Skip to main content
SpringerLink
Log in

Heterologous protein production in yeast

  • Published:
Antonie van Leeuwenhoek Aims and scope Submit manuscript

Abstract

The exploitation of recombinant DNA technology to engineer expression systems for heterologous proteins represented a major task within the field of biotechnology during the last decade. Yeasts attracted the attention of molecular biologists because of properties most favourable for their use as hosts in heterologous protein production. Yeasts follow the general eukaryotic posttranslational modification pattern of expressed polypeptides, exhibit the ability to secrete heterologous proteins and benefit from an established fermentation technology. Aside from the baker's yeastSaccharomyces cerevisiae, an increasing number of alternative non-Saccharomyces yeast species are used as expression systems in basic research and for an industrial application.

In the following review a selection from the different yeast systems is described and compared.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anthony C (1982) The Biochemistry of Methylotrophs. Academic Press, New York

    Google Scholar 

  • Barr PJ, Brake AJ & Valenzuela P (1989) Yeast Genetic Engineering. Butterworths, Boston

    Google Scholar 

  • Beach D & Nurse P (1981) High frequency transformation of the fission yeastSchizosaccharomyces pombe. Nature 290: 140–142

    Google Scholar 

  • Beggs JD (1978) Transformation of yeast by a replicating hybrid plasmid. Nature 275: 104–109

    Google Scholar 

  • Bennetzen JL & Hall BD (1982) The primary structure of theSaccharomyces cerevisiae gene for alcohol dehydrogenase I. J. Biol. Chem. 257: 3018–3025

    Google Scholar 

  • Bianchi MM, Falcone C, Chen XJ, Wéslowski-Louvel M, Frontali L & Fukuhara H (1987) Transformation of the yeastKluyveromyces lactis by new vectors derived from the 1,6 μm circular plasmid pKD1. Curr. Genet. 12: 185–192

    Google Scholar 

  • Bitter GA, Chen KK, Banks AR & Lai PH (1984) Secretion of foreign proteins fromSaccharomyces cerevisiae directed by α-factor fusions. Proc. Natl. Acad. Sci. USA 81: 5330–5334

    Google Scholar 

  • Botstein D & Shortle D (1985) Strategies and applications of in vitro mutagenesis. Science 229: 1193–1201

    Google Scholar 

  • Brake AJ, Merryweather JP, Coit DG, Heberlein UA, Masiarz FR, Mullenbach GT, Urdea MS, Valenzuela P & Barr PJ (1984) α-factor-directed synthesis and secretion of mature foreign proteins inSaccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 81: 4642–4646

    Google Scholar 

  • Buckholz RG & Gleeson MAG (1991) Yeast systems for the commercial production of heterologous proteins. Bio/Technology 9: 1067–1072

    Google Scholar 

  • Burke ET, Carle GS & Olson MV (1987) Cloning of large fragments of exogenous DNA into yeast by means of artifical chromosome vector. Science 236: 806–812

    Google Scholar 

  • Burke RL, Tekamp-Olson P & Najarian R (1983) The isolation, characterization, and sequence of the pyruvate kinase gene ofSaccharomyces cerevisiae. J. Biol. Chem. 258: 2193–2201

    Google Scholar 

  • Cabezon T, DeWilde M, Herion P, Loriau R & Bollen A (1984) Expression of human α1-antitrypsin cDNA in the yeastSaccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 81: 6594–6598

    Google Scholar 

  • Chen XJ, Saliola M, Falcone C, Bianchi MM & Fukuhara H (1986) Sequence organization of the circular plasmid pKD1 from the yeastKluyveromyces drosophilarum. Nucleic Acids Res. 14: 4471–4481

    Google Scholar 

  • Clare JJ, Rayment FB, Ballantine SP, Sreekrishna K & Romanos MA (1991) High-level expression of tetanus toxin fragment C inPichia pastoris strains containing multiple tandem integrations of the gene. Bio/Technology 9: 455–460

    Google Scholar 

  • Clarke L & Carbon J (1980) Isolation of a yeast centromere and construction of functional small circular chromosomes. Nature 257: 504–509

    Google Scholar 

  • Cregg JM & Madden PA (1987) Development of yeast transformation systems and construction of methanol-utilizing-defective mutants ofPichia pastoris by gene disruption. In: Stewart GG, Russell I, Klein RD & Hiebsch RR (Eds) Biological Research on Industrial Yeast, Vol. II (pp 1–18). CRC Press, Boca Raton, Florida

    Google Scholar 

  • Cregg JM, Barringer KJ, Hessler AY & Madden KR (1985)Pichia pastoris as a host system for transformations. Mol. Cell. Biol. 5: 3376–3385

    Google Scholar 

  • Cregg JM, Tschopp JF, Stillman C, Siegel R, Akong M, Craig WS, Buckholz RG, Madden KR, Kellaris PA, Davis GR, Smiley BL, Cruze J, Torregrossa R, Velicelebi G & Thill GP (1987) High-level expression and efficient assembly of hepatitis B surface antigen in the methylotrophic yeast,Pichia pastoris. Bio/Technology 5: 479–485

    Google Scholar 

  • Cullen D, Gray GL, Wilson LJ, Hayenga KJ, Lamsa MH, Rey MW, Norton S & Berka RM (1987) Controlled expression and secretion of bovine chymosin inAspergillus nidulans. Bio/Technology 5: 369–376

    Google Scholar 

  • Da Silva NA & Bailey JE (1991) Influence of dilution rate and induction of cloned gene expression in continuous fermentations of recombinant yeast. Biotechnol. Bioeng. 37: 309–317

    Google Scholar 

  • Da Silva NA & Bailey JE (1991) Influence of plasmid origin and promoter strength in fermentations of recombinant yeast. Biotechnol. Bioeng. 37: 318–324

    Google Scholar 

  • Das S & Hollenberg CP (1982) A high-frequency transformation system for the yeastKluyveromyces lactis. Curr. Genet. 6: 123–128

    Google Scholar 

  • Davidow LS, Apostolakos D, O'Donell MM, Proctor AR, Ogrydziak DM, Wing RA, Stasko I & DeZeeuw JR (1985) Integrative transformation of the yeastYarrowia lypolytica. Curr. Genet. 10: 39–48

    Google Scholar 

  • De Baetselier A, Vasavada A, Dohet P, Ha-Thi V, De Beukelaer M, Erpicum T, De Clerck L, Hanotier J & Rosenberg S (1991) Fermentation of a yeast producingA. niger glucose oxidase: scale-up, purification and characterization of the recombinant enzyme. Bio/Technology 9: 559–561

    Google Scholar 

  • Derynck R, Singh A & Goeddel DV (1983) Expression of the human interferon-α cDNA in yeast. Nucleic Acids Res. 11: 1819–1837

    Google Scholar 

  • DeWilde M, Cabezon T, Harford N, Rutgers T, Simoen E & Van Wijnendaele F (1985) Production in yeast of hepatitis B surface antigen by r-DNA technology. 18.Congress. Joint IABS/WHO symposium on standardization and control of biologicals produced by recombinant DNA technology, Geneva, Switzerland, 1983. Develop. Biol. Standard 59: 99–107

    Google Scholar 

  • Dickson RC & Markin JS (1978) Molecular cloning and expression inE. coli of a yeast gene coding for β-galactosidase. Cell 15: 123–130

    Google Scholar 

  • Digan ME, Lair SV, Brierley RA, Siegel RS, Williams ME, Ellis SB, Kellaris PA, Provow SA, Craig WS, Velicelebi G, Harpold MM & Thill GP (1989) Continuous production of a novel lysozyme via secretion from the yeast,Pichia pastoris. Bio/Technology 7: 160–164

    Google Scholar 

  • Dobson MJ, Tuite MF, Roberts NA, Kingsman AJ, Kingsman SM, Perkins RE, Conroy SC, Dunbar B & Fothergill LA (1982) Conservation of high efficiency promoter sequences inSaccharomyces cerevisiae. Nucleic Acids Res. 10: 2625–2637

    Google Scholar 

  • Dohmen RJ, Strasser AWM, Zitomer RS & Hollenberg CP (1989) Regulated overproduction of α-amylase by transformation of the amylolytic yeastSchwanniomyces occidentalis. Curr. Genet. 15: 319–325

    Google Scholar 

  • Dohmen RJ, Strasser AWM, Höner CB & Hollenberg CP (1991) An efficient transformation procedure enabling longterm storage of competent cells of various yeast genera. Yeast 7: 691–692

    Google Scholar 

  • Edens L, Bom I, Ledeboer AM, Maat J, Toonen MY, Visser C & Verrips CT (1984) Synthesis and processing of the plant protein thaumatin in yeast. Cell 37: 629–633

    Google Scholar 

  • Ellis SB, Brust PF, Koutz PJ, Waters AF, Harpold MM & Gingeras TR (1985) Isolation of alcohol oxidase and two other methanol regulatable genes from the yeast,Pichia pastoris. Mol. Cell. Biol. 5: 1111–1121

    Google Scholar 

  • Emini EA, Ellis RW, Miller WJ, McAleer WJ, Scolnick EM & Gerety RJ (1986) Production and analysis of recombinant hepatitis B vaccine. Journal of Infection 13(suppl A): 3–9

    Google Scholar 

  • Emtage JS, Angal S, Doel MT, Harris TJR, Jenkins B, Lilley G & Lowe PA (1983) Synthesis of calf prochymosin (prorennin) inEscherichia coli. Proc. Natl. Acad. Sci. USA 80: 3671–3675

    Google Scholar 

  • Ernst JF (1986) Improved secretion of heterologous proteins bySaccharomyces cerevisiae: effects of promoter substitution in alpha-factor fusions. DNA 5: 483–491

    Google Scholar 

  • Fellinger AJ, Verbakel JMA, Veale RA, Sudbery PE, Bom IJ, Overbeke N & Verrips CT (1991) Expression of the α-galactosidase fromCyamopsis tetragnoloba (guar) byHansenula polymorpha. Yeast 7: 463–474

    Google Scholar 

  • Finkelstein DB & Strausberg S (1983) Heat shock-regulated production ofEscherichia coli β-galactosidase inSaccharomyces cerevisiae. Mol. Cell. Biol. 3: 1625–1633

    Google Scholar 

  • Gellissen G, Strasser AWM, Melber K, Merckelbach A, Weydemann U, Keup P, Dahlems U, Piontek M, Hollenberg CP & Janowicz ZA (1990) Die methylotrophe HefeHansenula polymorpha als Expressionssystem für heterologe Proteine. BioEngineering 5: 20–26

    Google Scholar 

  • Gellissen G, Janowicz ZA, Merckelbach A, Piontek M, Keup P, Weydemann U, Hollenberg CP & Strasser AWM (1991) Heterologous gene expression inHansenula polymorpha: efficient secretion of glucoamylase. Bio/Technology 9: 291–295

    Google Scholar 

  • Gleeson MA & Sudbery PE (1988) The methylotrophic yeasts. Yeast 4: 1–15

    Google Scholar 

  • Gleeson MA, Ortori GS & Sudbery PE (1986) Transformation of the methylotrophic yeastHansenula polymorpha. J. Gen. Microbiol. 132: 3459–3465

    Google Scholar 

  • Goff CG, Moir DT, Kohno T, Gravius TC, Smith RA, Yamasaki E & Taunton-Rigby A (1984) The expression of calf prochymosin inSaccharomyces cerevisiae. Gene 27: 35–46

    Google Scholar 

  • Grimm C & Kohli J (1988) Observations on integrative transformation inSchizosaccharomyces pombe. Mol. Gen. Genet. 215: 87–93

    Google Scholar 

  • Grinna LS & Tschopp JF (1989) Size distribution and general structural features of N-linked oligosaccharides from the methylotrophic yeast,Pichia pastoris. Yeast 5: 107–115

    Google Scholar 

  • Gunge N (1986) Linear DNA killer plasmids from the yeastKluyveromyces. Yeast 2: 153–162

    Google Scholar 

  • Hagenson MJ, Holden KA, Parker KA, Wood PJ, Cruze JA, Fuke M, Hopkins TR & Stroman DW (1989) Expression of streptokinase inPichia pastoris yeast. Enzyme Microb. Technol. 11: 650–656

    Google Scholar 

  • Hallewell RA, Mills R, Tekamp-Olson P, Blacher R, Rosenberg S, Otting F, Masiarz FR & Scandella CJ (1987) Amino terminal acetylation of authentic human Cu,Zn superoxide dismutase produced in yeast. Bio/Technology 5: 363–366

    Google Scholar 

  • Harford N, Cabezon T, Crabeel M, Simoen E, Rutgers T & de Wilde M (1983) Expression of hepatitis B surface antigen in yeast. Second WHO/IABS Symposium on Viral Hepatitis: standardization on immunoprophylaxis of infections by hepatitis B viruses, Athens, Greece 1982. Develop. Biol. Standard 54: 125–130

    Google Scholar 

  • Harkkii A, Uusitabo J, Bailey M, Pentillä M & Knowles JKC (1989) A novel fungal expression system: secretion of active calf chymosin from the filamentous fungusTrichoderma reesei. Bio/Technology 7: 596–603

    Google Scholar 

  • Hinnen A, Hicks JB & Fink GR (1978) Transformation of yeast. Proc. Natl. Acad. Sci. USA 75: 1929–1933

    Google Scholar 

  • Hinnen A, Meyhack B & Tsapis R (1983) High expression and secretion of foreign proteins in yeast. In: Korhola M & Vaisanen E (Eds) Gene Expression in Yeast, Foundation for Biotechnical and Industrial Fermentation Research, Vol. 1 (pp 157–166). Kauppakirjapaino, Helsinki

    Google Scholar 

  • Hinnen A, Meyhack B & Heim J (1989) Heterologous gene expression in yeast. In: Barr PJ, Brake AJ & Valenzuela P (Eds) Yeast Genetic Engineering (pp 193–214). Butter-worths, Boston

    Google Scholar 

  • Hitzeman RA, Hagie FF, Levine HL, Goeddel DV, Ammerer G & Hall BD (1981) Expression of a human gene for interferon in yeast. Nature 293: 717–722

    Google Scholar 

  • Hitzeman RA, Leung DW, Perry LJ, Kohr WJ, Levine HL & Goeddel DV (1983) Secretion of human interferons by yeast. Science 219: 620–625

    Google Scholar 

  • Hodgkins MA, Sudbery PE, Perry-Williams S & Goodey A (1990) Secretion of human serum albumin fromHansenula polymorpha. Yeast 6S: 435

    Google Scholar 

  • Holland JP & Holland MJ (1980) Sructural comparison of two nontandemly repeated yeast glyceraldehyde-3-phosphate dehydrogenase genes. J. Biol. Chem. 255: 2596–2605

    Google Scholar 

  • Holland MJ, Holland JP, Thill GP & Jackson KA (1981) The primary structure of two yeast enolase genes. Homology between the 5′ noncoding flanking regions of yeast enolase and glyceraldehyde-3-phosphate dehydrogenase gene. J. Biol. Chem. 256: 1385–1395

    Google Scholar 

  • Hollenberg CP & Janowicz ZA (1987) DNA molecules coding for FMDH control region. Europan patent Application, EPA No. 0299108

  • Innis MA (1989) Glycosylation of heterologous proteins inSaccharomyces cerevisiae. In: Barr PJ, Brake AJ & Valenzuela P (Eds) Yeast Genetic Engineering (pp 233–246). Butter-worths, Boston

    Google Scholar 

  • Innis MA, Holland MJ, McCabe PC, Cole GE, Wittman VP, Tal R, Watt KWK, Gelfand DH, Holland JP & Maede JH (1985) Expression, glycosylation, and secretion of anAspergillus glucoamylase bySaccharomyces cerevisiae. Science 228: 21–26

    Google Scholar 

  • Itakura K, Hirose T, Crea R, Riggs AD, Heynecker H, Bolivar F & Boyer HW (1977) Expression inEscherichia coli of a chemically synthesized gene for the hormone somatostatin. Science 198: 1056–1063

    Google Scholar 

  • Janowicz ZA, Eckart MR, Drewke C, Roggenkamp RO & Hollenberg CP (1985) Cloning and characterization of the DAS gene encoding the major methanol assimilatory enzyme from the methylotrophic yeastHansenula polymorpha. Nucleic Acids Res. 13: 2043–3062

    Google Scholar 

  • Janowicz ZA, Merckelbach A, Eckart M, Weydemann U, Roggenkamp R & Hollenberg CP (1988) Expression system based on the methylotrophic yeastHansenula polymorpha. Yeast 4S: 155

    Google Scholar 

  • Janowicz ZA, Melber K, Merckelbach A, Jacobs E, Harford N, Comberbach M & Hollenberg CP (1991) Simultaneous expression of the S and L surface antigens of hepatitis B, and formation of mixed particles in the methylotrophic yeast,Hansenula polymorpha. Yeast 7: 431–443

    Google Scholar 

  • Jigami Y, Muraki M, Harada N & Tanaka H (1986) Expression of synthetic human-lysozyme gene inSaccharomyces cerevisiae: use of a synthetic chicken-lysozyme signal sequence for secretion and processing. Gene 43: 273–279

    Google Scholar 

  • Johnston M & Davis RW (1984) Sequences that regulate the divergentGALI-GAL10 promoter inSaccharomyces cerevisiae. Mol. Cell. Biol. 4: 1440–1448

    Google Scholar 

  • Julius D, Brake A, Blair L, Kunisawa R & Thorner J (1984) Isolation of the putative structural gene for the lysine-arginine-cleaving endopeptidase required for processing of yeast prepro-α-factor. Cell 37: 1075–1083

    Google Scholar 

  • Karin M, Najarian R, Haslinger A, Valenzuela P, Welch J & Fogel S (1984) Primary structure and transcription of an amplified genetic locus: theCUPI locus of yeast. Proc. Natl. Acad. Sci. USA 81: 337–341

    Google Scholar 

  • Kaufman RJ, Wasley LC & Dorner AJ (1988) Synthesis, processing and secretion of recombinant human factor VIII expressed in mammalian cells. J. Biol. Chem. 263: 6352–6362

    Google Scholar 

  • Kellermann E & Hollenberg CP (1988) The glucose- and ethanol-dependent regulation ofPDCI fromSaccharomyces cerevisiae are controlled by two distinct promoter regions. Curr. Genet. 14: 337–344

    Google Scholar 

  • Kingsman SM, Kingsman AJ & Mellor J (1987) The production of mammalian proteins inSaccharomyces cerevisiae. Tibtech. 5: 53–57

    Google Scholar 

  • Kingsman SM, Kingsman AJ, Dobson MJ, Mellor J & Roberts NA (1988) Heterologous gene expression inSaccharomyces cerevisiae. In: Russell GE (Ed) Yeast Biotechnology (pp 113–152). Intercept Ltd, Wimborne, Dorset

    Google Scholar 

  • Klebe RJ, Harriss JV, Sharp ZD & Douglas MG (1983) A general method for polyethylene-glycol-induced transformation of bacteria and yeast. Gene 25: 333–341

    Google Scholar 

  • Klein RD & Favreau MA (1988) Transformation ofSchwanniomyces occidentalis withADE2 gene cloned fromS. occidentalis. J. Bacteriol. 170: 5572–5578

    Google Scholar 

  • Kojo H, Greenberg BD & Sugino A (1981) Yeast 2μm plasmid DNA replication in vitro: origin and direction. Proc. Natl. Acad. Sci. USA 78: 7261–7265

    Google Scholar 

  • Koutz P, Davis GR, Stillman C, Barringer K, Cregg J & Thill G (1989) Structural comparison of thePichia pastoris alcohol oxidase genes. Yeast 5: 167–177

    Google Scholar 

  • Kramer RA, DeChiara TM, Schaber MD & Hilliker S (1984) Regulated expression of a human interferon gene in yeast: control by phosphate concentration or temperature. Proc. Natl. Acad. Sci. USA 81: 367–370

    Google Scholar 

  • Kunze G, Bode R & Birnbaum D (1987) Autonomous and integrative transformation of the yeastCandida maltosa. In: Neijssel OM, Van der Meer RR & Luyben KCAM (Eds) Proc 4th Congr of Biotechnol, Vol. I (pp 398–401). Elsevier, Amsterdam

    Google Scholar 

  • Kurjan J & Herskowitz I (1982) Structure of a yeast pheromone gene (MFα): a putative α-factor precursor contains four tandem copies of mature α-factor. Cell 30: 933–943

    Google Scholar 

  • Lai PH, Everett R, Wang FF, Arakawa T & Goldwasser E (1986) Structural characterisation of human erythropoietin. J. Biol. Chem. 291: 3116–3121

    Google Scholar 

  • Ledeboer AM, Edens L, Maat J, Visser C, Bos JW, Verrips CT, Janowicz ZA, Eckart M, Roggenkamp R & Hollenberg CP (1985) Molecular cloning and characterization of a gene coding for methanol oxidase inHansenula polymorpha. Nucleic Acids Res. 13: 3063–3082

    Google Scholar 

  • Lee JD & Komagata K (1980) Taxonomic study of methanol-assimilating yeasts. J. Appl. Microbiol. 26: 133–158

    Google Scholar 

  • Lemontt JF, Wei C-M & Dackowski WR (1985) Expression of active human uterine tissue plasminogen activator in yeast. DNA 4: 419–428

    Google Scholar 

  • Mellor J, Dobson MJ, Roberts NA, Tuite MF, Emtage JS, White S, Lowe PA, Patel T, Kingsman AJ & Kingsman SM (1983) Efficient synthesis of enzymatically active calf chymosin inSaccharomyces cerevisiae. Gene 24: 1–14

    Google Scholar 

  • Meyhack B, Bajwa W, Rudolph H & Hinnen A (1982) Two yeast acid phosphatase structural genes are the result of a tandem duplication and show different degrees of homology in their promoter and coding sequences. EMBO J. 1: 675–680

    Google Scholar 

  • Moir DT (1989) Yeast mutants with increased secretion efficiency. In: Barr PJ, Brake AJ & Valenzuela P (Eds) Yeast Genetic Engineering (pp 215–231). Butterworths, Boston

    Google Scholar 

  • Moir DT, Mao J, Duncan MJ, Smith RA & Kohne T (1985) Production of calf chymosin by the yeastSaccharomyces cerevisiae. In: Developments in Industrial Microbiology, Vol. 26 (pp 75–85). Society for industrial microbiology, Arlington, VA

    Google Scholar 

  • Müller-Wiefel DE, Feist K, Twittenhof W & Brune T (1988) One year experience with the treatment of renal anaemia by recombinant human erythropoietin. Monatsschrift Kinderheilkunde 136: 514

    Google Scholar 

  • Neurath AR, Jameson BA & Huima T (1987) Hepatitis B virus proteins eliciting protective immunity. Microbiol. Sci. 4: 45–51

    Google Scholar 

  • Orr-Weaver TL, Szostak JW & Rothstein RJ (1981) Yeast transformation: a model system for the study of recombination. Proc. Natl. Acad. Sci. USA 78: 6354–6358

    Google Scholar 

  • Petre J, van Wijnendaele F, de Neys B, Conrath K, van Opstal O, Hauser P, Rutgers T, Cabezon T, Capiau C, Harford N, de Wilde M, Stephenne J, Carr S, Hemling H & Swadish J (1987) Development of a hepatitis B vaccine from transformed yeast cells. Postgrad. Med. J. 63(suppl 2): 73–81

    Google Scholar 

  • Phaff HJ (1985) Biology of yeasts other thanSaccharomyces. In: Demain AL, Solomon NA (Eds) Biology of Industrial Microorganisms (pp 537–562). Benjamin/Cumming, Menlo Park

    Google Scholar 

  • Piontek M, Hollenberg CP & Strasser AWM (1990)Schwanniomyces occidentalis: a promising system for expression of foreign proteins. Yeast 6S: 422

    Google Scholar 

  • Reiser J, Glumoff V, Kälin M & Ochsner U (1990) Transfer and expression of heterologous genes in yeasts other thanSaccharomyces cerevisiae. In: Reiser J (Ed) Advances in Biochemical Engineering/Biotechnology, Vol. 43. Applied Molecular Genetics (pp 75–102). Springer, Berlin

    Google Scholar 

  • Reiss B, Sprengel R & Schaller H (1984) Protein fusions with the kanamycin resistance gene from transposon Tn5. EMBO J. 3: 3317–3322

    Google Scholar 

  • Robinson JH & Browne MJ (1991) Redesigning t-PA for improved thrombolytic therapy. Tibtech. 9: 86–90

    Google Scholar 

  • Roggenkamp RO, Janowicz ZA, Stanikowski B & Hollenberg CP (1984) Biosynthesis and regulation of peroxysomal methanol oxidase from the methylotrophic yeastHansenula polymorpha. Mol. Gen. Genet. 194: 489–493

    Google Scholar 

  • Roggenkamp RO, Hansen H, Eckart M, Janowicz ZA & Hollenberg CP (1986) Transformation of the methylotrophic yeastHansenula polymorpha by autonomous replication and integration vectors. Mol. Gen. Genet. 202: 302–308

    Google Scholar 

  • Rosenberg S, Barr PJ, Najarian RC & Hallewell RA (1984) Synthesis in yeast of a functional oxidation mutant of human α1-antitrypsin. Nature 312: 77–80

    Google Scholar 

  • Rothstein SJ, Lazarus CM, Smith WE, Baulcombe DC & Gatenby AA (1984) Secretion of a wheat α-amylase expressed in yeast. Nature 308: 662–665

    Google Scholar 

  • Russell GE (1988) Yeast Biotechnology. Intercept, Wimborne, Dorset

    Google Scholar 

  • Sahm H (1977) Metabolism of methanol by yeast. In: Ghose TK, Frechter A & Blankenbrough H (Eds) Advances in Microbiological Engineering, Vol. 6 (pp 77–103). Springer, Berlin

    Google Scholar 

  • Schekman R & Novick P (1982) The secretory process and yeast cell-surface assembly. In: Strathern JN, Jones EW & Broach JR (Eds) The Molecular Biology of the YeastSaccharomyces cerevisiae (pp 361–393). Cold Spring Harbour Laboratory, Cold Spring Harbour, New York

    Google Scholar 

  • Schmitt HD, Ciriacy M & Zimmermann FK (1983) The synthesis of yeast pyruvate decarboxylase is regulated by large variations in the messenger RNA level. Mol. Gen. Genet 192: 247–252

    Google Scholar 

  • Shen SH, Bastien L, Nguyen T, Fung M & Slilaty SN (1989) Synthesis and secretion of hepatitis B middle surface antigen by the methylotrophic yeastHansenula polymorpha. Gene 84: 304–309

    Google Scholar 

  • Siegel RS, Buckholz R & Thill GP (1989) Production of epidermal growth factor inPichia pastoris yeast cells. European patent application W090/10697

  • Sierkstra LN, Verbakel JMA & Verrips CT (1991) Optimisation of a host/vector system for heterologous gene expression byHansenula polymorpha. Curr. Genet. 19: 81–87

    Google Scholar 

  • Smith RA, Duncan MJ & Moir DT (1985) Heterologous protein secretion from yeast. Science 229: 1219–1224

    Google Scholar 

  • Sreekrishna K, Nelles L, Potenz R, Cruze J, Mazzaferro P, Fish W, Fuke M, Holden K, Phelps D, Wood P & Parker K (1989) High-level expression, purification, and characterisation of recombinant human tumor necrosis factor synthesized in the methylotrophic yeast,Pichia pastoris. Biochemistry 28: 4117–4125

    Google Scholar 

  • Stepien PP, Brousseau R, Wu R, Narang S & Thomas DY (1983) Synthesis of a human insulin gene VI. Expression of the synthetic proinsulin gene in yeast. Gene 24: 289–297

    Google Scholar 

  • Struhl K, Stinchkomb DT, Scherer S & Davis RW (1979) High frequency transformation of yeast: autonomous replication of hybrid molecules. Proc. Natl. Acad. Sci. USA 76: 1035–1039

    Google Scholar 

  • Sturley SL & Young TW (1988) Genetic manipulation of commerical yeast strains. In: Russell GE (Ed) Yeast Biotechnology (pp 1–38). Intercept, Wimborne, Dorset

    Google Scholar 

  • Taussig R & Carlson M (1983) Nucleotide sequence of the yeastSUC2 gene for invertase. Nucleic Acids Res. 11: 1943–1954

    Google Scholar 

  • Thim L, Hansen MT, Norris K, Hoegh I, Boel E, Forstrom J, Ammerer G & Fiil NP (1986) Secretion and processing of insulin precursor in yeast. Proc. Natl. Acad. Sci. USA 83: 6766–6770

    Google Scholar 

  • Tschopp JF, Brust BF, Cregg JM, Stillman CA & Gingeras TR (1987) Expression of the lacZ gene from two methanol-regulated promoters inPichia pastoris. Nucleic Acids Res. 9: 3859–3876

    Google Scholar 

  • Tschopp JF, Sverlow G, Kosson R, Craig W & Grinna L (1987) High-level secretion of glycosylated invertase in the methylotrophic yeast,Pichia pastoris. Bio/Technology 5: 1305–1308

    Google Scholar 

  • Tuite MF, Dobson MJ, Roberts NA, King RM, Burke DC, Kingsman SM & Kingsman AJ (1982) Regulated high efficiency expression of human interferon-alpha inSaccharomyces cerevisiae. EMBO J. 1: 603–608

    Google Scholar 

  • Valenzuela P, Medina A, Rutter WJ, Ammerer G & Hall BD (1982) Synthesis and assembly of hepatitis B virus surface antigen particles in yeast. Nature 298: 347–350

    Google Scholar 

  • van den Berg JA, van der Laken KJ, van Ooyen AJJ, Renniers TCHM, Rietveld K, Schaap A, Brake AJ, Bishop RJ, Schultz K, Moyer D, Richman M & Shuster JR (1990)Kluyveromyces as a host for heterologous gene expression: expression and secretion of prochymosin. Bio/Technology 8: 135–139

    Google Scholar 

  • Vedvick T, Buckholz RG, Engel M, Urcan M, Kinney J, Provow S, Siegel RS & Thill GP (1991) High-level secretion of biologically active aprotinin from the yeastPichia pastoris. J. Industrial Microbiol. 7: 197–202

    Google Scholar 

  • Veenhuis M, van Dijken JP & Harder W (1983) The significance of peroxysomes in the metabolism of one-carbon compounds in yeasts. Adv. Microb. Physiol. 24: 1–82

    Google Scholar 

  • Waters MG, Evans EA & Blobel G (1988) Prepro α-factor has a cleavable signal sequence. J. Biol. Chem. 263: 6209–6214

    Google Scholar 

  • Wegner GH (1990) Emerging applications of the methylotrophic yeasts. FEMS Microbiology Reviews 87: 279–284

    Google Scholar 

  • Wood WI, Capon DJ, Simonsen CC, Eaton DL, Gitschier J, Keyt B, Seeburg PH, Smith DH, Hollingshead P, Wion KL, Delwart E, Tuddenham GD, Vehar GA & Lacon RM (1984) Expression of active human factor VIII from recombinant DNA clones. Nature 312: 330–337

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Rhein Biotech GmbH, Eichsfelder Str. 11, 4000, Düsseldorf 13, Germany

    Gerd Gellissen, Karl Melber, Zbigniew A. Janowicz, Ulrike M. Dahlems, Ulrike Weydemann, Michael Piontek & Alexander W. M. Strasser

  2. Institut für Mikrobiologie, Heinrich-Heine-Universität, Universitätsstr. 1, 4000, Düsseldorf 1, Germany

    Cornelis P. Hollenberg

Authors
  1. Gerd Gellissen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karl Melber
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zbigniew A. Janowicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ulrike M. Dahlems
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ulrike Weydemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Piontek
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alexander W. M. Strasser
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cornelis P. Hollenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gellissen, G., Melber, K., Janowicz, Z.A. et al. Heterologous protein production in yeast. Antonie van Leeuwenhoek 62, 79–93 (1992). https://doi.org/10.1007/BF00584464

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00584464

Key words

Search

Navigation