp Asp Ile Ile Asn Asn Ala Ser Leu Ala Leu Asn Pro Cys 275 280 285Phe Asn Arg Tyr His Ile Pro Asp Ala Cys Pro Thr Pro Trp Asn Pro 290 295 300Val Gly Gly Pro Ile Val Gly Leu Gly Pro Thr Asn Tyr Phe Asn Arg305 310 315 320Ser Asp Val Gln Lys Ala Ile Asn Ala Tyr Pro Thr Asp Tyr Phe Val 325 330 335Cys Lys Asp Gly Ile Phe Pro Thr Ala Asn Gly Leu Asp Thr Ser Pro 340 345 350Pro Ser Ser Leu Gly Pro Leu Pro Arg Val Ile Glu Gln Thr Asn Asn 355 360 365Thr Ile Ile Ala His Gly Leu Met Asp Phe Glu Leu Leu Ala Gln Gly 370 375 380Thr Leu Ile Ser Ile Gln Asn Met Thr Trp Asn Gly Lys Gln Gly Phe385 390 395 400Glu Arg Glu Pro Val Glu Pro Leu Phe Val Pro Tyr Gly Gly Ser Ser 405 410 415Gly Gly Gly Val Leu Gly Thr Ala His Thr Glu Arg Gly Leu Thr Phe 420 425 430Ser Thr Val Phe Ser Ser Gly His Glu Ile Pro Glu Tyr Ala Pro Gly 435 440 445Ala Ala Tyr Arg Gln Leu Glu Phe Leu Leu Gly Arg Val Ala Asn Leu 450 455 460Ser Thr Ile Ile Glu Gln Val Gln Ile Thr Glu Gln Asn Gly465 470 475142210PRTAspergillus niger 142Met Ser Lys Leu Ser Ala Ala Ile Ser Lys Leu Ser Leu Ser Thr Ile1 5 10 15Ala Thr Thr Leu Leu Leu Leu Thr Pro Pro Thr Thr Ala Tyr Phe Tyr 20 25 30Lys Tyr Pro Ala Leu Phe Val Tyr Lys Asp Thr Asn Cys Thr Asp Ile 35 40 45Ser Phe Ser Leu Val Tyr Pro Ser Leu Gly Asn Cys Asn Gly Gly Tyr 50 55 60Tyr Asp Tyr Ala Gly Ser Phe Gln Met Phe Asn Ile Asp Ala Ala Tyr65 70 75 80Thr Cys Asn Gly Ser Asp Ser Thr Leu Met Phe Glu Met Tyr Asn Ser 85 90 95Ser Gly Ser Asp Cys Gly Asp Glu Ser Asp Leu Leu Phe Arg Gln Pro 100 105 110Val Thr Glu Glu Cys Thr Val Ala Asp Val Glu Ser Pro Gly Pro Leu 115 120 125Glu Met Pro Val Trp Phe Glu Leu Gly Ser Leu Leu Gly Asn Cys Gly 130 135 140Gly Met Ala Gly Thr Met Leu Phe Gly Val Gly Ile Leu Glu Gly Gly145 150 155 160Leu Glu Thr Lys Leu Tyr Trp Lys Cys Tyr Ser Ser Arg Leu Asn Thr 165 170 175Ser Val Thr Val His Arg Leu Ser Leu Ile Leu Ser Met Gly Cys Thr 180 185 190Ser Val Ser Asp Ser Tyr Asn Glu Leu Ala Ala Ala His Tyr Tyr Glu 195 200 205Asp Leu 210143608PRTAspergillus niger 143Met Arg His Leu Leu Ser Leu Leu Val Leu Leu Ile Ala Ser Ala Ala1 5 10 15Leu Val Ser Ala Val Pro Ala Gly Ser Ile Ile Thr Pro Gln Pro Pro 20 25 30Val Glu Pro Val His Leu Leu Ser Ser Gln Pro Ser Asp Pro Arg Arg 35 40 45Pro Trp Ile Arg Leu Arg Asp Trp Ile Ile Glu Ser Ile Trp Gly Ile 50 55 60Glu Lys Pro Ala Ser Arg Arg Phe Pro Leu Asn Asp Ser Pro Arg Asn65 70 75 80Arg Ser Pro Pro Ser Arg Ile Leu Ala Arg Tyr Gly Ser Asp Val Val 85 90 95Leu Arg Phe Ser Leu Arg Asn His Asp Glu Ala Glu Ala Leu Ala Gln 100 105 110Ala Ala Asp Ile Leu Phe Leu Asp Val Trp Ala Ser Thr Pro Ala Phe 115 120 125Val Asp Ile Arg Leu Ala Glu Glu Val Thr Ala Tyr Thr Pro Leu Ile 130 135 140Asp Asn Leu Ala Glu Arg Ile Tyr Thr Thr Tyr Pro Ser Lys Lys Pro145 150 155 160Ile Gly Leu Glu Gly Gln Ser Gly Phe Ala Ser Ser Ser Arg Pro Ala 165 170 175Pro Lys Phe Gly Asp Leu Phe Phe His Glu Tyr Gln Pro Leu Ser Val 180 185 190Ile Ile Pro Trp Met Arg Leu Leu Ala Ser Met Phe Pro Ser His Val 195 200 205Arg Met Ile Ser Val Gly Val Ser Tyr Glu Gly Arg Glu Ile Pro Ala 210 215 220Leu Arg Leu Ser Ala Gly Ser Ser Thr Ala Ala Ser Gly Pro Arg Lys225 230 235 240Thr Ile Ile Val Thr Gly Gly Ser His Ala Arg Glu Trp Ile Gly Thr 245 250 255Ser Thr Val Asn His Val Met Tyr Thr Leu Ile Thr Lys Tyr Gly Lys 260 265 270Ser Lys Ala Val Thr Arg Leu Leu Gln Asp Phe Asp Trp Ile Met Ile 275 280 285Pro Thr Ile Asn Pro Asp Gly Tyr Val Tyr Thr Trp Glu Thr Asp Arg 290 295 300Leu Trp Arg Lys Asn Arg Gln Arg Thr Ser Leu Arg Phe Cys Pro Gly305 310 315 320Ile Asp Leu Asp Arg Ala Trp Gly Phe Glu Trp Asp Gly Gly Arg Thr 325 330 335Arg Ala Asn Pro Cys Ser Glu Asn Tyr Ala Gly Asp Glu Pro Phe Glu 340 345 350Gly Met Glu Ala Gln Gln Leu Ala Gln Trp Ala Leu Asn Glu Thr Gln 355 360 365Asn Asn Asn Ala Asp Ile Val Ser Phe Leu Asp Leu His Ser Tyr Ser 370 375 380Gln Thr Ile Leu Tyr Pro Phe Ser Tyr Ser Cys Ser Ser Ile Pro Pro385 390 395 400Thr Leu Glu Ser Leu Glu Glu Leu Gly Leu Gly Leu Ala Lys Ala Ile 405 410 415Arg Tyr Ala Thr His Glu Ile Tyr Asp Val Thr Ser Ala Cys Glu Gly 420 425 430Ile Val Thr Ala Ser Ala Ala Asp Asn Asn Pro Gly Arg Phe Phe Pro 435 440 445Ile Gly Gly Asn Ser Gly Gly Ser Ala Leu Asp Trp Phe Tyr His Gln 450 455 460Val His Ala Thr Tyr Ser Tyr Gln Ile Lys Leu Arg Asp Arg Gly Ser465 470 475 480Tyr Gly Phe Leu Leu Pro Ser Glu His Ile Ile Pro Thr Gly Lys Glu 485 490 495Ile Tyr Asn Val Val Leu Lys Leu Gly Ser Phe Leu Ile Gly Gly Asp 500 505 510Ser Phe Asp Val Asp Trp Glu Ser Glu Leu Phe Asp Leu Ser Lys Asp 515 520 525Glu Ser Asp Leu Asp Ser Arg Tyr Ser Lys Ser Asn Asp Arg Ser Pro 530 535 540Ala Tyr Leu His Asn Ala Asn Gly Pro Leu Pro Asn Ile Asp Glu Asp545 550 555 560Glu Asp Lys Glu Trp Val Met Val Glu Glu Glu Asp Tyr Thr Asp Asp 565 570 575Asp Asp Asp Asp Asp Asp Asp Asp Glu Glu Glu Glu Glu Glu Glu Glu 580 585 590Asp Thr Tyr Trp Ala Thr Glu His Thr Tyr Glu Phe Arg Arg Arg Arg 595 600 605144416PRTAspergillus niger 144Met Ala Phe Leu Lys Arg Ile Leu Pro Leu Leu Ala Leu Ile Leu Pro1 5 10 15Ala Val Phe Ser Ala Thr Glu Gln Val Pro His Pro Thr Ile Gln Thr 20 25 30Ile Pro Gly Lys Tyr Ile Val Thr Phe Lys Ser Gly Ile Asp Asn Ala 35 40 45Lys Ile Glu Ser His Ala Ala Trp Val Thr Glu Leu His Arg Arg Ser 50 55 60Leu Glu Gly Arg Ser Thr Thr Glu Asp Asp Leu Pro Ala Gly Ile Glu65 70 75 80Arg Thr Tyr Arg Ile Ala Asn Phe Ala Gly Tyr Ala Gly Ser Phe Asp 85 90 95Glu Lys Thr Ile Glu Glu Ile Arg Lys His Asp His Val Ala Tyr Val 100 105 110Glu Gln Asp Gln Val Trp Tyr Leu Asp Thr Leu Val Thr Glu Arg Arg 115 120 125Ala Pro Trp Gly Leu Gly Ser Ile Ser His Arg Gly Gly Ser Ser Thr 130 135 140Asp Tyr Ile Tyr Asp Asp Ser Ala Gly Glu Gly Thr Tyr Ala Tyr Val145 150 155 160Val Asp Thr Gly Ile Leu Ala Thr His Asn Glu Phe Gly Gly Arg Ala 165 170 175Ser Leu Ala Tyr Asn Ala Ala Gly Gly Glu His Val Asp Asp Val Gly 180 185 190His Gly Thr His Val Ala Gly Thr Ile Gly Gly Lys Thr Tyr Gly Val 195 200 205Ser Lys Asn Ala His Leu Leu Ser Val Lys Val Phe Val Gly Glu Ser 210 215 220Ser Ser Thr Ser Val Ile Leu Asp Gly Phe Asn Trp Ala Ala Asn Asp225 230 235 240Ile Val Ser Lys Asn Arg Thr Ser Lys Ala Ala Ile Asn Met Ser Leu 245 250 255Gly Gly Gly Tyr Ser Tyr Ala Phe Asn Asn Ala Val Glu Asn Ala Phe 260 265 270Asp Glu Gly Val Leu Ser Cys Val Ala Ala Gly Asn Glu Asn Arg Asp 275 280 285Ala Ala Arg Thr Ser Pro Ala Ser Ala Pro Asp Ala Ile Thr Val Ala 290 295 300Ala Ile Asn Arg Ser Asn Ala Arg Ala Ser Phe Ser Asn Tyr Gly Ser305 310 315 320Val Val Asp Ile Phe Ala Pro Gly Glu Gln Val Leu Ser Ala Trp Thr 325 330 335Gly Ser Asn Ser Ala Thr Asn Thr Ile Ser Gly Thr Ser Met Ala Thr 340 345 350Pro His Val Thr Gly Leu Ile Leu Tyr Leu Met Gly Leu Arg Asp Leu 355 360 365Ala Thr Pro Ala Ala Ala Thr Thr Glu Leu Lys Arg Leu Ala Thr Arg 370 375 380Asn Ala Val Thr Asn Val Ala Gly Ser Pro Asn Leu Leu Ala Tyr Asn385 390 395 400Gly Asn Ser Gly Val Ser Lys Gly Gly Ser Asp Asp Gly Asp Glu Asp 405 410 415145455PRTAspergillus niger 145Met Ile Thr Leu Leu Ser Ala Leu Phe Gly Ser Val Val Tyr Ala Ala1 5 10 15Thr Gln Thr Val Leu Gly Pro Glu Gly Ala Asp Pro Phe Thr Val Phe 20 25 30Arg Ser Pro His Ser Pro Ala Phe Ser Ile Arg Ile Gln Glu Gln Asn 35 40 45Asp Ser Ile Cys Asp Ala Arg Ser Pro Gln Phe Thr Gly Trp Leu Asp 50 55 60Ile Gly Pro Lys His Leu Phe Phe Trp Tyr

Phe Glu Ser Gln Asn Asp65 70 75 80Pro Phe His Asp Pro Leu Thr Leu Trp Met Thr Gly Gly Pro Gly Asp 85 90 95Ser Ser Met Ile Gly Leu Phe Glu Glu Val Gly Pro Cys Arg Ile Asn 100 105 110Glu Phe Gly Asn Gly Thr Asp His Asn Pro Trp Ala Trp Thr Lys Asn 115 120 125Ser Ser Leu Leu Phe Val Asp Gln Pro Val Asp Val Gly Phe Ser Tyr 130 135 140Ile Asp Glu Gly Tyr Glu Leu Pro His Asp Ser Arg Glu Ala Ala Val145 150 155 160Asp Met His Arg Phe Leu Arg Leu Phe Ile Ser Glu Ile Phe Pro His 165 170 175Lys Gln Phe Leu Pro Val His Leu Ser Gly Glu Ser Tyr Ala Gly Arg 180 185 190Tyr Ile Pro Tyr Leu Ala Thr Gln Ile Leu Glu Gln Asn Glu Leu Tyr 195 200 205Lys Asp Ser Pro Arg Ile Pro Leu Lys Ser Cys Leu Val Gly Asn Gly 210 215 220Phe Met Ser Pro Lys Asp Ala Thr Phe Gly Tyr Trp Glu Thr Leu Cys225 230 235 240Thr Thr Asn Ser Gly Val Pro Ser Pro Ile Phe Asn Glu Thr Arg Cys 245 250 255Asp Ile Met Ala Ala Asn Met Pro His Cys Met Asp Leu Tyr Asp Ile 260 265 270Cys Ile Gln His Ser Asp Pro Ala Ile Cys His Ala Ala Gln Ser Val 275 280 285Cys Tyr Asp Ser Val Val Gly Leu Met Ala Lys Leu Leu Leu Arg Met 290 295 300Thr Thr Val Thr Ala Pro Cys Glu Ile Asp Glu Met Cys Tyr Ile Glu305 310 315 320Ala Ala Leu Ile Glu Arg Tyr Leu Asn Ser Pro Ser Val Trp Glu Ala 325 330 335Leu Ser Pro Pro Gln Gln Val Thr Glu Tyr Lys Phe Val Ala Thr Ser 340 345 350Val Ile Asp Ala Phe Ala Gln Ser Ala Asp Gly Met Val Ser Ser Ser 355 360 365Lys Gln Ile Ala Phe Leu Leu Ala Asn Asn Val Asp Phe Leu Ala Tyr 370 375 380Gln Gly Asn Leu Asp Leu Ala Cys Asn Thr Ala Gly Asn Leu Arg Trp385 390 395 400Ala Asn Ser Leu Ser Trp Lys Gly Gln Thr Glu Phe Thr Ala Lys Pro 405 410 415Leu Leu Pro Trp Glu Ile Gln Val Ser Val Gly Glu Gly Thr Asp Glu 420 425 430Thr Ser Arg Phe Ala Phe Val Thr Val Asp Asn Ala Gly His Leu Leu 435 440 445Arg Asp Ser Lys Ile Ser Asn 450 455146791PRTAspergillus niger 146Met Arg Phe Leu Thr Tyr Ser Leu Pro Phe Ile Ala Ser Ala Ile Ser1 5 10 15Leu Phe Gly Val Asn Val Gln Ala Arg Ser Gln Ala Pro Ser Ala Ile 20 25 30Arg His Val Ser Thr Leu Asp Gln Pro Thr Ile Lys Thr Pro Ser Gln 35 40 45Arg Val Asp His Leu Asp His Phe Asp Ile Thr Phe Asn Ile His Asp 50 55 60Lys His Gln Arg Ile Lys Leu Glu Leu Glu Pro Asn His Asp Ile Leu65 70 75 80Ala Glu Asp Ala Ser Val Gln Tyr Leu Asp Ala Asp Gly Asn Val Arg 85 90 95Arg His Glu Pro Ile Ala Pro His Glu His Lys Val Phe Lys Gly Arg 100 105 110Ser Leu Leu Gly Arg Gly Lys Gly Met Trp Asp Pro Val Gly Trp Ala 115 120 125Arg Ile Tyr Leu Lys Gln Asp Gly Ser Glu Pro Leu Phe Glu Gly Val 130 135 140Phe Ser Ile Asp Gly Asp Asn His His Val Gln Leu Lys Ser Ala Tyr145 150 155 160Met Glu Lys Lys Arg Pro Val Asp Val Asp Leu Pro Asp Ser Ala Thr 165 170 175Asp Tyr Met Ile Phe Tyr Arg Asp Ser Asp Met Val Arg Leu His Thr 180 185 190Glu Leu Lys Arg Ser Ser Leu Gly Ser Thr Ser Cys Gln Ala Asp Gln 195 200 205Leu Gly Phe Asn Thr Asn Pro Asn His Pro Val Leu Gln Pro Tyr Gly 210 215 220Gln Ala Glu Thr Asp Thr Trp Gly Ala Ile Ser Leu Asn Ser Leu Phe225 230 235 240Gly Leu Asn Lys Arg Gln Ser Asp Ile Gly Ser Val Ser Gly Asn Ala 245 250 255Gly Gly Val Asn Leu Ala Ser Thr Ile Gly Asp Thr Ser Gly Cys Pro 260 265 270Ser Thr Lys Gln Val Ala Leu Ile Gly Val Ala Thr Asp Cys Ala Phe 275 280 285Thr Gly Ser Phe Asn Asn Glu Thr Ala Ala Lys Glu Trp Val Ile Ser 290 295 300Thr Val Asn Ser Ala Ser Asn Val Tyr Glu Lys Ser Phe Asn Ile Thr305 310 315 320Ile Gly Leu Arg Asn Leu Thr Ile Thr Asp Ser Ser Cys Pro Asp Asn 325 330 335Pro Pro Ala Ala Thr Ala Trp Asn Met Pro Cys Ser Ser Gly Asn Leu 340 345 350Thr Ser Arg Leu Asp Leu Phe Ser Lys Trp Arg Gly Glu Gln Ser Asp 355 360 365Asp Asn Ala Tyr Trp Thr Leu Met Ser Asp Cys Ala Thr Gly Asn Glu 370 375 380Val Gly Leu Ser Trp Leu Gly Gln Leu Cys Asn Ser Asp Ala Ser Ser385 390 395 400Asp Gly Ser Ser Thr Val Ser Gly Thr Asn Val Val Val Arg Ser Ser 405 410 415Gly Ser Asp Trp Gln Ile Phe Ala His Glu Ser Gly His Thr Phe Gly 420 425 430Ala Val His Asp Cys Asp Ser Gln Thr Cys Ala Glu Asp Leu Glu Ala 435 440 445Ser Ser Gln Cys Cys Pro Leu Thr Ser Ser Thr Cys Asn Ala Asn Gly 450 455 460Lys Tyr Ile Met Asn Pro Thr Thr Gly Thr Asp Ile Thr Ala Phe Ser465 470 475 480Gln Cys Thr Ile Gly Asn Ile Cys Ala Ala Leu Gly Arg Asn Ser Val 485 490 495Lys Ser Ser Cys Leu Ser Ala Asn Arg Asp Val Thr Thr Tyr Thr Gly 500 505 510Ser Gln Cys Gly Asn Gly Ile Val Glu Ser Gly Glu Asp Cys Asp Cys 515 520 525Gly Gly Glu Asp Gly Cys Gly Asp Asn Asn Cys Cys Asp Ala Lys Thr 530 535 540Cys Lys Phe Lys Ser Gly Ala Val Cys Asp Asp Ser Asn Asp Ser Cys545 550 555 560Cys Ser Ser Cys Gln Phe Ser Ser Ala Gly Thr Val Cys Arg Ala Ser 565 570 575Arg Gly Asp Cys Asp Val Ala Glu Thr Cys Ser Gly Asn Ser Ser Thr 580 585 590Cys Pro Thr Asp Ser Phe Lys Lys Asp Gly Thr Ser Cys Gly Ser Ser 595 600 605Gly Ser Gly Leu Ala Cys Ala Ser Gly Gln Cys Thr Ser Arg Asp Tyr 610 615 620Gln Cys Arg Ser Val Met Gly Ser Leu Leu His Ser Asn Asp Thr Tyr625 630 635 640Ala Cys Ser Ser Phe Ser Ser Ser Cys Glu Leu Val Cys Thr Ser Pro 645 650 655Lys Ile Gly Thr Cys Tyr Ser Val Asn Gln Asn Phe Leu Asp Gly Thr 660 665 670Pro Cys Gly Ser Gly Gly Tyr Cys Ser Asn Gly Asp Cys Lys Gly Gln 675 680 685Asn Val Glu Ser Trp Ile Lys Asn His Lys Gly Ile Val Ile Gly Val 690 695 700Ala Cys Ala Val Gly Ala Leu Ile Leu Leu Ala Leu Met Thr Cys Ile705 710 715 720Val Asn Arg Cys Arg Arg Ala Arg Ala Pro Lys Pro Val Pro Arg Pro 725 730 735Val Pro Tyr Gly Pro Trp Pro Gly Ala Arg Pro Pro Pro Pro Pro Pro 740 745 750Met Asn Gln Trp Pro Ala Arg Gly Tyr Gln Gly Leu Gly Asn Glu Pro 755 760 765Pro Pro Pro Tyr Pro Gly Val Pro Gly Gln Pro Val Pro Gln His Met 770 775 780Pro Pro Gln Gly Arg Tyr Ala785 790147481PRTAspergillus niger 147Met Arg Phe Leu Ser Ser Ala Ala Leu Phe Gly Leu Ala Tyr Ala Ser1 5 10 15Thr Gln Ala Val Leu Gln Pro Glu Glu Pro Ser Asp Phe Arg Thr Phe 20 25 30His Ser Pro Tyr Ser Pro His His Ser Ile Arg Ile Arg Gln Gln Asn 35 40 45Glu Ser Ile Cys Ala Ala His Ser Ala Gln Tyr Thr Gly Trp Leu Asp 50 55 60Ile Gly Arg Lys His Leu Phe Phe Trp Tyr Phe Glu Ser Gln Asn Asp65 70 75 80Pro Ala Asn Asp Pro Leu Thr Leu Trp Met Thr Gly Gly Pro Gly Gly 85 90 95Ser Ser Met Ile Gly Leu Phe Glu Glu Val Gly Pro Cys Leu Ile Asn 100 105 110Glu Tyr Gly Asn Gly Thr Tyr Tyr Asn Pro Trp Gly Trp Ser Arg Asn 115 120 125Ser Ser Leu Leu Phe Val Asp Gln Pro Val Asp Val Gly Phe Ser Tyr 130 135 140Val Asp Glu Gly Glu Asp Leu Pro Gly Asp Ser His Gln Ala Ala Ile145 150 155 160Asp Met His Arg Phe Leu Gln Leu Phe Val Ser Glu Val Phe Pro Gln 165 170 175Leu Gln Thr Leu Pro Val His Leu Ser Gly Glu Ser Tyr Ala Gly His 180 185 190Tyr Val Pro Tyr Leu Gly Ser Gln Ile Val Gln Gln Asn Lys Leu Tyr 195 200 205Pro Thr Glu Pro Gln Val Leu Leu His Ser Cys Leu Val Gly Asn Gly 210 215 220Tyr Tyr Ser Pro Arg Asp Thr Thr Tyr Gly Tyr Trp Glu Thr Leu Cys225 230 235 240Thr Thr Asn Pro Gly Val Pro Glu Pro Val Phe Asn Arg Thr Arg Cys 245 250 255Asp Ile Met Ala Ala Asn Met Pro Arg Cys Met Glu Val Ser Asp Val 260 265 270Cys Val Arg Asn Pro Asp Pro Ala Ile Cys His Ala Ala Ser Glu Val 275 280 285Cys Tyr Glu Gly Val Ile Gly Trp Tyr Asp Asp Glu Ser Gly Glu Gly 290 295 300Gly Arg Asn Arg Phe Asp Ile Thr Ala Pro Cys Ala Leu Asp Gly Ile305 310 315 320Cys Tyr Ile Glu Ala Ala Arg Ile Glu Gln Tyr Leu Asn Thr Pro Ala 325 330 335Val Trp Ala Ala Leu Ser Pro Pro Lys Glu Ile Lys Glu Tyr Lys Val 340 345 350Thr Ser Asp Asn Val Ser Arg Ala Phe Asp Leu Thr Ser Asp Thr Met 355 360 365Thr Pro Ala Ser Glu Gln Val Ala Phe Leu Leu Ala Asn Gln Val His 370 375 380Phe Leu Ala Tyr Gln Gly Asn Leu Asp Leu Ala Cys Asn Thr Ala Gly385 390 395 400Asn Leu Arg Trp Ala His Ser Leu Pro Trp Arg Gly Gln Val Glu Phe 405 410 415Ala Ser Lys Ala Leu Arg Pro Trp Ser Trp Val Asp Val Val Ser Gly 420 425 430Lys Gly Gly Val Ala Gly Thr Thr Lys Glu Glu Ser Arg Phe Ala Leu 435 440 445Val Thr Val Asp Gly Ala Gly His Phe Leu Pro Gln Asp Arg Pro Asp 450 455 460Ile Ala Leu Asp Met Met Val Arg Trp Ile Ser Gly Ala Ser Phe Thr465 470 475 480Glu148319PRTAspergillus niger 148Met Thr Leu Leu Leu Asn Phe His Ala Leu Phe Thr Val Ile Leu Val1 5 10 15Ala Asn Leu Ser Thr Arg Cys Ser Ala Leu Leu Ser Gly Arg Asp Phe 20 25 30Cys Ser Thr Pro Ala Pro Gly Glu Ser Leu Arg Ala Glu His Arg Arg 35 40 45Leu Tyr Asp Val Gln Ala Gln Arg Asp Ser Thr Ala Glu Glu Ser Arg 50 55 60Glu Val Val Pro Trp Ile Glu Ile Glu Thr Trp Phe His Ile Val Ser65 70 75 80Ser Asn Glu Ala Ala Asn Thr Val Ser Asp Asp Met Ile Thr Ser Gln 85 90 95Leu Ser Tyr Leu Gln Lys Ala Tyr Glu Ser Ala Thr Ile Thr Tyr Arg 100 105 110Leu Glu Gly Ile Thr Arg His Ile Asn Asp Ser Trp Ala Arg Asn Asp 115 120 125Asp Glu Leu Gly Met Lys Asn Ala Leu Arg Arg Gly Asn Tyr Gly Thr 130 135 140Leu Asn Val Tyr Phe Gln Thr Asp Leu Gln Ala Ser Ser Asp Glu Asn145 150 155 160Ser Arg Asp Tyr Pro Asn Asp Gly Asn Arg Arg Thr Asp Val Ser Asp 165 170 175Gln Ser Ser Ser Thr Val Leu Gly Phe Cys Thr Leu Pro Asp Pro Ser 180 185 190Val Asn Ser Ser Ser Pro Arg Ser Ser Tyr Ile Lys Asp Gly Cys Asn 195 200 205Val Leu Ala Asp Ile Met Pro Gly Gly Ser Leu Ala Gln Tyr Asn Lys 210 215 220Gly Gly Thr Ala Val His Glu Val Gly His Trp Asn Gly Leu Leu His225 230 235 240Thr Phe Glu Gly Glu Ser Cys Ser Pro Asp Asn Glu Gly Asp Tyr Ile 245 250 255Asp Asp Thr Pro Glu Gln Ser Glu Pro Thr Ser Gly Cys Pro Ala Glu 260 265 270Lys Asp Ser Cys Pro Asp Leu Pro Gly Leu Asp Ala Ile His Asn Phe 275 280 285Met Asp Tyr Ser Ser Asp Asp Cys Tyr Glu Ser Phe Thr Pro Asp Gln 290 295 300Ala Glu Arg Met Arg Ser Met Trp Ser Ala Met Arg Glu Gly Lys305 310 315149639PRTAspergillus niger 149Met His Val Ser Leu Phe Leu Leu Ser Val Thr Ala Ala Phe Ala Ser1 5 10 15Pro Thr Pro His Asn Tyr Val Val His Glu Arg Arg Asp Ala Leu Pro 20 25 30Ser Val Trp Val Glu Glu Ser Arg Leu Asp Lys Gly Ala Leu Leu Pro 35 40 45Met Arg Ile Gly Leu Thr Gln Ser Asn Leu Asp Arg Gly His Asp Leu 50 55 60Leu Met Glu Val Ser His Pro Gln Ser Ser Arg Tyr Gly Lys His Leu65 70 75 80Ser Ser Glu Glu Val His Asp Leu Phe Ala Pro Ser Asn Glu Ala Val 85 90 95Glu Thr Val Arg Thr Trp Ile Glu Ser Ala Gly Ile Ala Pro Ser Arg 100 105 110Ile Ser Gln Ser Tyr Asn Lys Gln Trp Leu Gln Phe Asp Ala His Ala 115 120 125Ser Glu Val Glu Gln Leu Leu Gln Thr Glu Tyr Tyr Ile Tyr Thr His 130 135 140Ala Asp Thr Gly Ser Ser His Val Thr Cys His Glu Tyr His Val Pro145 150 155 160Glu Thr Ile Gln Ser His Ile Asp Tyr Ile Thr Pro Gly Val Lys Met 165 170 175Leu Glu Val Arg Gly Thr Pro Ser Lys Lys Arg Asp Ala Glu Lys Arg 180 185 190Ser Leu Gly Ser Leu Pro Pro Ile Leu Ala Pro Leu Pro Ile Asn Ile 195 200 205Thr Lys Ile Phe Asp Asp Pro Leu Ala His Cys Asp Leu Ala Val Thr 210 215 220Pro Asp Cys Ile Arg Ala Met Tyr Asn Ile Thr Lys Gly Thr Thr Ala225 230 235 240Thr Lys Gly Asn Glu Leu Gly Ile Phe Glu Asp Leu Gly Asp Ile Tyr 245 250 255Ser Gln Asp Asp Leu Asn Leu Phe Phe Ala Asn Phe Ala Ser Asp Ile 260 265 270Pro Gln Gly Thr His Pro Thr Leu Asp Ser Ile Asp Gly Ala Thr Ala 275 280 285Pro Thr Asp Val Thr Asn Ala Gly Pro Glu Ser Asp Leu Asp Phe Gln 290 295 300Ile Ala Tyr Pro Ile Ile Trp Pro Gln Asn Thr Ile Leu Tyr Gln Thr305 310 315 320Asp Asp Pro Asn Tyr Glu Asp Asn Tyr Asn Phe Lys Gly Leu Leu Asn 325 330 335Asn Phe Leu Tyr Ala Ile Asp Gly Ser Tyr Cys Asn Glu Thr Ser Ser 340 345 350Leu Asp Pro Gln Tyr Pro Asp Pro Ser Pro Gly Gly Tyr Ser Ser Pro 355 360 365Lys Gln Cys Gly Val Tyr Thr Pro Thr Asn Val Ile Ser Ile Ser Tyr 370 375 380Gly Ser Pro Glu Ala Asp Leu Pro Ile Ala Tyr Gln Arg Arg Gln Cys385 390 395 400His Glu Phe Met Lys Leu Gly Leu Gln Gly Ile Ser Val Val Val Ala 405 410 415Ser Gly Asp Ser Gly Val Ala Ser Ser Thr Gly Thr Cys Phe Gly Asp 420 425 430Ala Asp Asn Val Phe Val Pro Asp Phe Pro Ala Thr Cys Pro Tyr Leu 435 440 445Thr Ala Val Gly Gly Thr Tyr Leu Pro Leu Gly Ala Asp Ala Ala Lys 450 455 460Asp Gln Glu Ile Ala Val Thr Arg Phe Pro Ser Gly Gly Gly Phe Ser465 470 475 480Asn Ile Tyr Ala Arg Pro Ser Tyr Gln Asn

His Ser Val Glu Thr Tyr 485 490 495Phe Ser Thr Thr Ser Asp Asp Leu Thr Tyr Pro Tyr Tyr Ser Gly Val 500 505 510Asn Tyr Thr Asp Phe Ser Asn Thr Asp Gly Val Tyr Asn Arg Ile Gly 515 520 525Arg Gly Tyr Pro Asp Val Ser Ala Ile Ala Asp Asn Ile Ile Ile Tyr 530 535 540Asn Gln Gly Glu Ala Thr Leu Val Gly Gly Thr Ser Ala Ala Ala Pro545 550 555 560Ala Phe Ala Ala Met Leu Thr Arg Ile Asn Glu Glu Arg Leu Ala Lys 565 570 575Gly Lys Ser Thr Val Gly Phe Val Asn Pro Val Leu Tyr Glu His Pro 580 585 590Glu Ala Phe Arg Asp Val Thr Val Gly Ser Asn Pro Gly Cys Gly Thr 595 600 605Asp Gly Phe Pro Val Ala Gly Gly Trp Asp Pro Val Thr Gly Leu Gly 610 615 620Thr Pro Arg Phe Glu Asp Leu Met Asp Ile Phe Val Gly Asp Asp625 630 635150371PRTAspergillus niger 150Met Ala Ser Lys Thr Leu Leu Leu Ile Pro Ala Leu Ala Thr Ala Ala1 5 10 15Leu Gly Ser Val Leu Asp Leu Asp Ile Lys Val Asp Leu Gly Thr Pro 20 25 30Gly Gly Pro Phe Asp Leu Met Tyr Asp Thr Gly Ser Ser Thr Leu Trp 35 40 45Val Leu Asp Ser Asn Cys Thr Asp Asp Cys Pro Asn Val Ser Gly Tyr 50 55 60Ser Arg His Gly Tyr Asn Leu Thr Ser Thr Gly Val Asn Leu Gly Val65 70 75 80Asn Asp Ser Ile Ala Tyr Ser Gly Gly Thr Val Ser Gly Phe Thr Ala 85 90 95Thr Asp Ile Leu Thr Val Pro Asp Thr Asn Val Ser Tyr Arg Gln Ser 100 105 110Phe Ala Val Ile Thr Asp Ser Thr Trp Ala Ala Leu Ala Ala Asp Gly 115 120 125Phe Ile Gly Leu Ala Ser Ser Thr Ile Ala Phe Lys Asn Thr Thr Thr 130 135 140Ala Val Glu Gln Met Met Gln Asp Gly Leu Leu Asp Glu Pro Arg Phe145 150 155 160Ala Ile Tyr Ala Gly Ser Gly Glu Ser Thr Val Thr Asn Pro Asn Pro 165 170 175Glu Asn Asn Gly Val Phe Thr Phe Gly Gly Ser His Glu Glu Thr Tyr 180 185 190Ala Asp Gly Glu Leu Gln Trp Met Lys Met Leu Ser Pro Phe Glu Ile 195 200 205Tyr Lys Thr Asn Leu Leu Gly Ile Gln Gly His Asn Asn Ser Asp Gly 210 215 220Gln Ala Leu Ser Ser Asp Val Leu Asn Trp Tyr Gly Gln Thr Asn Leu225 230 235 240Phe Asn Val Ala Gly Ala Ser Ser Ile Ser Ile Pro Asn Asp Gln Ile 245 250 255Glu Ala Met Tyr Ala Leu Thr Pro Phe Ser Tyr Ala Asp Ile Ser Ser 260 265 270Gly Tyr Arg Pro Leu Cys Ser Asp Phe Asn Asp Thr Trp Ser Ile Ser 275 280 285Phe Thr Met Gly Phe Tyr Gly Glu Gly Val Thr Phe Asn Leu Thr Gly 290 295 300Asp Gln Leu Ala Val Pro Gly Tyr Gln Asp Asp Asp His Cys Phe Pro305 310 315 320Pro Phe Asn Pro Trp Asp Ser Tyr Asn Thr Ile Ile Gly Gln His Trp 325 330 335Leu Ser Asn Phe Tyr Ala Val Phe Asp Phe Gly Ser Phe Asp Pro Glu 340 345 350Thr Tyr Asp Ile Arg Val Gly Leu Ala Pro Leu Lys Lys Glu Tyr Leu 355 360 365Pro Ser Ala 370151414PRTAspergillus niger 151Met Phe Pro Cys Ser Arg Ile Trp Ser Leu Leu Val Ala Ala Ala Thr1 5 10 15Ala Ser Ala Val Pro Thr Ser Leu Ala Thr Thr His Leu Gln Ser Val 20 25 30Asp Leu Leu Leu Thr Arg Ser Ser Tyr Gly Phe Leu Thr Asp Ile Ala 35 40 45Leu Gly Thr Pro Gly Gln Ser Leu Pro Tyr Leu Val Asp Trp Thr Trp 50 55 60Thr Gly His Tyr Val Val Thr Thr Leu Cys Tyr Asn Asp Pro Thr Ala65 70 75 80Thr Tyr Asp Cys Leu Asn Val Asp Gln Lys Ile Phe Asn Gln Thr Leu 85 90 95Ser Ser Thr Phe Ile Asn Gln Thr Asp Gln Tyr Gly Tyr Leu Tyr Trp 100 105 110Asp Pro Asn His Phe Tyr Phe Thr Glu Pro Ala Ala Ala Asp Val Ala 115 120 125Thr Asp Met Leu Arg Ile Gly Pro Thr Ala Val Asn Thr Thr Ile Gln 130 135 140Ala Ala Asn Phe Val Phe Asn Glu Thr Ile Ser Ala Phe Pro Phe Ser145 150 155 160Gly Val Tyr Gly Leu Ser Pro Val Phe Gln Gly Asp Asn Arg Ser Val 165 170 175Gln Ala Ser Phe Tyr Gln Gly Trp Arg Ser Gly Ala Trp His Ser Pro 180 185 190Ile Val Ser Phe Ile Tyr Cys His Asp Asn Ala Thr Lys Ala Val Cys 195 200 205Ser Gly Tyr Asp Gly Leu Gln Thr Leu Gly Gly Tyr Asn Thr Ser His 210 215 220Val Gln Gly Asp Ile Thr Trp Tyr Asp Ile Ile Val Thr Glu Ala Ile225 230 235 240Asn Thr Leu Asp Phe Val Tyr Ala Pro Ala Val Ile Asn Tyr Trp Ala 245 250 255Leu Asn Leu Thr Arg Phe Ser Ile Gly Asp Glu Glu Gln Glu Leu Asn 260 265 270Lys Thr Thr Thr Leu Asp Gly Lys Gln Ala Ala Val Ala Ala Phe Asp 275 280 285His Ala Ser Tyr Gly Arg Gly Ala Pro Val Ser Val Tyr Gly Tyr Gln 290 295 300Arg Leu Val Glu Leu Val Gly Ala Lys Ala Val Thr Leu Ser Asp Pro305 310 315 320Pro Asn Asn Gly Glu Gln Gly Phe Tyr Gln Phe Asp Cys Arg Asn Ser 325 330 335Ser Leu Leu Pro Pro Leu Arg Tyr Glu Phe Ala Gly Ser Glu Arg Ala 340 345 350Trp Glu Ile Val Pro Glu Asn Tyr Val Glu Val Leu Ala Asn Gly Thr 355 360 365Asn Lys Cys Thr Phe Asn Val Arg Thr Leu Gly Asp Gly Ala Met Val 370 375 380Met Gly Asn Phe Gly Glu Thr Phe Ala Ile Asp Lys Tyr Val Met Phe385 390 395 400Asp Phe Glu Lys Leu Gln Val Gly Ile Ala Asp Phe Ala Trp 405 410152480PRTAspergillus niger 152Met His Leu Pro Gln Arg Leu Val Thr Ala Ala Cys Leu Cys Ala Ser1 5 10 15Ala Thr Ala Phe Ile Pro Tyr Thr Ile Lys Leu Asp Thr Ser Asp Asp 20 25 30Ile Ser Ala Arg Asp Ser Leu Ala Arg Arg Phe Leu Pro Val Pro Lys 35 40 45Pro Ser Asp Ala Leu Ala Asp Asp Ser Thr Ser Ser Ala Ser Asp Glu 50 55 60Ser Leu Ser Leu Asn Ile Lys Arg Ile Pro Val Arg Arg Asp Asn Asp65 70 75 80Phe Lys Ile Val Val Ala Glu Thr Pro Ser Trp Ser Asn Thr Ala Ala 85 90 95Leu Asp Gln Asp Gly Ser Asp Ile Ser Tyr Ile Ser Val Val Asn Ile 100 105 110Gly Ser Asp Glu Lys Ser Met Tyr Met Leu Leu Asp Thr Gly Gly Ser 115 120 125Asp Thr Trp Val Phe Gly Ser Asn Cys Thr Ser Thr Pro Cys Thr Met 130 135 140His Asn Thr Phe Gly Ser Asp Asp Ser Ser Thr Leu Glu Met Thr Ser145 150 155 160Glu Glu Trp Ser Val Gly Tyr Gly Thr Gly Ser Val Ser Gly Leu Leu 165 170 175Gly Lys Asp Lys Leu Thr Ile Ala Asn Val Thr Val Arg Met Thr Phe 180 185 190Gly Leu Ala Ser Asn Ala Ser Asp Asn Phe Glu Ser Tyr Pro Met Asp 195 200 205Gly Ile Leu Gly Leu Gly Arg Thr Asn Asp Ser Ser Tyr Asp Asn Pro 210 215 220Thr Phe Met Asp Ala Val Ala Glu Ser Asn Val Phe Lys Ser Asn Ile225 230 235 240Val Gly Phe Ala Leu Ser Arg Ser Pro Ala Lys Asp Gly Thr Val Ser 245 250 255Phe Gly Thr Thr Asp Lys Asp Lys Tyr Thr Gly Asp Ile Thr Tyr Thr 260 265 270Asp Thr Val Gly Ser Asp Ser Tyr Trp Arg Ile Pro Val Asp Asp Val 275 280 285Tyr Val Gly Gly Thr Ser Cys Asp Phe Ser Asn Lys Ser Ala Ile Ile 290 295 300Asp Thr Gly Thr Ser Tyr Ala Met Leu Pro Ser Ser Asp Ser Lys Thr305 310 315 320Leu His Ser Leu Ile Pro Gly Ala Lys Ser Ser Gly Ser Tyr His Ile 325 330 335Ile Pro Cys Asn Thr Thr Thr Lys Leu Gln Val Ala Phe Ser Gly Val 340 345 350Asn Tyr Thr Ile Ser Pro Lys Asp Tyr Val Gly Ala Thr Ser Gly Ser 355 360 365Gly Cys Val Ser Asn Ile Ile Ser Tyr Asp Leu Phe Gly Asp Asp Ile 370 375 380Trp Leu Leu Gly Asp Thr Phe Leu Lys Asn Val Tyr Ala Val Phe Asp385 390 395 400Tyr Asp Glu Leu Arg Val Gly Phe Ala Glu Arg Ser Ser Asn Thr Thr 405 410 415Ser Ala Ser Asn Ser Thr Ser Ser Gly Thr Ser Ser Thr Ser Gly Ser 420 425 430Thr Thr Thr Gly Ser Ser Thr Thr Thr Thr Ser Ser Ala Ser Ser Ser 435 440 445Ser Ser Ser Asp Ala Glu Ser Gly Ser Ser Met Thr Ile Pro Ala Pro 450 455 460Gln Tyr Phe Phe Ser Ala Leu Ala Ile Ala Ser Phe Met Leu Trp Leu465 470 475 480153466PRTAspergillus niger 153Met Thr Ser Ser Thr Leu Arg Leu Ala Val Ala Leu Ala Leu Ser Thr1 5 10 15Cys Ser Ser Ala Leu Ser Ser Gln Arg Asp Asp Ser Leu Val Val Pro 20 25 30Phe Pro Phe Gly Asn Leu Glu Asp Val His Ile Ala Lys Arg Asp Ser 35 40 45Ser Lys Thr Val Glu Ala Pro Leu Val Ile Tyr Gly Asp Ser Tyr Trp 50 55 60Met Asn Ala Ser Ile Gly Thr Pro Ala Gln Ser Leu Ser Phe Leu Leu65 70 75 80Asp Leu Thr Arg Ser Arg Val Glu Pro Ala Tyr Thr Leu Asp Glu Asn 85 90 95Tyr Glu Cys Ser Asp Asp Glu Leu Cys Ser Glu Phe Gly Phe Tyr Lys 100 105 110Pro Thr Asp Ser Ser Thr Tyr Gln His Leu Thr Tyr Thr Gln Arg His 115 120 125Asp Ala Gly Val Asp Tyr Ser Tyr Leu Asp Thr Ile Thr Leu Gly Asp 130 135 140His Ala Thr Asp Asn Val Pro Leu Asp Met Tyr Leu Leu Ser Tyr Ile145 150 155 160Ser Tyr Ser Ser Leu Gly Leu Ser Ser Val Asn Thr Ser Phe Pro Tyr 165 170 175Ile Leu Val Asp Arg Gly Leu Thr Thr Ser Pro Ser Phe Ser Leu Ile 180 185 190Gly Asp Asn Gly Asn Thr Thr Thr Pro Ser Ile Ile Phe Gly Gly Ile 195 200 205Asn Thr Ser Lys Phe Asn Gly Pro Leu Gln Ala Phe Ser Phe Ala Asp 210 215 220His Ser Ile Thr Asn Asn Pro Phe Val Thr Val Glu Ala Asp Ser Leu225 230 235 240Gln Leu Thr Thr Asn Thr Asn Asp Asn Ser Thr Tyr Pro Ile Pro Ser 245 250 255Ser Thr Pro Met Met Leu Arg Thr Glu Glu Leu Ile Thr Tyr Leu Pro 260 265 270Asn Ser Thr Val Gln Ser Leu Tyr Thr Asp Leu Asn Ile Thr Met Asp 275 280 285Gly Val Ile Ser Thr Ser Arg Phe Tyr Gly Val Leu Pro Cys Ala Arg 290 295 300Gln Glu Thr Glu Ser His Thr Ile Ser Leu Ala Ile Gly Asn Met Thr305 310 315 320Phe Ser Val Ser Trp Asp Glu Leu Phe Val Pro Trp Thr Arg Asp Gly 325 330 335Leu Cys Lys Phe Gly Ile Gln Ala Gln Asp Ser Asp Tyr Lys Thr Arg 340 345 350Ala Glu Leu Gly Val Pro Phe Leu Arg Arg Met Tyr Val Ala Val Asp 355 360 365Tyr Asn Asn Gln Phe Val Gly Val Ala Thr Leu Lys Asp Asp Asp Asp 370 375 380Gln Asn Gly Gly Glu Asp Glu Ile Val Glu Ile Gly Thr Gly Thr Ala385 390 395 400Leu Pro Ser Ala Val Gly Asp Trp Pro Ala Ser Val Thr Ala Tyr Thr 405 410 415Pro Ala Ala Ser Thr Gly Thr Ala Ala Ala Thr Leu Thr Phe Thr Thr 420 425 430Ala Thr Ser Ser Gly Gly Gly Val Val Pro Thr Gly Leu Ser Glu Leu 435 440 445Gly Arg Ala Phe Leu Val Pro Gly Val Leu Gly Met Ala Val Leu Gln 450 455 460Ala Val465154543PRTAspergillus niger 154Met Met Arg Pro Ile Leu Leu Pro Leu Leu Gly Val Phe Leu Gln Thr1 5 10 15Ser Ser Ala Ser Asn Pro Tyr Val Met Ser Trp Ser Ser Gln Ala Tyr 20 25 30Gly Pro Asp Gly Pro Trp Gln Ala Val Ser Ile Asp Val Gly Ser Asn 35 40 45Gln Gln Thr Val Asp Leu Tyr Pro Gly Ala Asn Tyr Ala Ser Thr Ile 50 55 60Leu Met Ser Thr Leu Cys Thr Asn Lys Thr Leu Ser Ser Thr Cys Tyr65 70 75 80Ala Ala Glu Ala Gly Thr Phe Asn Gln Asn Thr Ser Thr Thr Ala Tyr 85 90 95Thr Thr Ala Ser Ser Trp Glu Thr Thr Tyr Trp Ala Val Glu Gly Gly 100 105 110Ser Gln Glu Ala Val Leu Gly Asp Glu Val Thr Leu Gly Ser Phe Val 115 120 125Val Pro Asn Val Ser Phe Glu Ala Ile Tyr Gln Thr Tyr Gln Thr Tyr 130 135 140Pro Asn Gly Ile Ala Tyr Pro Val Ser Val Gly Ser Leu Ala Leu Gly145 150 155 160Gly Pro Tyr Leu Ser Asp Thr Val Ser Asn Ser Thr Val Leu Asn Met 165 170 175Ile Ala Gly Trp Leu Tyr Ser Ser Asn Asp Ile Pro Ser Tyr Ser Tyr 180 185 190Gly Met His Ile Gly Ser Val Asp Pro Lys Ile Pro Gly Ser Leu Ile 195 200 205Leu Gly Gly Tyr Asp Lys Ser Arg Val Ile Gly Asp Val Ser Ala Gln 210 215 220Gly Val Val Ser Ser Ser Gly Leu Leu Glu Leu Glu Leu Lys Asp Ile225 230 235 240Gly Leu Gly Val Ala Ala Gly Ser Ser Pro Phe Ser Phe Asn Asn Glu 245 250 255Ser Gly Leu Phe Leu Gln Ser Ser Gly Ser Val Gln Ala Lys Thr Val 260 265 270Gln Ile Asp Pro Thr Lys Pro Tyr Met Tyr Leu Pro Gln Ala Thr Cys 275 280 285Asp Ala Ile Thr Ser Thr Met Pro Ile Ser Phe Asn Ser Ser Leu Gly 290 295 300Leu Tyr Phe Trp Asp Thr Thr Ser Asp Asp Tyr Leu Asn Ile Thr Ser305 310 315 320Ser Ala Ala Tyr Leu Ser Phe Val Phe Asn Met Asn Gly Val Asn Asn 325 330 335Lys Asn Ile Thr Ile Lys Ile Pro Phe Ser Gln Leu Asn Leu Thr Leu 340 345 350Gln Glu Pro Leu Val Asp Gln Asn Val Thr Tyr Phe Pro Cys Phe Leu 355 360 365Thr Thr Ser Thr Pro Val Leu Gly Arg Ala Phe Leu Gln Ser Ala Phe 370 375 380Val Gly Val Asn Trp Phe Asn Gly Asn Asn Ser Gly Thr Trp Phe Leu385 390 395 400Ala Gln Ala Pro Gly Pro Gly Tyr Ala Ser Glu Asp Ile Thr Arg Ile 405 410 415Ala Val Ser Asp Thr Ser Leu Ser Ala Ser Asn Gly Thr Trp Glu Glu 420 425 430Thr Trp Ala Thr Tyr Trp Gly Ile Lys Thr Ser Asp Asn Ser Ser Ser 435 440 445Ser Lys Ser Gly Leu Ser Ser Gly Ala Lys Ile Gly Ile Gly Val Gly 450 455 460Val Gly Val Gly Gly Ala Val Leu Ile Ala Ala Gly Ile Ala Ile Ala465 470 475 480Phe Cys Leu Arg Arg Arg Arg Gly Ala Ser Gln Glu Ala Ala Gly Glu 485 490 495Gln Arg Arg Ser Met Phe Arg Gly Phe Ala Glu Leu Pro Gly Gly Ala 500 505 510His Ser Glu Pro Ala Lys Glu Leu Asp Thr Lys Met His Lys Pro Pro 515 520 525Gln Glu Met Met Ala Ser Gln Glu Val Glu Arg Tyr Glu Leu Gly 530 535 540155844PRTAspergillus niger 155Met Arg Leu Thr Gly Gly Val Ala Ala Ala Leu Gly Leu Cys Ala Ala1 5 10 15Ala Ser Ala Ser Leu His Pro His Arg Ser Tyr Glu Thr His Asp Tyr 20 25 30Phe Ala

Leu His Leu Asp Glu Ser Thr Ser Pro Ala Asp Val Ala Gln 35 40 45Arg Leu Gly Ala Arg His Glu Gly Pro Val Gly Glu Leu Pro Ser His 50 55 60His Thr Phe Ser Ile Pro Arg Glu Asn Ser Asp Asp Val His Ala Leu65 70 75 80Leu Asp Gln Leu Arg Asp Arg Arg Arg Leu Arg Arg Arg Ser Gly Asp 85 90 95Asp Ala Ala Val Leu Pro Ser Leu Val Gly Arg Asp Glu Gly Leu Gly 100 105 110Gly Ile Leu Trp Ser Glu Lys Leu Ala Pro Gln Arg Lys Leu His Lys 115 120 125Arg Val Pro Pro Thr Gly Tyr Ala Ala Arg Ser Pro Val Asn Thr Gln 130 135 140Asn Asp Pro Gln Ala Leu Ala Ala Gln Lys Arg Ile Ala Ser Glu Leu145 150 155 160Gly Ile Ala Asp Pro Ile Phe Gly Glu Gln Trp His Leu Tyr Asn Thr 165 170 175Val Gln Leu Gly His Asp Leu Asn Val Thr Gly Ile Trp Leu Glu Gly 180 185 190Val Thr Gly Gln Gly Val Thr Thr Ala Ile Val Asp Asp Gly Leu Asp 195 200 205Met Tyr Ser Asn Asp Leu Arg Pro Asn Tyr Phe Ala Ala Gly Ser Tyr 210 215 220Asp Tyr Asn Asp Lys Val Pro Glu Pro Arg Pro Arg Leu Ser Asp Asp225 230 235 240Arg His Gly Thr Arg Cys Ala Gly Glu Ile Gly Ala Ala Lys Asn Asp 245 250 255Val Cys Gly Val Gly Val Ala Tyr Asp Ser Arg Ile Ala Gly Ile Arg 260 265 270Ile Leu Ser Ala Pro Ile Asp Asp Thr Asp Glu Ala Ala Ala Ile Asn 275 280 285Tyr Ala Tyr Gln Glu Asn Asp Ile Tyr Ser Cys Ser Trp Gly Pro Tyr 290 295 300Asp Asp Gly Ala Thr Met Glu Ala Pro Gly Thr Leu Ile Lys Arg Ala305 310 315 320Met Val Asn Gly Ile Gln Asn Gly Arg Gly Gly Lys Gly Ser Val Phe 325 330 335Val Phe Ala Ala Gly Asn Gly Ala Ile His Asp Asp Asn Cys Asn Phe 340 345 350Asp Gly Tyr Thr Asn Ser Ile Tyr Ser Ile Thr Val Gly Ala Ile Asp 355 360 365Arg Glu Gly Asn His Pro Pro Tyr Ser Glu Ser Cys Ser Ala Gln Leu 370 375 380Val Val Ala Tyr Ser Ser Gly Ala Ser Asp Ala Ile His Thr Thr Asp385 390 395 400Val Gly Thr Asp Lys Cys Ser Thr Thr His Gly Gly Thr Ser Ala Ala 405 410 415Gly Pro Leu Ala Ala Gly Thr Val Ala Leu Ala Leu Ser Val Arg Pro 420 425 430Glu Leu Thr Trp Arg Asp Val Gln Tyr Leu Met Ile Glu Ala Ala Val 435 440 445Pro Val His Glu Asp Asp Gly Ser Trp Gln Asp Thr Lys Asn Gly Lys 450 455 460Lys Phe Ser His Asp Trp Gly Tyr Gly Lys Val Asp Thr Tyr Thr Leu465 470 475 480Val Lys Arg Ala Glu Thr Trp Asp Leu Val Lys Pro Gln Ala Trp Leu 485 490 495His Ser Pro Trp Gln Arg Val Glu His Glu Ile Pro Gln Gly Glu Gln 500 505 510Gly Leu Ala Ser Ser Tyr Glu Val Thr Glu Asp Met Leu Lys Gly Ala 515 520 525Asn Leu Glu Arg Leu Glu His Val Thr Val Thr Met Asn Val Asn His 530 535 540Thr Arg Arg Gly Asp Leu Ser Val Glu Leu Arg Ser Pro Asp Gly Arg545 550 555 560Val Ser His Leu Ser Thr Pro Arg Arg Pro Asp Asn Gln Glu Val Gly 565 570 575Tyr Val Asp Trp Thr Phe Met Ser Val Ala His Trp Gly Glu Ser Gly 580 585 590Ile Gly Lys Trp Thr Val Ile Val Lys Asp Thr Asn Val Asn Glu His 595 600 605Thr Gly Gln Phe Ile Asp Trp Arg Leu Asn Leu Trp Gly Glu Ala Ile 610 615 620Asp Gly Ala Glu Gln Pro Leu His Pro Met Pro Thr Glu His Asp Asp625 630 635 640Asp His Ser Tyr Glu Glu Gly Asn Val Ala Thr Thr Ser Ile Ser Ala 645 650 655Val Pro Thr Lys Thr Glu Leu Pro Asp Lys Pro Thr Gly Gly Val Asp 660 665 670Arg Pro Val Asn Val Lys Pro Thr Thr Ser Ala Met Pro Thr Gly Ser 675 680 685Leu Thr Glu Pro Ile Asp Asp Glu Glu Leu Gln Lys Thr Pro Ser Thr 690 695 700Glu Ala Ser Ser Thr Pro Ser Pro Ser Pro Thr Thr Ala Ser Asp Ser705 710 715 720Ile Leu Pro Ser Phe Phe Pro Thr Phe Gly Ala Ser Lys Arg Thr Gln 725 730 735Val Trp Ile Tyr Ala Ala Ile Gly Ser Ile Ile Val Phe Cys Ile Gly 740 745 750Leu Gly Val Tyr Phe His Val Gln Arg Arg Lys Arg Ile Arg Asp Asp 755 760 765Ser Arg Asp Asp Tyr Asp Phe Glu Met Ile Glu Asp Glu Asp Glu Leu 770 775 780Gln Ala Met Asn Gly Arg Ser Asn Arg Ser Arg Arg Arg Gly Gly Glu785 790 795 800Leu Tyr Asn Ala Phe Ala Gly Glu Ser Asp Glu Glu Pro Leu Phe Ser 805 810 815Asp Glu Asp Asp Glu Pro Tyr Arg Asp Arg Gly Ile Ser Gly Glu Gln 820 825 830Glu Arg Glu Gly Ala Asp Gly Glu His Ser Arg Arg 835 840156149PRTAspergillus niger 156Met Lys Thr Phe Ser Thr Val Thr Ser Leu Leu Ala Leu Phe Ser Ser1 5 10 15Ala Leu Ala Ala Pro Val Asp Ser Ala Glu Ala Ala Gly Thr Thr Val 20 25 30Ser Val Ser Tyr Asp Thr Ala Tyr Asp Val Ser Gly Ala Ser Leu Thr 35 40 45Thr Val Ser Cys Ser Asp Gly Ala Asn Gly Leu Ile Asn Lys Gly Tyr 50 55 60Ser Asn Phe Gly Ser Leu Pro Gly Phe Pro Lys Ile Gly Gly Ala Pro65 70 75 80Thr Ile Ala Gly Trp Asn Ser Pro Asn Cys Gly Lys Cys Tyr Ala Leu 85 90 95Thr Tyr Asn Gly Gln Thr Val Asn Ile Leu Ala Ile Asp Ser Ala Pro 100 105 110Gly Gly Phe Asn Ile Ala Leu Glu Ala Met Asn Thr Leu Thr Asn Asn 115 120 125Gln Ala Gln Gln Leu Gly Arg Ile Glu Ala Thr Tyr Thr Glu Val Asp 130 135 140Val Ser Leu Cys Ala145157296PRTAspergillus niger 157Met Ala Gln Ile Phe Trp Leu Ser Leu Phe Leu Leu Val Ser Trp Val1 5 10 15Arg Ala Glu Ser Asn Arg Thr Glu Val Asp Leu Ile Phe Pro Arg Asn 20 25 30Asp Thr Phe Ala Pro Met Pro Leu Met Pro Val Val Phe Ala Val Gln 35 40 45Ala Pro Ser Val Ala His Lys Val Asn Thr Tyr Ile Glu Tyr Gly Tyr 50 55 60Tyr Pro Val Gly Arg Pro Asn Glu Thr Val Ile Gly Gln Thr Asp His65 70 75 80Val Ser Asp Ser Thr Asn Glu Thr Thr Tyr Phe Ser Val Ser Gly Ile 85 90 95Gly Arg Thr Phe Asn Thr Thr Gly Ser Trp Glu Leu Phe Trp Arg Leu 100 105 110Arg Trp Thr Asn Cys Ser Ile Ser Glu Asp Ser Arg Tyr Tyr Asn Gln 115 120 125Ser Tyr Pro Trp Ile Ser Ser Pro Tyr Ile Asp Gly Ser Leu Asn Ile 130 135 140Asp Lys Val Tyr Glu Gly Phe His Tyr Thr Ala Tyr Asn Val Ile Val145 150 155 160Asp Arg Val Thr Phe Ser Thr Arg Glu Asp Ala Ser Gln Pro Asn Leu 165 170 175Thr Thr Leu Thr Asn Ser Glu Asn Cys Asp Lys Val Ser Ser Leu Ala 180 185 190Leu Leu Ser Ile Val Asp Ser Leu Arg Ile Pro Pro Gln Leu Pro Gln 195 200 205Glu Asp Ile Asp Thr Val Ser Met Cys Pro Gln Leu Ala Asp Ala Arg 210 215 220Leu Asn Ser Thr Ser Thr Ser Ser Pro Cys Ser Val Ser Ile Ser Pro225 230 235 240Glu Val Glu Ser Asn Ile Leu Ala Lys Ile Ala Asp Asn Glu Cys Asn 245 250 255Asn Ala Leu His Pro Ala Val Ser Cys Thr Thr Glu Glu Thr Lys Glu 260 265 270Gly Ser Ala Ser Ser His Asp His Gly His Ala Val Trp Leu Val Ile 275 280 285Thr Leu Ala Phe Ala Phe Leu Phe 290 295158310PRTAspergillus niger 158Met Gly Gly Arg Asp Val Ala Ile Leu Ser Arg His Phe Ala Val Thr1 5 10 15Ser Ser Gln Ser Val Asn Gly Val Val Ser Gly Met Phe Gln His Thr 20 25 30Val Thr Ser Ser Pro Ser Phe Thr Thr Asn Gln Phe Phe Lys Lys Lys 35 40 45Phe Thr Ala Ala Ile Ala Thr Ala Ile Phe Ala Ser Val Ala Val Ala 50 55 60Ala Pro Gln Arg Gly Leu Glu Ala Arg Leu Lys Ala Arg Gly Ser Ser65 70 75 80Lys Gly Ser Arg Pro Leu Gln Ala Val Ala Arg Pro Ala Ser Thr Lys 85 90 95Asn Gln Thr Asn Val Glu Tyr Ser Ser Asn Trp Ser Gly Ala Val Leu 100 105 110Val Glu Pro Pro Ser Ala Ala Ala Thr Tyr Thr Ala Val Thr Gly Thr 115 120 125Phe Thr Val Pro Glu Pro Thr Gly Asn Ser Gly Gly Ser Gln Ala Ala 130 135 140Ser Ala Trp Val Gly Ile Asp Gly Asp Thr Tyr Gly Asn Ala Ile Leu145 150 155 160Gln Thr Gly Val Asp Phe Thr Val Thr Asp Gly Glu Ala Ser Phe Asp 165 170 175Ala Trp Tyr Glu Trp Tyr Pro Asp Tyr Ala Tyr Asp Phe Ser Gly Ile 180 185 190Asp Ile Ser Ala Gly Asp Glu Ile Val Ala Ile Val Glu Ser Tyr Thr 195 200 205Ser Thr Thr Gly Ile Ala Ile Ile Glu Asn Lys Ser Thr Gly Gln Lys 210 215 220Val Ser Lys Glu Leu Ser Ser Ser Ser Ser Leu Gly Gly Gln Asn Ala225 230 235 240Glu Trp Ile Val Glu Asp Phe Glu Glu Asn Gly Ser Leu Val Asn Leu 245 250 255Val Asp Phe Gly Thr Val Thr Phe Thr Gly Ala Val Ala Lys Ala Ala 260 265 270Gly Gly Glu Ser Val Gly Leu Thr Asp Ala Thr Ile Ile Glu Ile Glu 275 280 285Glu Asn Gly Gln Val Val Thr Asp Val Thr Ile Asp Ser Asp Ser Glu 290 295 300Val Thr Ile Thr Tyr Glu305 310159681PRTAspergillus niger 159Met Arg Cys Ser Leu Ile Ser Leu Leu Gly Leu Ala Ala Ile Pro Ala1 5 10 15Leu Gly Gly Cys Pro Phe Ala His Thr Ala Asn Met Gly Ile Asp Asn 20 25 30Met Val Lys Ala His Ala His Met Ser Arg Pro Leu Ile Ala Ser Lys 35 40 45Ser Ser Pro Ser Thr Val Pro Thr Ser Ser Ser Thr Pro Ser Val Gly 50 55 60Gln Lys Gly Val Phe Met Met Asn Arg Ile Ala Pro Gly Thr Ser Glu65 70 75 80Leu Tyr Ile Ala Asn Thr Asp Gly Ser Asn Glu Arg Pro Leu Leu Ser 85 90 95Asn Pro Val Tyr Glu Tyr His Ala Ser Phe Ser Pro Asp Val Glu Trp 100 105 110Ile Thr Phe Thr Ser Glu Arg Asn Gly Asp Gly Asn Ser Asp Ile Tyr 115 120 125Arg Val Arg Thr Asn Gly Ser Asp Leu Gln Glu Leu Val Ala Thr Pro 130 135 140Ala Val Glu Asp Ser Val Val Ile Ser Pro Asn Gly Arg Leu Ala Ala145 150 155 160Tyr Val Ser Thr Ala Asn Asn Met Lys Ala Asn Ile Trp Ile Leu Asp 165 170 175Leu Gln Thr Gly Ala Gln Trp Asn Leu Thr Asn Thr Pro Thr Thr Ala 180 185 190Ala Asn Ser Ser Leu Met Glu Ser Tyr Leu Arg Pro Ala Trp Ser Pro 195 200 205Asp Gly Glu Trp Ile Ala Phe Ser Ser Asp Arg Asn Thr Gln Trp Asp 210 215 220Gly His Gly Val Pro Thr Phe Leu Gly Arg Thr Gly Trp Glu Thr Thr225 230 235 240Gln Glu Leu Ser Leu Tyr Ala Ile Arg Pro Asn Gly Ser Asp Phe Arg 245 250 255Gln Ile Ile Ser Lys Pro Tyr Tyr Ser Leu Gly Ser Pro Lys Trp Ser 260 265 270Ala Asp Gly Lys Arg Ile Val Tyr Tyr Glu Met Thr Arg Glu Asp Thr 275 280 285Tyr Asn Ala His Arg Pro Glu Thr Ile Thr Thr Ala Asn Ser Thr Ile 290 295 300Met Ser Val Asp Phe Glu Thr Gly Thr Asp Val Arg Val Glu Val Ala305 310 315 320Gly Ser Gly Val Lys Gln Phe Pro Gln Tyr Leu Asp Lys Asn Gly Thr 325 330 335Ile Ala Tyr Thr Leu Lys Gly Gly Thr Ser Glu Gly Phe Tyr Thr Thr 340 345 350Ala Gly Leu Tyr Val Asn Thr Thr Ser Ala Thr Leu Arg Ser Pro Ala 355 360 365Trp Ser Pro Asp Gly Lys Gln Val Val Tyr Glu Lys Ser Thr Trp Ser 370 375 380Ile Arg Ser Gly Tyr Lys Gln Leu Tyr Ser Trp Asp Ser Asp Trp Asp385 390 395 400Tyr Arg Phe Thr Asp Val Phe Pro Gln Val Ser His Gln Glu Arg Val 405 410 415Ala Ile Thr Gln Lys Gln Leu Gly Asn Ser Ser Ile Val Thr Leu Asn 420 425 430Thr Thr Gly Gly Asp Leu Gln Leu Val Tyr Asp Pro Ser Thr Ala Asp 435 440 445Phe Val Ser Asp Asp Glu Thr Thr Gly Leu Ser Ala Tyr Gln Pro Ser 450 455 460Trp Ser Pro Cys Gly Glu Trp Leu Val Phe Gly Val Gly Phe Trp Phe465 470 475 480Glu Thr Arg Glu Ala Ser Gly Gly Trp Ile Val Arg Ala Thr Ala Asn 485 490 495Gly Ser Tyr Ser Glu Val Leu Val Asn Ser Ser Tyr Ser Ile Thr Glu 500 505 510Asp Gly Ala Leu Asn Ser Gly Phe Pro Ser Phe Ser Pro Asp Gly Lys 515 520 525Lys Val Val Tyr Arg Val Trp Gly Ala Asp Thr Ala Thr Tyr Gly Asn 530 535 540Ala Ser Glu Ile Gly Leu Arg Val Leu Asp Leu Glu Thr Arg Lys Thr545 550 555 560Thr Val Leu Thr Thr Glu Trp Asp Asn Leu Pro Gln Phe Ser Pro Asp 565 570 575Gly Glu Leu Ile Leu Phe Thr Arg Lys Thr Ser Thr Tyr Asn Tyr Asp 580 585 590Val Cys Thr Ile Arg Pro Asp Gly Thr Asp Leu Arg Val Leu Thr Ser 595 600 605Ser Gly Ala Asn Asp Ala His Ala Val Trp Ser Gln Asp Gly Arg Ile 610 615 620Met Trp Ser Thr Gly Met Tyr Gly Phe Arg Phe Glu Cys Ala Leu Tyr625 630 635 640Gly Asp Thr Phe Gln Pro Tyr Gly Gln Val Met Ile Met Asp Ala Asp 645 650 655Gly Gly Asn Lys Lys Leu Met Thr Asn Ser Met Trp Glu Asp Ser Met 660 665 670Pro Leu Phe Leu Pro Arg Glu Val Leu 675 680160624PRTAspergillus niger 160Met Pro Pro Asp Ala Lys Ser Pro Gly Tyr Gln Pro Gly Met Ala Val1 5 10 15Leu Pro Ser Arg Pro His Pro Ala Lys Gly Lys Ala Ile Arg Phe Leu 20 25 30Leu Ser Leu Ala Leu Val Ala Phe Ala Ile Val Gln Leu Cys Gly Asn 35 40 45Phe His Lys Asn Arg Ser Val Glu Gln Gln Leu Gln Ser Gln Thr Leu 50 55 60Asp Asp Glu Ser Phe Lys Trp Glu Asp Val Thr Pro Thr Lys Gln Leu65 70 75 80Val Tyr His Pro Cys Phe Gly Asp His Glu Cys Ala Arg Leu Ser Leu 85 90 95Pro Met Asn Trp Asn Arg Thr Asp Gly Glu Gly Ser Lys Ile Ala Leu 100 105 110Ala Val Ile Lys Leu Pro Ala Lys Val Pro Val Thr Asp Ala Arg Tyr 115 120 125Gly Gly Ala Ile Leu Leu Asn Pro Gly Gly Pro Gly Gly Ser Gly Val 130 135 140Ser Met Val Phe Arg Tyr Gly Lys Ala Ile Gln Thr Ile Val Asp Ser145 150 155 160Pro Glu Ser Pro Ser Ala Asp Ser Ala Ser Gly Lys Tyr Phe Asp Val 165 170 175Val Ser Phe Asp Pro Arg Gly Val Asn Asn Thr Thr Pro Asn Phe Ser 180 185 190Cys Phe Pro Asp Pro Ala Thr Arg Lys Ala Trp Leu Leu Gln Ser Glu 195 200 205Ala Glu Gly Leu Leu Gly Ser Ser Glu Gly Val Phe Asp Thr Arg Trp 210

215 220Ala Arg Tyr Glu Ala Phe Glu Arg Leu Leu Ser Thr Ala Pro Asn Thr225 230 235 240Phe Pro Val Gly Thr Asn Val Asp Ala Glu Arg Ile Arg Leu His Asn 245 250 255Arg Trp Lys Lys Gly Glu Glu Lys Leu Leu Tyr Trp Gly Phe Ser Tyr 260 265 270Gly Thr Ile Leu Gly Ser Thr Phe Ala Ala Met Gln Pro His Arg Ile 275 280 285Asn Arg Ala Val Ile Asp Gly Val Cys Asn Ala Asp Asp Tyr Tyr Ala 290 295 300Gly Asn Trp Leu Thr Asn Leu Gln Asp Ser Asp Ala Ala Phe Asn Lys305 310 315 320Phe Phe Glu Tyr Cys Tyr Thr Ala Gly Pro Ser Ala Cys Pro Phe Ala 325 330 335Leu Gly Gly Asp Pro Glu Asp Leu Lys Ser Arg Tyr Glu Gln Ile Leu 340 345 350Thr Asn Leu Thr Ser Ser Pro Ile Ala Val Ser Pro Ser Gly Asn Arg 355 360 365Gly Pro Glu Ile Ile Thr Tyr Ser Asp Val Lys Ser Leu Val Val Gln 370 375 380Ala Leu Tyr Val Pro Leu Lys Leu Phe Asp Leu Val Ala Arg Leu Leu385 390 395 400Ala Glu Leu Glu Gln Gly Asn Gly Ser Ser Phe Ala Asp Leu Lys Tyr 405 410 415Glu Ala Lys Gln Trp Pro Val Pro Pro Pro Cys Asp Ser Ser Ser Thr 420 425 430Gln Tyr Lys Val Pro Gly Glu Ser Asp Gln Glu Ala Gly Arg Asn Ile 435 440 445Leu Cys Thr Asp Gly Pro Gly Leu Asp Gly Thr Ala Lys Glu Asp Phe 450 455 460Arg Ser Tyr Trp Asn Met Leu Arg Gly Gln Ser Lys Ala Val Gly Asp465 470 475 480Phe Trp Ala Glu Val Arg Met Ser Cys Val Lys Leu Glu Thr Arg Pro 485 490 495Glu Trp Arg Tyr Asp Gly Met Arg Ile Gln Gly Pro Phe Ala Gly Asn 500 505 510Thr Ser His Pro Leu Leu Phe Ile Gly Asn Thr Tyr Asp Pro Val Thr 515 520 525Pro Leu Arg Asn Ala His Thr Met Ala Arg Gly Phe Pro Glu Ser Ile 530 535 540Val Leu Glu Gln Asn Ser Val Gly His Cys Thr Leu Ser Gly Pro Ser545 550 555 560Leu Cys Thr Ala Lys Ala Ile Arg Gln Tyr Phe Gln Thr Gly Glu Leu 565 570 575Pro Asp Pro Gly Thr Val Cys Gln Val Glu Glu Leu Pro Phe Arg Leu 580 585 590Ala Gly Tyr Glu Arg Ser Gln Val Met Ser Pro Gly Asp Thr Glu Leu 595 600 605Met Ser Ala Leu His Ser Leu Ser Glu Phe Arg His Leu Leu Gly Ala 610 615 620161554PRTAspergillus niger 161Met Leu Ser Ser Leu Leu Leu Gly Gly Leu Leu Gly Leu Ala Thr Ala1 5 10 15Gln Phe Pro Pro Glu Pro Glu Gly Ile Thr Val Leu Lys Ser Lys Leu 20 25 30His Glu Asn Val Thr Ile Ser Phe Lys Glu Pro Gly Ile Cys Glu Thr 35 40 45Thr Pro Gly Val Arg Ser Tyr Ser Gly Tyr Val His Leu Pro Pro Ala 50 55 60Ser Thr Ser Phe Phe Trp Phe Phe Glu Ala Arg Lys Asp Pro Ser Asn65 70 75 80Ala Pro Leu Ala Ile Trp Leu Asn Gly Gly Pro Gly Gly Ser Ser Leu 85 90 95Met Gly Leu Leu Glu Glu Leu Gly Pro Cys Ser Ile Ala Ser Asp Ser 100 105 110Lys Thr Thr Val Leu Asn Pro Trp Ser Trp Asn Asn Glu Val Asn Leu 115 120 125Leu Phe Leu Asp Gln Pro Thr Gln Val Gly Phe Ser Tyr Asp Val Pro 130 135 140Thr Asn Gly Thr Leu Thr Ala Asn Gly Thr Ala Phe Ala Ala His Ala145 150 155 160Leu Trp His Phe Ala Gln Thr Trp Phe Phe Glu Phe Pro His Tyr Lys 165 170 175Pro Asn Asp Asp Arg Val Ser Leu Trp Ala Glu Ser Tyr Gly Gly His 180 185 190Tyr Gly Pro Gly Ile Phe Arg Phe Phe Gln Gln Gln Asn Asp Lys Ile 195 200 205Ala Glu Gly Thr Ala Glu Asp Gly Ala Gln Tyr Leu His Leu Asp Thr 210 215 220Leu Gly Ile Val Asn Gly Leu Met Asp Met Val Ile Gln Glu Glu Ala225 230 235 240Tyr Ile Thr Trp Pro Tyr Asn Asn Val Arg Leu Ala Pro Ser Ser Phe 245 250 255Asn Ser Arg Gly Phe Arg Asp Gln Ala Leu Ala Cys Glu Ala Ala Leu 260 265 270Lys Glu Arg Asp Ser Gly Leu Pro His Ser Gly Lys Asn Ile Ser Glu 275 280 285Ile Cys Gly Gly Leu Ala Leu Glu Trp Gly Asp Gly Pro Ile Thr Tyr 290 295 300Tyr His Thr Phe Asn Arg Gly Trp Tyr Asp Ile Ala His Pro Lys Asn305 310 315 320Asp Pro Phe Pro Ala Lys His Met Leu Gly Tyr Leu Thr Gln Glu Ser 325 330 335Val Leu Ala Ala Leu Gly Val Pro Val Asn Phe Thr Ser Ser Ser Ser 340 345 350Ala Val Ala Thr Gln Phe Ile Lys Thr Phe Asp Ile Val His Gly Gly 355 360 365Phe Leu Asp Ala Ile Gly Tyr Leu Leu Asp Ser Gly Val Lys Val His 370 375 380Met Met Tyr Gly Asp Arg Asp Tyr Ala Cys Asn Trp Val Gly Gly Glu385 390 395 400Lys Ala Ser Leu Ala Val Pro Tyr Ser Arg Ile Thr Glu Phe Ala Asp 405 410 415Thr Gly Tyr Ser Pro Leu Leu Thr Pro Asp Gly Ile Ser Gly Met Thr 420 425 430Arg Gln Leu Gly Asn Tyr Ser Phe Thr Arg Val Phe Gln Ala Gly His 435 440 445Glu Val Pro Ser Tyr Gln Pro Val Ala Ala Tyr Glu Ile Phe Met Arg 450 455 460Ala Thr Phe Asn Lys Asp Ile Pro Thr Gly Leu Leu Ala Val Asp Asp465 470 475 480Glu Phe Gln Ser Val Gly Pro Lys Asp Thr Trp His Ile Lys Asn Ile 485 490 495Pro Pro Ile Met Pro Lys Pro Gln Cys Tyr Val Leu Ser Pro Gly Thr 500 505 510Cys Thr Pro Glu Val Trp Glu Thr Val Leu Asn Gly Ser Ala Thr Val 515 520 525Lys Asp Trp Tyr Val Val Asp Asp Ser Ala Gly Val Glu Asp His Glu 530 535 540Gly Phe Ser Ile Leu Gly Gly Asp Glu Leu545 550162578PRTAspergillus niger 162Met Thr Arg Phe Gln Leu Leu Pro Leu Val Ala Gly Leu Leu Ala Pro1 5 10 15Ser Ile Ala Ala Leu Ser Ile Pro Ser Pro Gln Gln Ile Leu Asp Ser 20 25 30Leu Thr Phe Gly Glu His Thr Asp Gly Phe Cys Pro Leu Ala Pro Lys 35 40 45Val Glu Val Pro Asp Asp Gly Phe Phe Pro Ala Leu Lys Phe Val Glu 50 55 60Asp Ala Ser Phe Lys Ser Arg Gln Val Asn Arg Leu Ser Arg Ala Val65 70 75 80Gln Val Pro Thr Ala Ile Asp Asp Tyr Met Lys Asp Pro Tyr Asp Glu 85 90 95Lys Phe Ala Pro Phe Leu Asp Phe Gln Lys Leu Leu Gln Thr Leu Phe 100 105 110Pro Leu Thr His Ser Tyr Ala Arg Val Asp His Ile Asn Arg Phe Gly 115 120 125Leu Val Phe Thr Leu Asn Gly Thr Asp Asp Ser Leu Lys Pro Leu Leu 130 135 140Phe Thr Ala His Gln Asp Val Val Pro Ile Asn Asp Pro Ala Asp Trp145 150 155 160Thr Tyr Pro Pro Phe Asp Gly His Tyr Asp Gly Glu Trp Leu Trp Gly 165 170 175Arg Gly Ala Ser Asp Cys Lys Asn Val Leu Ile Gly Leu Met Ser Val 180 185 190Val Glu Asp Leu Leu Ser Gln Lys Trp Glu Pro Thr Arg Thr Val Val 195 200 205Leu Ala Phe Gly Phe Asp Glu Glu Ser His Gly Phe Leu Gly Ala Gly 210 215 220Ser Ile Ala Lys Phe Leu Glu Lys Lys Tyr Gly Pro Asp Ser Phe Glu225 230 235 240Phe Ile Leu Asp Glu Gly Gly Met Gly Leu Glu Val Leu Asp Asp Asn 245 250 255Asn Asn Gly Val Val Tyr Ala Leu Pro Gly Val Gly Glu Lys Gly Ser 260 265 270Ile Asp Val Val Leu Thr Leu Ala Val Pro Gly Gly His Ser Ser Val 275 280 285Pro Pro Pro His Thr Gly Ile Gly Ile Ile Ala Glu Ile Ile Tyr Glu 290 295 300Leu Glu Arg Gln Asp Leu Phe Val Pro Val Leu Asp Thr His His Pro305 310 315 320Thr Arg Lys Met Leu Glu Cys Gln Val Arg His Ser Pro Ser Gln Val 325 330 335Glu Pro Trp Leu Ala Ser Ala Leu Gln Ser Ser Asp Tyr Ile Ser Leu 340 345 350Ala Glu Lys Leu Ala Ser Ser Arg Gly Asp Lys Phe Arg Phe Ile Leu 355 360 365Gln Thr Ser Gln Ala Ala Asp Ile Ile Asn Gly Gly Val Lys Ser Asn 370 375 380Ala Leu Pro Glu Lys Ile Asn Ala Leu Val Asn Tyr Arg Ile Ala Leu385 390 395 400His Gln Thr Pro Asp Asp Ile Lys Asn Arg Ala Val Glu Ile Ile Ser 405 410 415Pro Ile Val Lys Lys Tyr Asn Leu Ser Leu Thr Ala Phe Pro Glu Ser 420 425 430Asp Thr Val Asp Pro Ser Leu Asn Asn His Leu Thr Leu Thr Thr Leu 435 440 445Ser Gly Ala Leu Ser Pro Ala Pro Val Ser Pro Thr Asp Ile Asp Thr 450 455 460Asp Ala Val Trp Ala Arg Phe Ser Gly Val Thr Arg Ser Val Phe Glu465 470 475 480Ser Val Pro Ser Leu Glu Gly Arg Lys Val Val Val Ser Gly Asp Ile 485 490 495Met Thr Gly Asn Thr Asp Thr Arg Phe Tyr Trp Ala Leu Ser Arg Asn 500 505 510Ile Tyr Arg Trp Ser Pro Ser Arg Ala Gly Lys Ala Leu Asn Ile His 515 520 525Thr Val Asp Glu Arg Ile Asp Ile Asp Ile His Leu Glu Ala Met Met 530 535 540Leu Tyr Tyr Asp Leu Ile Arg Ser Phe Asp Gly Arg Thr Asp Ser Ser545 550 555 560Val Ile Ser Ala Ala Ser Ala Ala Ala Asp Asp Glu Leu Ala His Asp 565 570 575Val Leu163456PRTAspergillus niger 163Met Lys Ser Thr Thr Leu Leu Ser Leu Ala Trp Ala Ala Gln Ser Ala1 5 10 15Tyr Ser Leu Ser Ile His Glu Arg Asp Glu Pro Ala Thr Leu Gln Phe 20 25 30Asn Phe Glu Arg Arg Gln Ile Ala Asp Arg Ser Arg Arg Lys Arg Ser 35 40 45Thr Ala Ser Ala Asp Leu Val Asn Leu Ala Thr Asn Leu Gly Tyr Thr 50 55 60Met Asn Leu Thr Leu Gly Thr Pro Gly Gln Glu Val Ser Val Thr Leu65 70 75 80Asp Thr Gly Ser Ser Asp Leu Trp Val Asn Gly Ala Asn Ser Ser Val 85 90 95Cys Pro Cys Thr Asp Tyr Gly Ser Tyr Asn Ser Ser Ala Ser Ser Thr 100 105 110Tyr Thr Phe Val Asn Asp Glu Phe Tyr Ile Gln Tyr Val Asp Gly Ser 115 120 125Glu Ala Thr Gly Asp Tyr Val Asn Asp Thr Leu Lys Phe Ser Asn Val 130 135 140Thr Leu Thr Asn Phe Gln Phe Ala Val Ala Tyr Asp Gly Asp Ser Glu145 150 155 160Glu Gly Val Leu Gly Ile Gly Tyr Ala Ser Asn Glu Ala Ser Gln Ala 165 170 175Thr Val Gly Gly Gly Glu Tyr Thr Asn Phe Pro Glu Ala Leu Val Asp 180 185 190Gln Gly Ala Ile Asn Trp Pro Ala Tyr Ser Leu Trp Leu Asp Asp Leu 195 200 205Asp Glu Gly Lys Gly Thr Ile Leu Phe Gly Gly Val Asn Thr Ala Lys 210 215 220Tyr Tyr Gly Ser Leu Gln Thr Leu Pro Ile Val Ser Ile Glu Asp Met225 230 235 240Tyr Val Glu Phe Ala Val Asn Leu Thr Ala Val His Leu Glu Lys Asn 245 250 255Gly Asn Ser Val Ser Val Asn Asn Ser Ala Thr Gln Phe Pro Ile Pro 260 265 270Ala Val Leu Asp Ser Gly Thr Ala Leu Thr Tyr Ile Pro Thr Ser Ala 275 280 285Ala Ala Ser Ile Tyr Glu Ala Val Gly Ala Gln Tyr Leu Ser Glu Tyr 290 295 300Gly Tyr Gly Val Ile Glu Cys Asp Val Lys Asp Glu Asp Phe Thr Phe305 310 315 320Leu Phe Asp Phe Gly Ser Phe Asn Met Ser Val Asp Ile Ser Glu Met 325 330 335Ile Leu Glu Ala Ser Ser Asp Met Thr Asp Met Asn Val Cys Thr Phe 340 345 350Gly Leu Ala Val Ile Glu Asn Glu Ala Leu Leu Gly Asp Thr Phe Leu 355 360 365Arg Ser Ala Tyr Val Val Tyr Asp Leu Gly Asn Asn Glu Ile Ser Leu 370 375 380Ala Lys Ala Asn Phe Asn Pro Gly Glu Asp His Val Leu Glu Ile Gly385 390 395 400Thr Gly Ser Asp Ala Val Pro Lys Ala Thr Gly Ala Thr Ala Thr Gly 405 410 415Ala Ala Ala Thr Ser Thr Ala Ser Ser Asp Lys Ser Asp Lys Glu Ser 420 425 430Ser Ala Thr Val Pro Arg Ser Gln Ile Val Ser Leu Val Ala Gly Val 435 440 445Leu Val Gly Val Phe Leu Val Leu 450 455164664PRTAspergillus niger 164Met Leu Val Arg Gln Leu Ala Leu Ala Leu Ala Ile Ala Ala Leu Ser1 5 10 15Asp Ala Ile Pro Thr Ser Ile Lys His Val Leu His Glu Lys Arg His 20 25 30Lys Pro Ala Ser Asp Trp Val Lys Gly Ala Arg Val Glu Ser Asp Ala 35 40 45Val Leu Pro Met Arg Ile Gly Leu Ala Gln Asn Asn Leu Asp Lys Gly 50 55 60Tyr Asp Phe Leu Met Glu Val Ser Asp Pro Lys Ser Ser Lys Tyr Gly65 70 75 80Gln Tyr Trp Ser Ala Asp Glu Val His Asp Ile Phe Ser Pro Ser Glu 85 90 95Glu Ala Val Glu Ala Val Arg Glu Trp Leu Val Ala Ser Gly Ile His 100 105 110Pro Ser Arg Val Val His Ser Asp Asn Lys Gly Trp Leu Ala Phe Asp 115 120 125Ala Tyr Ala His Glu Ala Glu Arg Leu Phe Met Thr Glu Phe His Glu 130 135 140His Glu Ser Asp Arg Ser Ala Lys Ile Arg Val Gly Cys Asp Gln Tyr145 150 155 160His Val Pro Glu His Ile Gln Lys His Ile Asp Tyr Ile Thr Pro Gly 165 170 175Val Lys Leu Thr Gln Val Val Lys Arg Thr Asn Lys Val Lys Arg Ala 180 185 190Ser Gln Leu Ala His Ser Ser Lys Ala Lys Ser Ala Ala Gln Gly Pro 195 200 205Gln Pro Leu Pro Asn Lys Ala Lys Phe Leu Pro Glu Asp Leu Arg Gly 210 215 220Cys Gly Tyr Asn Ile Thr Pro Ser Cys Ile Lys Ala Leu Tyr Gln Ile225 230 235 240Pro Asp Ala Lys Thr Ala Thr Pro Asn Asn Ser Leu Gly Leu Tyr Glu 245 250 255Gln Gly Asp Tyr Phe Ala Lys Ser Asp Leu Asp Leu Phe Tyr Lys Glu 260 265 270Tyr Ala Pro Trp Val Pro Gln Gly Thr Tyr Pro Ile Pro Ala Leu Ile 275 280 285Asp Gly Ala Asn Tyr Ser Val Pro Ser Tyr Ser Ser Leu Asn Thr Gly 290 295 300Glu Ser Asp Ile Asp Ile Asp Met Ala Tyr Ser Leu Leu Tyr Pro Gln305 310 315 320Gln Val Thr Leu Tyr Gln Val Asp Asp Gln Leu Tyr Glu Pro Val Glu 325 330 335Val Asp Thr Thr Asn Leu Phe Asn Thr Phe Leu Asp Ala Leu Asp Gly 340 345 350Ser Tyr Cys Thr Tyr Ser Ala Tyr Gly Glu Thr Gly Asp Asp Pro Ser 355 360 365Ile Asp Pro Val Tyr Pro Asp Thr Arg Pro Gly Gly Tyr Lys Gly Lys 370 375 380Leu Gln Cys Gly Val Tyr Lys Pro Thr Asn Val Ile Ser Ala Ser Tyr385 390 395 400Gly Gln Ser Glu Ala Asp Leu Pro Val Ser Tyr Thr Lys Arg Gln Cys 405 410 415Asn Glu Phe Met Lys Leu Gly Leu Gln Gly His Ser Ile Leu Phe Ala 420 425 430Ser Gly Asp Tyr Gly Val Ala Ser Phe Ala Gly Asp Gly Asp Glu Asn 435 440 445Gly Cys Leu Gly Pro Glu Gly Lys Ile Phe Asn Pro Gln Tyr Pro Ser 450 455 460Asn Cys Pro Tyr Val Thr Ser Val Gly Gly Thr

Met Leu Tyr Gly Tyr465 470 475 480Gln Thr Val Asn Asp Ser Glu Ser Val Met His Val Asn Leu Gly Gly 485 490 495Thr Ala Ser Asn Phe Ser Thr Ser Gly Gly Phe Ser Asn Tyr Phe Pro 500 505 510Gln Pro Ala Tyr Gln Phe Ala Ala Val Glu Gln Tyr Phe Gln Ser Ala 515 520 525Asn Leu Ser Tyr Pro Tyr Tyr Ser Glu Phe Glu Val Asp Val Asn Thr 530 535 540Thr Lys Gly Leu Tyr Asn Arg Leu Gly Arg Ala Tyr Pro Asp Val Ser545 550 555 560Ala Asn Gly Ala His Phe Arg Ala Tyr Met Asp Gly Tyr Asp Tyr His 565 570 575Trp Tyr Gly Ser Ser Leu Ala Ser Pro Leu Phe Ala Ser Val Leu Thr 580 585 590Leu Leu Asn Glu Glu Arg Phe Ala Ile Gly Lys Gly Pro Val Gly Phe 595 600 605Val Asn Pro Val Leu Tyr Ala Tyr Pro Gln Val Leu Asn Asp Ile Thr 610 615 620Asn Gly Thr Asn Ala Gly Cys Gly Thr Tyr Gly Phe Ser Ala Ile Glu625 630 635 640Gly Trp Asp Pro Ala Ser Gly Leu Gly Thr Pro Asn Tyr Pro Leu Met 645 650 655Lys Glu Leu Phe Leu Ser Leu Pro 660165520PRTAspergillus niger 165Met Arg Val Thr Thr Ala Ile Ala Ser Leu Leu Leu Val Gly Ser Ala1 5 10 15Thr Ser Leu Gln Asn Pro His Arg Arg Ala Val Pro Pro Pro Leu Ser 20 25 30His Arg Ser Val Ala Ser Arg Ser Val Pro Val Glu Arg Arg Thr Thr 35 40 45Asp Phe Glu Tyr Leu Thr Asn Lys Thr Ala Arg Phe Leu Val Asn Gly 50 55 60Thr Ser Ile Pro Glu Val Asp Phe Asp Val Gly Glu Ser Tyr Ala Gly65 70 75 80Leu Leu Pro Asn Thr Pro Thr Gly Asn Ser Ser Leu Phe Phe Trp Phe 85 90 95Phe Pro Ser Gln Asn Pro Glu Ala Ser Asp Glu Ile Thr Ile Trp Leu 100 105 110Asn Gly Gly Pro Gly Cys Ser Ser Leu Asp Gly Leu Leu Gln Glu Asn 115 120 125Gly Pro Phe Leu Trp Gln Pro Gly Thr Tyr Lys Pro Val Pro Asn Pro 130 135 140Tyr Ser Trp Thr Asn Leu Thr Asn Val Val Tyr Ile Asp Gln Pro Ala145 150 155 160Gly Thr Gly Phe Ser Pro Gly Pro Ser Thr Val Asn Asn Glu Glu Asp 165 170 175Val Ala Ala Gln Phe Asn Ser Trp Phe Lys His Phe Val Asp Thr Phe 180 185 190Asp Leu His Gly Arg Lys Val Tyr Ile Thr Gly Glu Ser Tyr Ala Gly 195 200 205Met Tyr Val Pro Tyr Ile Ala Asp Ala Met Leu Asn Glu Glu Asp Thr 210 215 220Thr Tyr Phe Asn Leu Lys Gly Ile Gln Ile Asn Asp Pro Ser Ile Asn225 230 235 240Ser Asp Ser Val Met Met Tyr Ser Pro Ala Val Arg His Leu Asn His 245 250 255Tyr Asn Asn Ile Phe Gln Leu Asn Ser Thr Phe Leu Ser Tyr Ile Asn 260 265 270Ala Lys Ala Asp Lys Cys Gly Tyr Asn Ala Phe Leu Asp Lys Ala Ile 275 280 285Thr Tyr Pro Pro Pro Ser Pro Phe Pro Thr Ala Pro Glu Ile Thr Glu 290 295 300Asp Cys Gln Val Trp Asp Glu Val Val Met Ala Ala Tyr Asp Ile Asn305 310 315 320Pro Cys Phe Asn Tyr Tyr His Leu Ile Asp Phe Cys Pro Tyr Leu Trp 325 330 335Asp Val Leu Gly Phe Pro Ser Leu Ala Ser Gly Pro Asn Asn Tyr Phe 340 345 350Asn Arg Ser Asp Val Gln Lys Ile Leu His Val Pro Pro Thr Asp Tyr 355 360 365Ser Val Cys Ser Glu Thr Val Ile Phe Ala Asn Gly Asp Gly Ser Asp 370 375 380Pro Ser Ser Trp Gly Pro Leu Pro Ser Val Ile Glu Arg Thr Asn Asn385 390 395 400Thr Ile Ile Gly His Gly Trp Leu Asp Tyr Leu Leu Phe Leu Asn Gly 405 410 415Ser Leu Ala Thr Ile Gln Asn Met Thr Trp Asn Gly Lys Gln Gly Phe 420 425 430Gln Arg Pro Pro Val Glu Pro Leu Phe Val Pro Tyr His Tyr Gly Leu 435 440 445Ala Glu Leu Tyr Trp Gly Asp Glu Pro Asp Pro Tyr Asn Leu Asp Ala 450 455 460Gly Ala Gly Tyr Leu Gly Thr Ala His Thr Glu Arg Gly Leu Thr Phe465 470 475 480Ser Ser Val Tyr Leu Ser Gly His Glu Ile Pro Gln Tyr Val Pro Gly 485 490 495Ala Ala Tyr Arg Gln Leu Glu Phe Leu Leu Gly Arg Ile Ser Ser Leu 500 505 510Ser Ala Lys Gly Asn Tyr Thr Ser 515 520166551PRTAspergillus niger 166Met Arg Gly Ser Arg Leu Val Leu Leu Leu Pro Leu Ala Ala Leu Ser1 5 10 15Cys Ala Met Pro Glu Asn Glu Trp Ser Ser Thr Ile Arg Arg Gln Leu 20 25 30Pro Lys Ala Ser Thr Gly Val Lys Ser Ile Lys Thr Pro Asn Asn Val 35 40 45Thr Ile Arg Tyr Lys Glu Pro Gly Thr Glu Gly Ile Cys Glu Thr Thr 50 55 60Pro Gly Val Lys Ser Tyr Ser Gly Tyr Val Asp Leu Ser Pro Glu Ser65 70 75 80His Thr Phe Phe Trp Phe Phe Glu Ser Arg Arg Asp Pro Glu Asn Asp 85 90 95Pro Val Thr Leu Trp Leu Asn Gly Gly Pro Gly Ser Asp Ser Leu Ile 100 105 110Gly Leu Phe Glu Glu Leu Gly Pro Cys His Ile Thr Pro Glu Tyr Glu 115 120 125Ser Ile Ile Asn Gln Tyr Ser Trp Asn Glu Val Thr Asn Leu Leu Phe 130 135 140Leu Ser Gln Pro Leu Gly Val Gly Phe Ser Tyr Ser Glu Thr Glu Ala145 150 155 160Gly Ser Leu Asn Pro Phe Thr Gly Ala Val Glu Asn Ala Ser Phe Ala 165 170 175Gly Val Gln Gly Arg Tyr Pro Val Ile Asp Ala Thr Ile Ile Asp Thr 180 185 190Thr Asp Ile Ala Ala Arg Ala Thr Trp Glu Val Leu Gln Gly Phe Leu 195 200 205Ser Gly Leu Ser Gln Leu Asp Ser Glu Val Lys Ser Lys Glu Phe Asn 210 215 220Leu Trp Thr Glu Ser Tyr Gly Gly His Tyr Gly Pro Ala Phe Phe Asn225 230 235 240His Phe Tyr Glu Gln Asn Ser Lys Ile Ala Ser Gly Glu Val Asn Gly 245 250 255Val Gln Leu Asn Phe Asn Ser Leu Gly Ile Ile Asn Gly Ile Ile Asp 260 265 270Ala Ala Ile Gln Ala Asp Tyr Tyr Ala Asp Phe Ala Val Asn Asn Thr 275 280 285Tyr Gly Ile Lys Ala Val Asn Asp Thr Val Tyr Asn Tyr Met Lys Phe 290 295 300Ala Asn Thr Met Pro Asn Gly Cys Gln Asp Gln Val Ala Ser Cys Lys305 310 315 320Leu Thr Asn Arg Thr Ser Leu Ser Asp Tyr Ala Ile Cys Thr Glu Ala 325 330 335Ala Asn Met Cys Arg Asp Asn Val Glu Gly Pro Tyr Tyr Gln Phe Gly 340 345 350Gly Arg Gly Val Tyr Asp Ile Arg His Pro Tyr Asn Asp Pro Thr Pro 355 360 365Pro Ser Tyr Phe Val Asp Tyr Leu Lys Lys Asp Ser Val Met Asp Ala 370 375 380Ile Gly Val Asp Ile Asn Tyr Thr Glu Ser Ser Gly Glu Val Tyr Tyr385 390 395 400Ala Phe Gln Gln Thr Gly Asp Phe Val Trp Pro Asn Phe Ile Glu Asp 405 410 415Leu Glu Glu Ile Leu Gln Leu Pro Val Arg Val Ser Leu Ile Tyr Gly 420 425 430Asp Ala Asp Tyr Ile Cys Asn Trp Phe Gly Gly Gln Ala Ile Ser Leu 435 440 445Ala Val Asn Tyr Pro His Ala Ala Gln Phe Arg Ala Ala Gly Tyr Thr 450 455 460Pro Met Thr Val Asp Gly Val Glu Tyr Gly Glu Thr Arg Glu Tyr Gly465 470 475 480Asn Phe Ser Phe Thr Arg Val Tyr Gln Ala Gly His Glu Val Pro Tyr 485 490 495Tyr Gln Pro Ile Ala Ala Leu Gln Leu Phe Asn Arg Thr Leu Phe Gly 500 505 510Trp Asp Ile Ala Ala Gly Thr Thr Gln Ile Trp Pro Glu Tyr Ser Thr 515 520 525Asn Gly Thr Ser Gln Ala Thr His Thr Glu Ser Phe Val Pro Leu Ser 530 535 540Thr Ala Ser Ser Thr Val Asn545 550167623PRTAspergillus niger 167Met Pro Phe Pro Phe Ser Ser Ala Leu Leu Gly Tyr Ile Leu Thr Thr1 5 10 15Ser Thr Thr Leu Thr Ser Leu Val Ala Gly Gln Tyr Tyr Pro Pro Thr 20 25 30Pro Glu Asp Leu Thr Val Ile His Ser Glu Ile Phe Pro Gly Ala Arg 35 40 45Ile Ser Tyr Lys Gln Pro Leu Gly Ile Cys Thr Thr Thr Pro Ser Thr 50 55 60Pro Ser Tyr Ser Gly Tyr Ile His Leu Pro Pro His Thr Leu Thr Asn65 70 75 80Leu Ser Ile Pro Gly Ile Ser Ile Ser Gln Pro Tyr Pro Ile Asn Thr 85 90 95Phe Phe Trp Tyr Phe Pro Ser Arg His His His Asn Asn Asp Thr Ser 100 105 110Pro Leu Thr Ile Trp Met Asn Gly Gly Pro Gly Gly Ser Ser Met Ile 115 120 125Gly Leu Phe Gln Glu Asn Gly Pro Cys Thr Val Asn Thr Asp Ser Asn 130 135 140Ser Thr Ala Tyr Asn Pro Trp Ser Trp Asn Glu Tyr Val Asp Met Leu145 150 155 160Tyr Ile Glu Gln Pro Val Gln Thr Gly Phe Ser Tyr Asp Val Leu Arg 165 170 175Asn Gly Thr Leu Asp Leu Asn Glu Thr Phe Leu Val Gly Thr Leu Pro 180 185 190Ser Gln Asp Val His Gly Thr Val Asn Gly Thr Val Asn Gly Gly Arg 195 200 205Ala Leu Trp Val Ala Leu Gln Val Trp Leu Gly Glu Phe Ser Glu Tyr 210 215 220Val Ser Ser Val Asp Gly Asn Gly Gly Gly Asp Asp Arg Val Ser Ile225 230 235 240Trp Thr Glu Ser Tyr Gly Gly Arg Tyr Gly Pro Ala Tyr Thr Ala Leu 245 250 255Phe Gln Glu Met Asn Glu Arg Ile Glu Ser Gly Glu Val Ser Thr Gly 260 265 270Lys Lys Ile His Leu Asp Thr Leu Gly Ile Ile Asn Gly Cys Val Asp 275 280 285Leu Leu Val Gln Val Pro Ser Phe Pro Glu Gln Ala Tyr Asn Asn Thr 290 295 300Tyr Gly Ile Glu Gly Ile Asn Arg Thr Leu Tyr Asp Arg Ala Met Asp305 310 315 320Ser Trp Ser Lys Pro Gly Gly Cys Arg Asp Met Ile Ile Glu Cys Arg 325 330 335Asp Ala Gly Glu Leu Gly Asp Pro Leu Ile Ile Cys Glu Glu Ala Ser 340 345 350Asp Tyr Cys Ser Arg Glu Ile Lys Ser Leu Tyr Thr Asn Thr Ser Gly 355 360 365Arg Gly Tyr Tyr Asp Ile Ala His Phe Thr Pro Asp Ala Ala Leu Val 370 375 380Pro Tyr Phe Val Gly Phe Leu Asn Arg Pro Trp Val Gln Lys Ala Leu385 390 395 400Gly Val Pro Val Asn Tyr Thr Met Ser Ser Glu Ala Val Gly Asn Ser 405 410 415Phe Ala Ser Thr Gly Asp Tyr Pro Arg Asn Asp Pro Arg Gly Met Ile 420 425 430Gly Asp Ile Gly Tyr Leu Leu Asp Ser Gly Val Lys Val Ala Met Val 435 440 445Tyr Gly Asp Arg Asp Tyr Ala Cys Pro Trp Arg Gly Gly Glu Asp Val 450 455 460Ser Leu Leu Val Glu Tyr Glu Asp Ala Glu Lys Phe Arg Ala Ala Gly465 470 475 480Tyr Ala Glu Val Gln Thr Lys Ser Ser Tyr Val Gly Gly Leu Val Arg 485 490 495Gln Tyr Gly Asn Phe Ser Phe Thr Arg Val Phe Gln Ala Gly His Glu 500 505 510Val Pro Phe Tyr Gln Pro Glu Thr Ala Tyr Glu Ile Phe Asn Arg Ala 515 520 525Gln Phe Asn Trp Asp Ile Ala Thr Gly Gly Ile Ser Leu Glu Gln Asn 530 535 540Gln Ser Tyr Gly Thr Glu Gly Pro Ser Ser Thr Trp His Ile Lys Asn545 550 555 560Glu Val Pro Glu Ser Pro Glu Pro Thr Cys Tyr Leu Leu Ala Met Asp 565 570 575Ser Thr Cys Thr Asp Glu Gln Arg Glu Arg Val Leu Ser Gly Asp Ala 580 585 590Val Val Arg Asp Trp Val Val Val Asp Asp Ile Glu Ala Glu Ser Ser 595 600 605Phe Ser Gly Val Gly Asp Gln Leu Ala Gln Val Pro Leu Gly His 610 615 620168439PRTAspergillus niger 168Met Arg Thr Ser Thr Leu Leu Leu Leu Trp Ser Thr Ala Gly Ala Ala1 5 10 15Leu Ala Ser Pro Tyr Pro Leu Pro Asp Ser Gln Val Val Phe Ala Ala 20 25 30Asp His Glu Val Pro Asn Thr Gln Gly Lys His Val Val Asp Glu Ala 35 40 45Ile Leu Ser Ala Leu Asn Ala His Ser Asp Pro Val Ala Ala Met Val 50 55 60Ser Leu Arg Pro Glu Thr Ala Ala Phe Leu Ala Glu Pro Arg Leu Leu65 70 75 80His Ile Arg Gly Glu Glu Lys Ala Glu Trp Met Thr Glu Gly Asp Lys 85 90 95Leu Arg Leu Arg Gln Arg Gly Lys Lys Phe Met Asp Ile Thr Glu His 100 105 110Gln Asp Phe Tyr Ala Glu Gln Ala Met Ala Ser Phe Ala Gly Asp Pro 115 120 125Asn Leu Pro Lys Leu Ser His Lys Gly Leu Val Lys Pro Leu Phe Ser 130 135 140Gln Ile Glu Thr Glu Arg Met His Asp Ile Leu Gln His Met Thr Ser145 150 155 160Tyr Tyr Asn Arg Tyr Tyr Gly Asp Tyr His Gly Glu Met Ser Ser Glu 165 170 175Trp Leu His Asp Tyr Ile Ala Ala Ile Ile Ser Lys Ser Pro Phe Arg 180 185 190Thr His Ile Ser Leu Glu Tyr Phe Thr His Pro Phe Arg Gln Ser Ser 195 200 205Ile Ile Ala Arg Phe Glu Pro Lys Val Arg Ser Phe Ser Gln Pro Leu 210 215 220Thr Ile Ile Gly Ala His Gln Asp Ser Ala Asn Tyr Leu Phe Pro Leu225 230 235 240Leu Pro Ala Pro Gly Ala Asp Asp Asp Cys Ser Gly Thr Val Ser Ile 245 250 255Leu Glu Ala Phe Arg Val Leu Ala Glu Asn Gly Tyr Thr Pro Lys Asp 260 265 270Gly Pro Val Glu Phe His Trp Tyr Ala Ala Glu Glu Ala Gly Leu Leu 275 280 285Gly Ser Gln Ala Ile Ala Arg Tyr Lys Lys Glu Gln Gly Ala Lys Ile 290 295 300Asp Ala Met Met Glu Phe Asp Met Thr Ala Phe Ile Ala Arg Asn Ala305 310 315 320Thr Glu Thr Ile Gly Phe Val Ala Thr Gln Ala Asp Ala Ala Leu Thr 325 330 335Asn Trp Ala Leu Asn Leu Ser Arg Glu Tyr Ile Ser Ile Pro Ala Glu 340 345 350Val Tyr Glu Leu Gly Pro Asn Ala Gly Ser Asp Tyr Met Ser Tyr Thr 355 360 365Lys Leu Asn Tyr Pro Ala Ala Phe Ala Ser Glu Gly Asn Pro Leu Ala 370 375 380Gly Gly Ser Phe Pro Gly Glu Met Asp Pro Tyr Val His Gly Ile Lys385 390 395 400Asp Arg Met Asp Val Asp Asp Glu Thr Gly Val Phe Ser Ile Glu His 405 410 415Met Ala Arg Phe Ser Glu Leu Ala Ile Ala Phe Val Val Glu Gln Ala 420 425 430Gly Trp Asp Asn Thr Trp Arg 435169526PRTAspergillus niger 169Met Arg Ser Phe Ser Val Val Ala Ala Ala Ser Leu Ala Leu Ser Trp1 5 10 15Ala Ser Leu Ala Gln Ala Ala Arg Pro Arg Leu Val Pro Lys Pro Ile 20 25 30Ser Arg Pro Ala Ser Ser Lys Ser Ala Ala Thr Thr Gly Glu Ala Tyr 35 40 45Phe Glu Gln Leu Leu Asp His His Asn Pro Glu Lys Gly Thr Phe Ser 50 55 60Gln Arg Tyr Trp Trp Ser Thr Glu Tyr Trp Gly Gly Pro Gly Ser Pro65 70 75 80Val Val Leu Phe Asn Pro Gly Glu Val Ser Ala Asp Gly Tyr Glu Gly 85 90 95Tyr Leu Thr Asn Asp Thr Leu Thr Gly Val Tyr Ala Gln Glu Ile Gln 100 105 110Gly Ala Val Ile Leu Ile Glu His Arg Tyr Trp Gly Asp Ser Ser Pro 115 120 125Tyr Glu Val Leu Asn Ala Glu Thr Leu

Gln Tyr Leu Thr Leu Asp Gln 130 135 140Ser Ile Leu Asp Met Thr Tyr Phe Ala Glu Thr Val Lys Leu Gln Phe145 150 155 160Asp Asn Ser Ser Arg Ser Asn Ala Gln Asn Ala Pro Trp Val Met Val 165 170 175Gly Gly Ser Tyr Ser Gly Ala Leu Thr Ala Trp Thr Glu Ser Ile Ala 180 185 190Pro Gly Thr Phe Trp Ala Tyr His Ala Thr Ser Ala Pro Val Glu Ala 195 200 205Ile Tyr Asp Phe Trp Gln Tyr Phe Tyr Pro Ile Gln Gln Gly Met Ala 210 215 220Gln Asn Cys Ser Lys Asp Val Ser Leu Val Ala Glu Tyr Val Asp Lys225 230 235 240Ile Gly Lys Asn Gly Thr Ala Lys Glu Gln Gln Glu Leu Lys Glu Leu 245 250 255Phe Gly Leu Gly Ala Val Glu His Tyr Asp Asp Phe Ala Ala Val Leu 260 265 270Pro Asn Gly Pro Tyr Leu Trp Gln Asp Asn Asp Phe Val Thr Gly Tyr 275 280 285Ser Ser Phe Phe Gln Phe Cys Asp Ala Val Glu Gly Val Glu Ala Gly 290 295 300Ala Ala Val Thr Pro Gly Pro Glu Gly Val Gly Leu Glu Lys Ala Leu305 310 315 320Ala Asn Tyr Ala Asn Trp Phe Asn Ser Thr Ile Leu Pro Asn Tyr Cys 325 330 335Ala Ser Tyr Gly Tyr Trp Thr Asp Glu Trp Ser Val Ala Cys Phe Asp 340 345 350Ser Tyr Asn Ala Ser Ser Pro Ile Phe Thr Asp Thr Ser Val Gly Asn 355 360 365Pro Val Asp Arg Gln Trp Glu Trp Phe Leu Cys Asn Glu Pro Phe Phe 370 375 380Trp Trp Gln Asp Gly Ala Pro Glu Gly Thr Ser Thr Ile Val Pro Arg385 390 395 400Leu Val Ser Ala Ser Tyr Trp Gln Arg Gln Cys Pro Leu Tyr Phe Pro 405 410 415Glu Val Asn Gly Tyr Thr Tyr Gly Ser Ala Lys Gly Lys Asn Ser Ala 420 425 430Thr Val Asn Ser Trp Thr Gly Gly Trp Asp Met Thr Arg Asn Thr Thr 435 440 445Arg Leu Ile Trp Thr Asn Gly Gln Tyr Asp Pro Trp Arg Asp Ser Gly 450 455 460Val Ser Ser Thr Phe Arg Pro Gly Gly Pro Leu Val Ser Thr Ala Asn465 470 475 480Glu Pro Val Gln Ile Ile Pro Gly Gly Phe His Cys Ser Asp Leu Tyr 485 490 495Met Glu Asp Tyr Tyr Ala Asn Glu Gly Val Arg Lys Val Val Asp Asn 500 505 510Glu Val Lys Gln Ile Lys Glu Trp Val Glu Glu Tyr Tyr Ala 515 520 525170424PRTAspergillus niger 170Met Gln Leu Leu Gln Ser Leu Ile Val Ala Val Cys Phe Ser Tyr Gly1 5 10 15Val Leu Ser Leu Pro His Gly Pro Ser Asn Gln His Lys Ala Arg Ser 20 25 30Phe Lys Val Glu Arg Val Arg Arg Gly Thr Gly Ala Leu His Gly Pro 35 40 45Ala Ala Leu Arg Lys Ala Tyr Arg Lys Tyr Gly Ile Ala Pro Ser Ser 50 55 60Phe Asn Ile Asp Leu Ala Asp Phe Lys Pro Ile Thr Thr Thr His Ala65 70 75 80Ala Ala Gly Ser Glu Ile Ala Glu Pro Asp Gln Thr Gly Ala Val Ser 85 90 95Ala Thr Ser Val Glu Asn Asp Ala Glu Phe Val Ser Pro Val Leu Ile 100 105 110Gly Gly Gln Lys Ile Val Met Thr Phe Asp Thr Gly Ser Ser Asp Phe 115 120 125Trp Val Phe Asp Thr Asn Leu Asn Glu Thr Leu Thr Gly His Thr Glu 130 135 140Tyr Asn Pro Ser Asn Ser Ser Thr Phe Lys Lys Met Asp Gly Tyr Thr145 150 155 160Phe Asp Val Ser Tyr Gly Asp Asp Ser Tyr Ala Ser Gly Pro Val Gly 165 170 175Thr Asp Thr Val Asn Ile Gly Gly Ala Ile Val Lys Glu Gln Ala Phe 180 185 190Gly Val Pro Asp Gln Val Ser Gln Ser Phe Ile Glu Asp Thr Asn Ser 195 200 205Asn Gly Leu Val Gly Leu Gly Phe Ser Ser Ile Asn Thr Ile Lys Pro 210 215 220Glu Ala Gln Asp Thr Phe Phe Ala Asn Val Ala Pro Ser Leu Asp Glu225 230 235 240Pro Val Met Thr Ala Ser Leu Lys Ala Asp Gly Val Gly Glu Tyr Glu 245 250 255Phe Gly Thr Ile Asp Lys Asp Lys Tyr Gln Gly Asn Ile Ala Asn Ile 260 265 270Ser Val Asp Ser Ser Asn Gly Tyr Trp Gln Phe Ser Thr Pro Lys Tyr 275 280 285Ser Val Ala Asp Gly Glu Leu Lys Asp Ile Gly Ser Leu Asn Thr Ser 290 295 300Ile Ala Asp Thr Gly Thr Ser Leu Met Leu Leu Asp Glu Asp Val Val305 310 315 320Thr Ala Tyr Tyr Ala Gln Val Pro Asn Ser Val Tyr Val Ser Ser Ala 325 330 335Gly Gly Tyr Ile Tyr Pro Cys Asn Thr Thr Leu Pro Ser Phe Ser Leu 340 345 350Val Leu Gly Glu Ser Ser Leu Ala Thr Ile Pro Gly Asn Leu Ile Asn 355 360 365Phe Ser Lys Val Gly Thr Asn Thr Thr Thr Gly Gln Ala Leu Cys Phe 370 375 380Gly Gly Ile Gln Ser Asn Gly Asn Thr Ser Leu Gln Ile Leu Gly Asp385 390 395 400Ile Phe Leu Lys Ala Phe Phe Val Val Phe Asp Met Arg Gly Pro Ser 405 410 415Leu Gly Val Ala Ser Pro Lys Asn 420171548PRTAspergillus niger 171Met Arg Ile Asp Ser Ala Ala Leu His Leu Val Pro Val Leu Leu Gly1 5 10 15Gln Val Gly Ala Leu Gln Leu Pro Leu Val Gln Asp Ser Asn Ser Gln 20 25 30Trp Gln Lys Pro Asn Ala Gly Asp Lys Pro Leu Ile Ser Ser Pro Leu 35 40 45Leu Gln Glu Gln Val Lys Ala Glu Asn Leu Leu Asp Arg Ala Arg Gln 50 55 60Leu Tyr Lys Ile Ala Glu Leu Gly Glu Asp Glu Tyr Asn His Pro Thr65 70 75 80Arg Val Ile Gly Ser Lys Gly His Leu Gly Thr Leu Asp Tyr Ile Tyr 85 90 95Ser Thr Leu Thr Asp Leu Gly Asp Tyr Tyr Thr Val Val Asn Gln Ser 100 105 110Phe Pro Ala Val Ser Gly Asn Val Phe Glu Ser Arg Leu Val Leu Gly 115 120 125His Asp Val Pro Lys Ser Ala Thr Pro Met Gly Leu Thr Pro Pro Thr 130 135 140Arg Asn Lys Glu Pro Val Tyr Gly Ser Leu Val Ala Val Ser Asn Leu145 150 155 160Gly Cys Glu Ala Ser Asp Tyr Ser Ser Asn Leu Lys Gly Ala Val Ala 165 170 175Phe Ile Ser Arg Gly Ser Cys Pro Phe Gly Thr Lys Ser Gln Leu Ala 180 185 190Gly Lys Ala Gly Ala Val Ala Ala Val Ile Tyr Asn Asn Glu Arg Gly 195 200 205Asp Leu Ser Gly Thr Leu Gly Asn Pro Thr Pro Asp His Val Ala Thr 210 215 220Phe Gly Ile Ser Asp Glu Asp Ala Ala Pro Val Leu Glu Lys Leu Asn225 230 235 240Lys Gly Glu Lys Val Asp Ala Ile Ala Tyr Val Asp Ala Ile Val Glu 245 250 255Thr Ile His Thr Thr Asn Ile Ile Ala Gln Thr Thr Asp Gly Asp Pro 260 265 270Asn Asn Cys Val Met Leu Gly Gly His Ser Asp Ser Val Ala Glu Gly 275 280 285Pro Gly Ile Asn Asp Asp Gly Ser Gly Thr Leu Thr Leu Leu Glu Leu 290 295 300Ala Thr Leu Leu Thr Gln Phe Arg Val Asn Asn Cys Val Arg Phe Ala305 310 315 320Trp Trp Ala Ala Glu Glu Glu Gly Leu Leu Gly Ser Asp Tyr Tyr Val 325 330 335Ser Val Leu Thr Pro Glu Glu Asn Arg Lys Ile Arg Leu Phe Met Asp 340 345 350Tyr Asp Met Leu Gly Ser Pro Asn Phe Ala Tyr Gln Val Tyr Asn Ala 355 360 365Thr Asn Ala Val Asn Pro Glu Gly Ser Glu Glu Leu Arg Asp Leu Tyr 370 375 380Thr Asp Phe Tyr Glu Asp His Gly Phe Asn Tyr Thr Tyr Ile Pro Phe385 390 395 400Asp Gly Arg Ser Asp Tyr Asp Ala Phe Ile Arg His Gly Ile Pro Gly 405 410 415Gly Gly Ile Ala Thr Gly Ala Glu Gly Ile Lys Thr Val Glu Glu Ala 420 425 430Asp Met Phe Gly Gly Val Ala Gly Gln Trp Tyr Asp Pro Cys Tyr His 435 440 445Gln Ile Cys Asp Thr Val Ala Asn Val Asn Leu Thr Ala Trp Glu Trp 450 455 460Asn Thr Lys Leu Val Ala His Ser Ile Ala Thr Tyr Ala Lys Ser Phe465 470 475 480Asp Gly Phe Pro Glu Arg Ser Asp Glu Pro Ile Ser Pro Ala Ala Phe 485 490 495Glu Glu Pro Lys Tyr His Gly His Ala Leu Gln Leu Leu Arg Gly Asn 500 505 510Thr Thr Gly Thr Gln Ser Val Leu Trp Gly Ala Gln Ile Gln Asn Gly 515 520 525Thr Ala Ala Ser Val Leu Asn Leu Leu Ser Ile Arg Arg Arg Gly Thr 530 535 540Phe Ser Leu Ser545

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Patents in class Recombinant DNA technique included in method of making a protein or polypeptide

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