Advertisement

World Journal of Microbiology and Biotechnology

, Volume 25, Issue 12, pp 2083–2094 | Cite as

Approaches for refining heterologous protein production in filamentous fungi

  • Ruchika Sharma
  • Meenu Katoch
  • P. S. Srivastava
  • G. N. Qazi
Review

Abstract

Fungi combine the advantages of a microbial system such as a simple fermentability with the capability of secreting proteins that are modified according to a general eukaryotic scheme. Filamentous fungi such as Aspergillus niger efficiently secrete genuine proteins but the secretion of recombinant proteins turned out be a difficult task. Aspergillus niger is an attractive organism because of its high secretion capacity and is frequently used as a model organism. Whereas high production yields can be obtained when homologous proteins are expressed, much lower amounts are obtained with the production of heterologous proteins. To fully exploit the potential of filamentous fungi, understanding of the molecular genetics, their physiology, and the glycosylation metabolism has to be investigated and clarified in more detail. This review summarizes recent developments in heterologous protein production by filamentous fungi and also generalizes the possibilities of improving the protein production by various genetic and bioprocessing approaches, thereby easing recognition of filamentous fungi as a relevant and reliable expression platform.

Keywords

Filamentous fungi Heterologous proteins Expression system 

References

  1. Aifa MS, Sayadi S, Gargouri A (1999) Heterologous expression of lignin peroxidase of Phanerochaete chrysosporium in Aspergillus niger. Biotechnol Lett 21:849–853Google Scholar
  2. Amanullah A, Christensen LH, Hansen K et al (2002) Dependence of morphology on agitation intensity in fed-batch cultures of Aspergillus oryzae and its implications for recombinant protein production. Biotechnol Bioeng 7:815–826Google Scholar
  3. AMFEP (2004) Association of Manufacturers and Formulators of Enzyme Products (Online) http://www. AMFEP. org
  4. Archer D (2000) Filamentous fungi as microbial cell factories for food use. Curr Opin Biotechnol 11:478–483Google Scholar
  5. Archer DB, Peberby JF (1997) The molecular biology of secreted enzyme production by fungi. Crit Rev Biotechnol 17:273–306Google Scholar
  6. Archer DB, Jeenes DJ, MacKenzie DA et al (1990) Hen egg white lysozyme expressed in and secreted from Aspergillus niger is correctly processed and folded. Biotechnology 8:741–745Google Scholar
  7. Archer DB, Mckenzie DA, Jeenes DJ et al (1992) Proteolytic degradation of heterologous protein expressed in Aspergillus niger. Biotechnol Lett 14:357–362Google Scholar
  8. Archer DB, Jeenes DJ, Mackenzie DA (1994) Strategies for improving heterologous protein production from filamentous fungi. Antonie Van Leeuwenhoek 65:245–250Google Scholar
  9. Bai Z, Harvey LM, White S et al (2004) Effects of oxidative stress on production of heterologous and native protein, and culture morphology in batch and chemostat cultures of Aspergillus niger (B1-D). Enzyme Microb Technol 34:10–21Google Scholar
  10. Banerjee AC, Kundu A, Ghosh SK (2003) Genetic manipulation of filamentous fungi. In: Roussos S (ed) New horizons in biotechnology. Kluwer, Dordrecht (Neth), pp 193–198Google Scholar
  11. Berka RM, Ward M, Wilson LJ et al (1990) Molecular cloning and deletion of the gene encoding aspergillopepsin A from Aspergillus awamori. Gene 86:153–162Google Scholar
  12. Bhargava S, Wenger KS, Marten MR (2003) Pulsed addition of limiting-carbon during Aspergillus oryzae fermentation leads to improved productivity of a recombinant enzyme. Biotechnol Bioeng 82:111–117Google Scholar
  13. Brodsky JL, McCracken AA (1999) ER protein quality control and proteasome-mediated protein degradation. Semin Cell Dev Biol 10:507–513Google Scholar
  14. Broekhuijsen MP, Mattern IE, Contreras R et al (1993) Secretion of heterologous proteins by Aspergillus niger: production of active human interleukin-6 in a protease deficient mutant by KEX2-like processing of a glucoamylase-hIL6 fusion protein. J Biotechnol 31:135–145Google Scholar
  15. Bucher P (1990) Weight matrix descriptions of four eukaryotic RNA polymerase II promoter elements derived from 502 unrelated promoter sequences. J Mol Biol 212:563–578Google Scholar
  16. Chapman R, Sidrauski C, Walter P (1998) Intracellular signaling from the endoplasmic reticulum to the nucleus. Annu Rev Cell Dev Biol 14:459–485Google Scholar
  17. Conesa A, Punt PJ, Luijk N et al (2001) The secretion pathway in filamentous fungi: a biotechnological view. Fungal Genet Biol 33:155–171Google Scholar
  18. Conesa A, Jeenes D, Archer DB et al (2002) Calnexin overexpression increases manganese peroxidase production in Aspergillus niger. Appl Environ Microbiol 68:846–851Google Scholar
  19. Contreras R, Carrez D, Kinghorn JR et al (1991) Efficient KEX2-like processing of a glucoamylase- interleukin-6 fusion protein by A. nidulans and secretion of mature interleukin-6. Biotechnology 9:378–380Google Scholar
  20. Cowan D (1996) Industrial enzyme technology. Trends Biotechnol 14:177–178Google Scholar
  21. Cudna RE, Dickson AJ (2003) Endoplasmic reticulum signaling as a determinant of recombinant protein expression. Biotechnol Bioeng 81:56–65Google Scholar
  22. Cui YQ, Van der Lans RGJM, Luyben KCAM (1997) Effect of agitation intensities on fungal morphology of submerged fermentation. Biotechnol Bioeng 55:715–726Google Scholar
  23. Denison SH (2000) pH regulation of gene expression in fungi. Fungal Genet Biol 29:61–71Google Scholar
  24. Dunn-Coleman NS, Bloebaum P, Berka R et al (1991) Commercial levels of chymosin production by Aspergillus. Biotechnology 9:976–981Google Scholar
  25. Durand H, Clanet M, Tiraby G (1988) Genetic improvement of Trichoderma reesei for large-scale cellulase production. Enzyme Microb Technol 10:341–345Google Scholar
  26. Elledge S, Davis RW (1988) A family of versatile centromeric vectors designed for use in the sectoring-shuffle mutagenesis assay in Saccharomyces cerevisiae. Gene 70:303–312Google Scholar
  27. Fields S, Song O (1989) A novel genetic system to detect protein–protein interactions. Nature 340:245–246Google Scholar
  28. Fincham JR (1989) Transformation in fungi. Microbiol Rev 53:148–170Google Scholar
  29. Finkelstein DB, Ball C (1992) Biotechnology of filamentous fungi. Butterworth-Heinemann, Boston, pp 221–416Google Scholar
  30. Finkelstein DB, Rambosek J, Crawford MS (1989) Protein secretion in Aspergillus niger. In: Hershberger CL, Queener SW, Hegeman G et al (eds) Genetics and molecular biology of industrial microorganisms. American Society for Microbiology, Washington DC, pp 295–300Google Scholar
  31. Fox SR, Patel UA, Yap MG et al (2004) Maximizing interferon gamma production by Chinese hamster ovary cells through temperature shift optimization: experimental and modeling. Biotechnol Bioeng 85:177–184Google Scholar
  32. Gasser B, Mattanovich D (2007) Antibody production with yeasts and filamentous fungi: on the road to large scale? Biotechnol Lett 29:201–212Google Scholar
  33. Gemgross TU (2004) Advances in the production of human therapeutic proteins in yeasts and filamentous fungi. NatCri Rev Biotechnol Biotechnol 22:1409–1414Google Scholar
  34. Gething MJ (1999) Role and regulation of the ER chaperone BiP. Semin Cell Dev Biol 10:465–472Google Scholar
  35. Gibbs PA, Seviour RJ, Schmid F (2000) Growth of filamentous fungi in submerged culture: problems and possible solutions. Crit Rev Biotechnol 20:17–48Google Scholar
  36. Goosen T, Jorgensen TR, Iversen JJL et al (2005) Unfolded protein response in Aspergillus niger chemostat fermentations. Fungal Genet Newsl 52:83Google Scholar
  37. Gouka RJ, Hessing JG, Punt PJ et al (1996) An expression system based on the promoter region of the Aspergillus awamori 1, 4-beta-endoxylanase A gene. Appl Microbiol Biotechnol 46:28–35Google Scholar
  38. Gouka RJ, Punt PJ, Van den Hondel CA (1997a) Efficient production of secreted proteins by Aspergillus: progress, limitations and prospects. Appl Microbiol Biotechnol 47:1–11Google Scholar
  39. Gouka RJ, Punt PJ, Van den Hondel CA (1997b) Glucoamylase gene fusions alleviate limitations for protein production in Aspergillus awamori at the transcriptional and (post) translational levels. Appl Environ Microbiol 63:488–497Google Scholar
  40. Grimm LH, Kelly S, Krull R, Hempel DC (2005) Morphology and productivity of filamentous fungi. Appl Microbiol Biotechnol 20:17–48Google Scholar
  41. Gyamerah M, Merichetti G, Adedayo O, Scharer JM, Moo-Young M (2002) Bioprocessing strategies for improving hen egg-white lysozyme (HEWL) production by recombinant Aspergillus niger (HEWLWT-13–16). Appl Microbiol Biotechnol 60:403–407Google Scholar
  42. Harkki A, Mantyla A, Penttila M et al (1991) Genetic engineering of Trichoderma to produce strains with novel cellulase profiles. Enzym Microb Technol 3:227–233Google Scholar
  43. Hata Y, Tsuchiya K, Kitamoto K et al (1991) Nucleotide sequence and expression of the glucoamylase-encoding gene (glaA) from Aspergillus oryzae. Gene 108:145–150Google Scholar
  44. Heogh I, Patkar S, Halkier T et al (1995) Two lipases from Candida Antarctica—cloning and expression in Aspergillus oryzae. Can J Bot 73:869–875Google Scholar
  45. Jeenes DJ, Mackenzie DA, Roberts IN et al (1991) Heterologous protein production by filamentous fungi. Biotechnol Genet Eng Rev 9:327–367Google Scholar
  46. Jeenes DJ, Marczinke B, MacKenzie DA et al (1993) A truncated glucoamylase gene fusion for heterologous protein secretion from Aspergillus niger. FEMS Microbiol Lett 107:267–271Google Scholar
  47. Jeenes DJ, Pfaller R, Archer DB (1997) Isolation and characterization of a novel stress inducible PDI family gene from A. niger. Gene 194:151–156Google Scholar
  48. Joutsjoki VV, Torkkeli TK, Nevalainen HM (1993) Transformation of T. reesei with the Hormoconis resinae glucoamylase P (gam P) gene: Production of a heterologous glucoamylase by Trichoderma reesei. Curr Genet 24:223–228Google Scholar
  49. Katz ME, Flynn PK, VanKuyk PA et al (1996) Mutations affecting extracellular protease production in the filamentous fungus Aspergillus nidulans. Mol Gen Genet 250:715–724Google Scholar
  50. Kaufman RJ (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13:1211–1233Google Scholar
  51. Keranen S, Penttila M (1995) Production of recombinant proteins in the filamentous fungus Trichoderma reesei. Curr Opin Biotechnol 6:534–537Google Scholar
  52. Kolar M, Punt PJ, Van den Hondel CAMJJ et al (1988) Transformation of Penicillium chrysogenum using dominant selection markers and expression of an Escherichia coli lacZ fusion gene. Gene 62:127–134Google Scholar
  53. Kruszewska JS, Butterweck AH, Migdalski A et al (1999) Overexpression of the Saccharomyces cervisiae mannosylphosphodolichol synthase encoding gene in T. reesei results in an increased level of protein secretion and abnormal cell ultrastructure. Appl Environ Microbiol 65:2382–2387Google Scholar
  54. Li ZJ, Shukla V, Fordyce AP et al (2000) Fungal morphology and fragmentation behavior in a fed-batch Aspergillus oryzae fermentation at the production scale. Biotechnol Bioeng 70:300–312Google Scholar
  55. Li ZJ, Shukla V, Wenger KS et al (2002) Effects of increased impeller power in a production-scale Aspergillus oryzae fermentation. Biotechnol Prog 18:437–444Google Scholar
  56. Li Q, Harvey LM, McNeil B (2008) The effects of bioprocess parameters on extracellular proteases in a recombinant Aspergillus niger B1-D. Appl Microbiol Biotechnol 78:333–341Google Scholar
  57. Liu F, Li W, Ridgway D et al (1998) Inhibition of extracellular protease secretion by Aspergillus niger using cell immobilization. Biotechnol Lett 20(6):539–542Google Scholar
  58. Liu L, Liu J, Qiu RX et al (2003) Improving heterologous gene expression in Aspergillus niger by introducing multiple copies of protein- binding sequence containing CCAAT to the promoter. Lett Appl Microbiol 36:358–361Google Scholar
  59. Machida M (2002) Progress of Aspergillus oryzae genomics. Adv Appl Microbiol 51:81–106Google Scholar
  60. Macrae WD, Buxton FP, Gwynne DI, Davies RW (1993) Heterologous protein secretion directed by a repressible acid phosphatase system of A. nidulans. Gene 132:193–198Google Scholar
  61. Mantyla A, Paloheimo M, Suominen P (1998) Industrial mutant and recombinant strains of Trichoderma reesei. In: Harman GE, Kubicek CP (eds) Trichoderma and gliocladium, vol 2. Taylor and Francis, London, pp 291–309Google Scholar
  62. Maras M, Van Die I, Contreras R et al (1999) Filamentous fungi as production organisms for glycoproteins of bio-medical interest. Glycoconj J 16:99–107Google Scholar
  63. Mattern IE, Van Noort JM, Van den Berg P et al (1992) Isolation and characterisation of mutants of A. niger deficient in extracellular proteases. Mol Gen Genet 234:332–336Google Scholar
  64. Minetoki T, Gomi K, Kitamoto K et al (1995) Nucleotide sequence and expression of alpha-glucosidase-encoding gene (agdA) from Aspergillus oryzae. Biosci Biotechnol Biochem 59:1516–1521Google Scholar
  65. Morita S, Kuriyama M, Nakatsu M et al (1994) High level expression of Fusarium alkaline protease gene in Acremonium chrysogenum. Biosci Biotechnol Biochem 58:627–630Google Scholar
  66. Mulder HJ, Saloheimo M, Penttila M et al (2004) The transcription factor overexpression increases manganese peroxidase production in Aspergillus niger. Appl Environ Microbiol 68:846–851Google Scholar
  67. Muller C (2001) Metabolic engineering of the morphology of Aspergillus oryzae by altering chitin synthesis. Ph.D. thesis, Denmark Technical University, Lyngby, DenmarkGoogle Scholar
  68. Nevalainen KMH, Valentino SJT, Bergquis PL (2005) Heterologous protein expression in filamentous fungi. Trends Biotechnol 23:468–474Google Scholar
  69. Ngiam C, Jeenes DJ, Punt PJ et al (2000) Characterization of a foldase, protein disulfide isomerase A, in the protein secretory pathway of Aspergillus niger. Appl Environ Microbiol 66:775–782Google Scholar
  70. Nyssonen E, Keranen S (1995) Multiple roles of the cellulase CBH1 in enhancing production of fusion antibodies by the filamentous fungus Trichoderma reesei. Curr Genet 28:71–79Google Scholar
  71. O’Donnell D, Wang L, Xu J et al (2001) Enhanced heterologous protein production in Aspergillus niger through pH control of extracellular protease activity. Biochem Eng J 8:187–193Google Scholar
  72. Pachlinger R, Mitterbauer R, Adam G et al (2005) Metabolically independent and accurately adjustable Aspergillus sp. expression system. Appl Environ Microb 71:672–678Google Scholar
  73. Parodi AJ (1999) Reglucosylation of glycoproteins and quality control of glycoprotein folding in the endoplasmic reticulum of yeast cells. Biochim Biophys Acta 1426:287–295Google Scholar
  74. Pedersen H, Beyer M, Nielsen J (2000) Glucoamylase production in batch, chemostat and fed-batch cultivations by an industrial strain of Aspergillus niger. Appl Microbiol Biotechnol 53:272–277Google Scholar
  75. Pedrazzini E, Vitale A (1996) The binding protein (BiP) and the synthesis of secretory proteins. Plant Physiol Biochem 34:207–216Google Scholar
  76. Penttila ME (1998) Heterologous protein production in Trichoderma. In: Harman GE, Kubicek CP (eds) Trichoderma and gliocladium, vol 2. Taylor and Francis, London, pp 365–382Google Scholar
  77. Punt PJ, Zegers ND, Busscher M et al (1991) Intracellular and extracellular production of proteins under the control of expression signals of the highly expressed Aspergillus nidulans gpdA gene. J Biotechnol 17:19–34Google Scholar
  78. Punt PJ, Veldhuisen G, Van den Hondel CAMJJ (1994) Protein targeting and secretion in filamentous fungi. Antonie Van Leeuwenhoek 65:211–216Google Scholar
  79. Punt PJ, Van Gemeren IA, Drint-Kuijvenhoven J et al (1998) Analysis of the role of the gene bipA, encoding the major endoplasmic reticulum chaperone protein in the secretion of homologous and heterologous proteins in black Aspergilli. Appl Microbiol Biotechnol 50:447–454Google Scholar
  80. Punt PJ, Biezen NV, Conesa A et al (2002) Filamentous fungi as cell factories for heterologous protein production. Trends Biotechnol 20:200–206Google Scholar
  81. Radzio R, Kuck U (1997) Synthesis of biotechnologically relevant heterologous proteins in filamentous fungi. Process Biochem 32:529–537Google Scholar
  82. Roberts IN, Jeenes DJ, Mackenzie DA et al (1992) Heterologous gene expression in A. Niger: a glucoamylase–porcine pancreatic phospholipase A2 fusion protein is secreted and processed to yield mature enzyme. Gene 122:155–161Google Scholar
  83. Ruiz-Duenas FJ, Martinez MJ, Martinez AT (1999) Heterologous expression of Pleurotus eryngii peroxidase confirms its ability to oxidize Mn2+ and different aromatic substrates. Appl Environ Microbiol 65:4705–4707Google Scholar
  84. Rutkowski DT, Kaufman RJ (2004) A trip to the ER: coping with stress. Trends Cell Biol 14:20–28Google Scholar
  85. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual second edition. Cold Spring Harbor Laboratory, New YorkGoogle Scholar
  86. Saunders G, Picknett TM, Tuite MF et al (1989) Heterologous gene expression in filamentous fungi. Trends Biotechnol 7:283–287Google Scholar
  87. Schmidt FR (2004) Recombinant expression systems in the pharmaceutical industry. Appl Microbiol Biotechnol 65:363–372Google Scholar
  88. Schneider JC, Guarente L (1991) Vectors for expression of cloned genes in yeast: regulation, overproduction, and underproduction. Methods Enzymol 194:373–388Google Scholar
  89. Sikorski RS, Hieter P (1989) A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae. Genetics 122:19–27Google Scholar
  90. Sitia R, Braakman I (2003) Quality control in the endoplasmic reticulum protein factory. Nature 426:891–894Google Scholar
  91. Smith TL, Gaskell J, Berka RM et al (1990) The promoter of the glucoamylase-encoding gene of Aspergillus niger functions in Ustilago maydis. Gene 88:259–262Google Scholar
  92. Stewart P, Whitwam RE, Kersten PJ et al (1996) Efficient expression of a Phanerochaete chrysosporium manganese peroxidase gene in Aspergillus oryzae. Appl Environ Microbiol 62:860–864Google Scholar
  93. Stroh WH (1998) Industrial enzymes market. Genet Eng News 18:11–38Google Scholar
  94. Swift RJ, Wiebe MG, Robson GD et al (1998) Recombinant glucoamylase production by Aspergillus niger B1 in chemostat and pH auxostat cultures. Fungal Genet Biol 25:100–109Google Scholar
  95. Tada S, Gomi K, Kitamoto K et al (1991) Construction of a fusion gene comprising Taka-amylase A promoter and the Escherichia coli beta-glucuronidase gene and analysis of its expression in Aspergillus oryzae. Gen Genet 229:301–306Google Scholar
  96. Teo VSJ, Cziferszky AE, Bergquist PL, Nevalainen KMH (2000) Codon optimization of the thermophile xylanase gene xynB from Dictyoglomus thermophilum for expression in Trichoderma reesei. FEMS Microbiol Lett 190:13–19Google Scholar
  97. Thongchul N, Yang ST (2003) Controlling filamentous fungal morphology by immobilization on a rotating fibrous atrix to enhance oxygen transfer and l (+)-lactic acid production by Rhizopus oryzae. In: Saha BC (ed) Fermentation biotechnology. American Chemical Society, Washington, DC, pp 36–51Google Scholar
  98. Tsuchiya K, Tada S, Gomi K et al (1992) High level expression of the synthetic human lysozyme gene in Aspergillus oryzae. Appl Microbiol Biotechnol 38:109–114Google Scholar
  99. Tsukagoshi N, Kobayashi T, Kato M (2001) Regulation of the amylolytic and (hemi)cellulolytic genes in asperigilli. J Gen Appl Microbiol 47:1–19Google Scholar
  100. Valkonen M, Ward M, Wang H et al (2003) Improvement of foreign-protein production in Aspergillus niger var. awamori by constitutive induction of the unfolded protein response. Appl Environ Microb 69(12):6979–6986Google Scholar
  101. Van den Brink HJM, Petersen SG, Rahbek-Nielsen H et al (2006) Increased production of chymosin by glycosylation. J Biotechnol 125:304–310Google Scholar
  102. Van den Hombergh JPTW, Sollewijn Gelpke MD, Van de Vondervoort PJI et al (1997a) Disruption of three acid proteases in Aspergillus niger—effects on protease spectrum, intracellular proteolysis and degradation of target proteins. Eur J Biochem 247:605–613Google Scholar
  103. Van den Hombergh JPTW, Van de Vondervoort PJI, Tachet LF et al (1997b) Aspergillus as a host for heterologous protein production: the problem of proteases. Trends Biotechnol 15:256–263Google Scholar
  104. Van den Hondel CAMJJ, Punt PJ, Van Gorcom RFM (1991) Heterologous gene expression in filamentous fungi. In: Bennet JW, Lasure LL (eds) More gene manipulations in fungi. Academic Press, San Diego, pp 396–428Google Scholar
  105. Van den Hondel CAMJJ, Punt PJ, Gorcom RFMV (1992) Production of extracellular proteins by the filamentous fungus Aspergillus. Antonie Van Leeuwenhoek 61:153–160Google Scholar
  106. Van Gemeren IA, Punt PJ, Drint-Kuyvenhoven A et al (1997) The ER chaperone encoding bipA gene of black Aspergilli is induced by heat shock and unfolded proteins. Gene 198:43–52Google Scholar
  107. Verdoes JC, Punt PJ, Schrickx JM et al (1993) Glucoamylase overexpression in Aspergillus niger: molecular genetic analysis of strains containing multiple copies of the glaA gene. Transgenic Res 2:84–92Google Scholar
  108. Verdoes JC, Punt PJ, Burlingame R, Bartels J, Van Dijk R, Slump E, Meens M, Joosten R, Emalfarb M (2007) A dedicated vector for efficient library construction and high throughput screening in the hyphal fungus Chrysosporium lucknowense. Ind Biotechnol 3:48–57Google Scholar
  109. Walsh DJ, Gibbs MD, Bergquist PL (1998) Expression and secretion of bacterial thermophilic hemicellulases in Kluveromyces lactis. In: Eriksson K-E, Cavaco-Paulo A (eds) Enzyme applications in fiber processing. Am Chem Soc Symp 687:155–167Google Scholar
  110. Wang H, Ward M (2000) Molecular characterization of a PDI-related gene prpA in Aspergillus niger var. awamori. Curr Genet 37:57–64Google Scholar
  111. Wang H, Entwistle J, Morlon E et al (2003) Isolation and characterisation of a calnexin homologue, clxA, from Aspergillus niger. Mol Genet Genomics 268:684–691Google Scholar
  112. Wang L, Ridgwaya D, Gu T et al (2005) Bioprocessing strategies to improve heterologous protein production in filamentous fungal fermentations. Biotechnol Adv 23:115–129Google Scholar
  113. Wang Y, Xue W, Sims AH, Zhao C, Wang A, Tang G, Qin J, Wang H (2008) Isolation of four pepsin-like protease genes from Aspergillus niger and analysis of the effect of disruptions on heterologous laccase expression. Fungal Genet Biol 45:17–27Google Scholar
  114. Ward M (1989) Heterologous gene expression in Aspergillus. In: Nevalainen H, Pentilla M (eds) EMBO-ALKO workshop on molecular biology of filamentous fungi. Foundation for Biotechnical and Industrial Fermentation Research, Espoo, pp 119–128Google Scholar
  115. Ward M, Wilson LJ, Kodama KH et al (1990) Improved production of chymosin in Aspergillus expression as a glucoamylase-chymosin fusion. Biotechnology 8:435–440Google Scholar
  116. Ward PP, Lo JY, Duke M, May GS, Headon DR, Coneely O (1992) Production of biologically active recombinant human lactoferrin in Aspergillus oryzae. Biotechnology 10:784–789Google Scholar
  117. Ward PP, Piddington CS, Cunningham GA et al (1995) System for production of commercial quantities of human lactoferrin: a broad spectrum natural antibiotic. Biotechnology 13:498–503Google Scholar
  118. Ward OP, Qin WM, Hanjoon JD, Singh EJYA (2006) Physiology and biotechnology of Aspergillus. Adv Appl Microbiol 58:1–75Google Scholar
  119. Welihinda AA, Tirasophon W, Kaufman RJ (1999) The cellular response to protein misfolding in the endoplasmic reticulum. Gene Expr 7:293–300Google Scholar
  120. Wiebe MG, Karandikar A et al (2001) Production of tissue plasminogen activator (t-PA) in Aspergillus niger. Biotechnol Bioeng 76:164–174Google Scholar
  121. Xu J, Wang L, Ridgway D et al (2000) Increased Heterologous Protein Production in Aspergillus niger, fermentation through extracellular proteases inhibition by pelleted growth. Biotechnol Prog 16:222–227Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Ruchika Sharma
    • 1
  • Meenu Katoch
    • 1
  • P. S. Srivastava
    • 2
  • G. N. Qazi
    • 1
  1. 1.Biotechnology DivisionIndian Institute of Integrative Medicine (CSIR)JammuIndia
  2. 2.Department of BiotechnologyJamia HamdardNew DelhiIndia

Personalised recommendations