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Heterologous production of secondary metabolites as pharmaceuticals in Saccharomyces cerevisiae

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Abstract

Heterologous expression of genes involved in the biosynthesis of various products is of increasing interest in biotechnology and in drug research and development. Microbial cells are most appropriate for this purpose. Availability of more microbial genomic sequences in recent years has greatly facilitated the elucidation of metabolic and regulatory networks and helped gain overproduction of desired metabolites or create novel production of commercially important compounds. Saccharomyces cerevisiae, as one of the most intensely studied eukaryotic model organisms with a rich density of knowledge detailing its genetics, biochemistry, physiology, and large-scale fermentation performance, can be capitalized upon to enable a substantial increase in the industrial application of this yeast. In this review, we describe recent efforts made to produce commercial secondary metabolites in Saccharomyces cerevisiae as pharmaceuticals. As natural products are increasingly becoming the center of attention of the pharmaceutical and nutraceutical industries, such as naringenin, coumarate, artemisinin, taxol, amorphadiene and vitamin C, the use of S. cerevisiae for their production is only expected to expand in the future, further allowing the biosynthesis of novel molecular structures with unique properties.

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References

  • Akashi T, Aoki T, Ayabe S (1999) Cloning and functional expression of a cytochrome P450 cDNA encoding 2-hydroxyisoflavanone synthase involved in biosynthesis of the isoflavonoid skeleton in licorice. Plant Physiol 121:821–828

    Article  PubMed  CAS  Google Scholar 

  • Anzellotti D, Ibrahim RK (2004) Molecular characterization and functional expression of flavonol 6-hydroxylase. BMC Plant Biol 4:20

    Article  PubMed  CAS  Google Scholar 

  • Asadollahi MA, Maury J, Moller K, Nielsen KF, Schalk M, Clark A, Nielsen J (2007) Production of plant sesquiterpenes in Saccharomyces cerevisiae: effect of ERG9 repression on sesquiterpene biosynthesis. Biotechnol Bioeng 99:666–677

    Article  CAS  Google Scholar 

  • Banhegyi G, Braun L, Csala M, Puskas F, Mandl J (1997) Ascorbate metabolism and its regulation in animals. Free Radic Biol Med 23:793–803

    Article  PubMed  CAS  Google Scholar 

  • Becker JV, Armstrong GO, van der Merwe MJ, Lambrechts MG, Vivier MA, Pretorius IS (2003) Metabolic engineering of Saccharomyces cerevisiae for the synthesis of the wine-related antioxidant resveratrol. FEMS Yeast Res 4:79–85

    Article  PubMed  CAS  Google Scholar 

  • Beekwilder J, Wolswinkel R, Jonker H, Hall R, de Vos CH, Bovy A (2006) Production of resveratrol in recombinant microorganisms. Appl Environ Microbiol 72:5670–5672

    Article  PubMed  CAS  Google Scholar 

  • Branduardi P, Fossati T, Sauer M, Pagani R, Mattanovich D, Porro D (2007) Biosynthesis of vitamin C by yeast leads to increased stress resistance. PLoS ONE 2:e1092

    Article  PubMed  CAS  Google Scholar 

  • Cereghino JL, Cregg JM (2000) Heterologous protein expression in the methylotrophic yeast Pichia pastoris. FEMS Microbiol Rev 24:45–66

    Article  PubMed  CAS  Google Scholar 

  • Chemler JA, Yan Y, Koffas MA (2006) Biosynthesis of isoprenoids, polyunsaturated fatty acids and flavonoids in Saccharomyces cerevisiae. Microb Cell Fact 5:20

    Article  PubMed  CAS  Google Scholar 

  • Dejong JM, Liu Y, Bollon AP, Long RM, Jennewein S, Williams D, Croteau RB (2006) Genetic engineering of taxol biosynthetic genes in Saccharomyces cerevisiae. Biotechnol Bioeng 93:212–224

    Article  PubMed  CAS  Google Scholar 

  • Dixon RA (2004) Phytoestrogens. Annu Rev Plant Physiol Plant Mol Biol 55:225–261

    CAS  Google Scholar 

  • Dominguez A, Ferminan E, Sanchez M, Gonzalez FJ, Perez-Campo FM, Garcia S, Herrero AB, San Vicente A, Cabello J, Prado M, Iglesias FJ, Choupina A, Burguillo FJ, Fernandez-Lago L, Lopez MC (1998) Non-conventional yeasts as hosts for heterologous protein production. Int Microbiol 1:131–142

    PubMed  CAS  Google Scholar 

  • Forster J, Famili I, Fu P, Palsson BO, Nielsen J (2003) Genome-scale reconstruction of the Saccharomyces cerevisiae metabolic network. Genome Res 13:244–253

    Article  PubMed  CAS  Google Scholar 

  • Gardner RG, Hampton RY (1999) A highly conserved signal controls degradation of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-CoA) reductase in eukaryotes. J Biol Chem 274:31671–31678

    Article  PubMed  CAS  Google Scholar 

  • Gasser B, Maurer M, Gach J, Kunert R, Mattanovich D (2006) Engineering of Pichia pastoris for improved production of antibody fragments. Biotechnol Bioeng 94:353–361

    Article  PubMed  CAS  Google Scholar 

  • Gellissen G (2000) Heterologous protein production in methylotrophic yeasts. Appl Microbiol Biotechnol 54:741–750

    Article  PubMed  CAS  Google Scholar 

  • Gellissen G, Hollenberg CP (1997) Application of yeasts in gene expression studies: a comparison of Saccharomyces cerevisiae, Hansenula polymorpha and Kluyveromyces lactis—a review. Gene 190:87–97

    Article  PubMed  CAS  Google Scholar 

  • Giga-Hama Y, Kumagai H (1999) Expression system for foreign genes using the fission yeast Schizosaccharomyces pombe. Biotechnol Appl Biochem 30(Pt 3):235–244

    PubMed  CAS  Google Scholar 

  • Goffeau A, Barrell BG, Bussey H, Davis RW, Dujon B, Feldmann H, Galibert F, Hoheisel JD, Jacq C, Johnston M, Louis EJ, Mewes HW, Murakami Y, Philippsen P, Tettelin H, Oliver SG (1996) Life with 6000 genes. Science 274:546, 563–547

    Google Scholar 

  • Hezari M, Lewis NG, Croteau R (1995) Purification and characterization of taxa-4(5),11(12)-diene synthase from Pacific yew (Taxus brevifolia) that catalyzes the first committed step of taxol biosynthesis. Arch Biochem Biophys 322:437–444

    Article  PubMed  CAS  Google Scholar 

  • Horswill AR, Escalante-Semerena JC (1999) The prpE gene of Salmonella typhimurium LT2 encodes propionyl-CoA synthetase. Microbiology 145(Pt 6):1381–1388

    Article  PubMed  CAS  Google Scholar 

  • Huh WK, Lee BH, Kim ST, Kim YR, Rhie GE, Baek YW, Hwang CS, Lee JS, Kang SO (1998) d-Erythroascorbic acid is an important antioxidant molecule in Saccharomyces cerevisiae. Mol Microbiol 30:895–903

    Article  PubMed  CAS  Google Scholar 

  • Huh WK, Kim ST, Kim H, Jeong G, Kang SO (2001) Deficiency of d-erythroascorbic acid attenuates hyphal growth and virulence of Candida albicans. Infect Immun 69:3939–3946

    Article  PubMed  CAS  Google Scholar 

  • Jennewein S, Park H, DeJong JM, Long RM, Bollon AP, Croteau RB (2005) Coexpression in yeast of Taxus cytochrome P450 reductase with cytochrome P450 oxygenases involved in Taxol biosynthesis. Biotechnol Bioeng 89:588–598

    Article  PubMed  CAS  Google Scholar 

  • Jiang H, Wood KV, Morgan JA (2005) Metabolic engineering of the phenylpropanoid pathway in Saccharomyces cerevisiae. Appl Environ Microbiol 71:2962–2969

    Article  PubMed  CAS  Google Scholar 

  • Khosla C, Keasling JD (2003) Metabolic engineering for drug discovery and development. Nat Rev Drug Discov 2:1019–1025

    Article  PubMed  CAS  Google Scholar 

  • Kim DH, Kim BG, Lee HJ, Lim Y, Hur HG, Ahn JH (2005) Enhancement of isoflavone synthase activity by co-expression of P450 reductase from rice. Biotechnol Lett 27:1291–1294

    Article  PubMed  CAS  Google Scholar 

  • Knekt P, Jarvinen R, Seppanen R, Rissanen A, Aromaa A, Heinonen OP, Albanes D, Heinonen M, Pukkala E, Teppo L (1991) Dietary antioxidants and the risk of lung cancer. Am J Epidemiol 134:471–479

    PubMed  CAS  Google Scholar 

  • Levine M (1986) New concepts in the biology and biochemistry of ascorbic acid. N Engl J Med 314:892–902

    PubMed  CAS  Google Scholar 

  • Maury J, Asadollahi MA, Moller K, Clark A, Nielsen J (2005) Microbial isoprenoid production: an example of green chemistry through metabolic engineering. Adv Biochem Eng Biotechnol 100:19–51

    PubMed  CAS  Google Scholar 

  • Mercke P, Crock J, Croteau R, Brodelius PE (1999) Cloning, expression, and characterization of epi-cedrol synthase, a sesquiterpene cyclase from Artemisia annua L. Arch Biochem Biophys 369:213–222

    Article  PubMed  CAS  Google Scholar 

  • Mercke P, Bengtsson M, Bouwmeester HJ, Posthumus MA, Brodelius PE (2000) Molecular cloning, expression, and characterization of amorpha-4,11-diene synthase, a key enzyme of artemisinin biosynthesis in Artemisia annua L. Arch Biochem Biophys 381:173–180

    Article  PubMed  CAS  Google Scholar 

  • Metcalf RL (1987) Plant volatiles as insect attractants. CRC Crit Rev Plant Sci 5:251–301

    CAS  Google Scholar 

  • Murray RDH (1991) Progress in the chemistry of organic natural products. Springer Wien, New York

    Google Scholar 

  • Mutka SC, Bondi SM, Carney JR, Da Silva NA, Kealey JT (2006) Metabolic pathway engineering for complex polyketide biosynthesis in Saccharomyces cerevisiae. FEMS Yeast Res 6:40–47

    Article  PubMed  CAS  Google Scholar 

  • Naidu KA (2003) Vitamin C in human health and disease is still a mystery? An overview. Nutr J 2:7

    Article  PubMed  Google Scholar 

  • Newman DJ, Cragg GM, Snader KM (2000) The influence of natural products upon drug discovery (Antiquity to late 1999). Nat Prod Rep 17:215–234

    Article  PubMed  CAS  Google Scholar 

  • Nielsen J (1998) Metabolic engineering: techniques for analysis of targets for genetic manipulations. Biotechnol Bioeng 58:125–132

    Article  PubMed  CAS  Google Scholar 

  • Nielsen J (2001) Metabolic engineering. Appl Microbiol Biotechnol 55:263–283

    Article  PubMed  CAS  Google Scholar 

  • O’Brien TJ, Ceryak S, Patierno SR (2003) Complexities of chromium carcinogenesis: role of cellular response, repair and recovery mechanisms. Mutat Res 533:3–36

    PubMed  CAS  Google Scholar 

  • Oswald M, Fischer M, Dirninger N, Karst F (2007) Monoterpenoid biosynthesis in Saccharomyces cerevisiae. FEMS Yeast Res 7:413–421

    Article  PubMed  CAS  Google Scholar 

  • Padh H (1990) Cellular functions of ascorbic acid. Biochem Cell Biol 68:1166–1173

    Article  PubMed  CAS  Google Scholar 

  • Padh H (1991) Vitamin C: newer insights into its biochemical functions. Nutr Rev 49:65–70

    PubMed  CAS  Google Scholar 

  • Patil KR, Akesson M, Nielsen J (2004) Use of genome-scale microbial models for metabolic engineering. Curr Opin Biotechnol 15:64–69

    Article  PubMed  CAS  Google Scholar 

  • Porro D, Sauer M, Branduardi P, Mattanovich D (2005) Recombinant protein production in yeasts. Mol Biotechnol 31:245–259

    Article  PubMed  CAS  Google Scholar 

  • Pretorius IS, Bauer FF (2002) Meeting the consumer challenge through genetically customized wine-yeast strains. Trends Biotechnol 20:426–432

    Article  PubMed  CAS  Google Scholar 

  • Ralston L, Subramanian S, Matsuno M, Yu O (2005) Partial reconstruction of flavonoid and isoflavonoid biosynthesis in yeast using soybean type I and type II chalcone isomerases. Plant Physiol 137:1375–1388

    Article  PubMed  CAS  Google Scholar 

  • Ro DK, Douglas CJ (2004) Reconstitution of the entry point of plant phenylpropanoid metabolism in yeast (Saccharomyces cerevisiae): implications for control of metabolic flux into the phenylpropanoid pathway. J Biol Chem 279:2600–2607

    Article  PubMed  CAS  Google Scholar 

  • Ro DK, Paradise EM, Ouellet M et al (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440:940–943

    Article  PubMed  CAS  Google Scholar 

  • Robin J, Jakobsen M, Beyer M, Noorman H, Nielsen J (2001) Physiological characterisation of Penicillium chrysogenum strains expressing the expandase gene from Streptomyces clavuligerus during batch cultivations. Growth and adipoyl-7-aminodeacetoxycephalosporanic acid production. Appl Microbiol Biotechnol 57:357–362

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez E, Gramajo H (1999) Genetic and biochemical characterization of the alpha and beta components of a propionyl-CoA carboxylase complex of Streptomyces coelicolor A3(2). Microbiology 145(Pt 11):3109–3119

    PubMed  CAS  Google Scholar 

  • Rodriguez AP, Leiro RF, Trillo MC, Cerdan ME, Siso MI, Becerra M (2006) Secretion and properties of a hybrid Kluyveromyces lactis-Aspergillus niger beta-galactosidase. Microb Cell Fact 5:41

    Article  PubMed  CAS  Google Scholar 

  • Schoenbohm C, Martens S, Eder C, Forkmann G, Weisshaar B (2000) Identification of the Arabidopsis thaliana flavonoid 3′-hydroxylase gene and functional expression of the encoded P450 enzyme. Biol Chem 381:749–753

    Article  PubMed  CAS  Google Scholar 

  • Shiba Y, Paradise EM, Kirby J, Ro DK, Keasling JD (2007) Engineering of the pyruvate dehydrogenase bypass in Saccharomyces cerevisiae for high-level production of isoprenoids. Metab Eng 9:160–168

    Article  PubMed  CAS  Google Scholar 

  • Spickett CM, Smirnoff N, Pitt AR (2000) The biosynthesis of erythroascorbate in Saccharomyces cerevisiae and its role as an antioxidant. Free Radic Biol Med 28:183–192

    Article  PubMed  CAS  Google Scholar 

  • Sudbery PE (1996) The expression of recombinant proteins in yeasts. Curr Opin Biotechnol 7:517–524

    Article  PubMed  CAS  Google Scholar 

  • Takahashi S, Zhao Y, O’Maille PE et al (2005) Kinetic and molecular analysis of 5-epiaristolochene 1,3-dihydroxylase, a cytochrome P450 enzyme catalyzing successive hydroxylations of sesquiterpenes. J Biol Chem 280:3686–3696

    Article  PubMed  CAS  Google Scholar 

  • Takahashi S, Yeo Y, Greenhagen BT et al (2007) Metabolic engineering of sesquiterpene metabolism in yeast. Biotechnol Bioeng 97:170–181

    Article  PubMed  CAS  Google Scholar 

  • Theobald U, Mailinger W, Reuss M, Rizzi M (1993) In vivo analysis of glucose-induced fast changes in yeast adenine nucleotide pool applying a rapid sampling technique. Anal Biochem 214:31–37

    Article  PubMed  CAS  Google Scholar 

  • Theobald U, Mailinger W, Baltes M, Rizzi M, Reuss M (1997) In vivo analysis of metabolic dynamics in Saccharomyces cerevisiae. I. Experimental observations. Biotechnol Bioeng 55:305–316

    Article  CAS  PubMed  Google Scholar 

  • Tian L, Dixon RA (2006) Engineering isoflavone metabolism with an artificial bifunctional enzyme. Planta 224:496–507

    Article  PubMed  CAS  Google Scholar 

  • Trommer H, Bottcher R, Poppl A, Hoentsch J, Wartewig S, Neubert RH (2002) Role of ascorbic acid in stratum corneum lipid models exposed to UV irradiation. Pharm Res 19:982–990

    Article  PubMed  CAS  Google Scholar 

  • Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160:1–40

    Article  PubMed  CAS  Google Scholar 

  • Vannelli T, Wei Qi W, Sweigard J, Gatenby AA, Sariaslani FS (2007) Production of p-hydroxycinnamic acid from glucose in Saccharomyces cerevisiae and Escherichia coli by expression of heterologous genes from plants and fungi. Metab Eng 9:142–151

    Article  PubMed  CAS  Google Scholar 

  • Vaseghi S, Baumeister A, Rizzi M, Reuss M (1999) In vivo dynamics of the pentose phosphate pathway in Saccharomyces cerevisiae. Metab Eng 1:128–140

    Article  PubMed  CAS  Google Scholar 

  • Vivier MA, Pretorius IS (2002) Genetically tailored grapevines for the wine industry. Trends Biotechnol 20:472–478

    Article  PubMed  CAS  Google Scholar 

  • Wheeler GL, Jones MA, Smirnoff N (1998) The biosynthetic pathway of vitamin C in higher plants. Nature 393:365–369

    Article  PubMed  CAS  Google Scholar 

  • Withers ST, Keasling JD (2007) Biosynthesis and engineering of isoprenoid small molecules. Appl Microbiol Biotechnol 73:980–990

    Article  PubMed  CAS  Google Scholar 

  • Yan Y, Kohli A, Koffas MA (2005) Biosynthesis of natural flavanones in Saccharomyces cerevisiae. Appl Environ Microbiol 71:5610–5613

    Article  PubMed  CAS  Google Scholar 

  • Yan Y, Huang L, Koffas MA (2007) Biosynthesis of 5-deoxyflavanones in microorganisms. Biotechnol J 2:1250–1262

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Li SZ, Li J, Pan X, Cahoon RE, Jaworski JG, Wang X, Jez JM, Chen F, Yu O (2006) Using unnatural protein fusions to engineer resveratrol biosynthesis in yeast and Mammalian cells. J Am Chem Soc 128:13030–13031

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This research was funded by Shanghai Science and Technology Committee (No. 054319936) and the National Natural Science Foundation of China (No. 20702062).

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Authors and Affiliations

  1. Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China

    Beibei Huang, Jing Guo, Bo Yi, Xiaojing Yu & Wansheng Chen

  2. Modern Research Center for Traditional Chinese Medicine, Second Military Medical University, Shanghai, 200433, China

    Beibei Huang, Jing Guo, Bo Yi, Xiaojing Yu & Wansheng Chen

  3. Department of Pharmacognosy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China

    Lianna Sun

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  1. Beibei Huang
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Correspondence to Lianna Sun or Wansheng Chen.

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Huang, B., Guo, J., Yi, B. et al. Heterologous production of secondary metabolites as pharmaceuticals in Saccharomyces cerevisiae . Biotechnol Lett 30, 1121–1137 (2008). https://doi.org/10.1007/s10529-008-9663-z

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