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Yeast metabolic engineering for the production of pharmaceutically important secondary metabolites

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Abstract

In the last few decades, there has been a rapid increase in the discovery of drugs from natural products, particularly secondary metabolites. Various efforts have been undertaken to enhance and optimize the production system of these secondary metabolites to meet the increasing global market demand. Recently, metabolic engineering has been used for the heterologous synthesis of secondary metabolites in the engineered yeast strains. Here, we highlight the recent advancements in the production of pharmaceutically important secondary metabolites in metabolically engineered yeast, such as Saccharomyces cerevisiae and Pichia pastoris. Furthermore, we also emphasize the important application of synthetic biology methods that are supported by state-of-the-art post-genomic tools to improve the efficiency and success rate of yeast metabolic engineering for the production of natural drugs. Metabolic engineering using yeast as a microbial host factory to produce pharmaceutically useful secondary metabolites is a very promising strategy, which can be used to support the industrial production system.

Key points

•Next-generation sequencing application for genome mining of secondary metabolites

•Various synthetic biology tools for yeast metabolic engineering construction

•Examples of successfully produced medicinal secondary metabolites in engineered yeast

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References

  • Agrawal P, Khater S, Gupta M, Sain N, Mohanty D (2017) RiPPMiner: a bioinformatics resource for deciphering chemical structures of RiPPs based on prediction of cleavage and cross-links. Nucleic Acids Res 45:80–88

    Google Scholar 

  • Alberti S, Gitler AD, Lindquist S (2007) A suite of Gateway® cloning vectors for high-throughput genetic analysis in Saccharomyces cerevisiae. Yeast 24:913–919

    CAS  PubMed  PubMed Central  Google Scholar 

  • Albertsen L, Chen Y, Bach LS, Rattleff S, Maury J, Brix S (2011) Diversion of flux toward sesquiterpene production in Saccharomyces cerevisiae by fusion of host and heterologous enzymes. Appl Environ Microbiol 77:1033–1040

    CAS  PubMed  Google Scholar 

  • Aliper A, Jellen L, Cortese F, Artemov A, Karpinsky-Semper D, Moskalev A, Swick AG, Zhavoronkov A (2017) Towards natural mimetics of metformin and rapamycin. Aging 9:11

    Google Scholar 

  • Anett P, Steiger MG, Caterina H, Lang C, Mattanovich D, Sauer M (2015) Enhanced glutathione production by evolutionary engineering of Saccharomyces cerevisiae strains. Biotechnol J 10:1719–1726

    Google Scholar 

  • Babiskin AH, Smolke CD (2011) Synthetic library of RNA control modules for predictable tuning of gene expression in yeast. Mol Syst Biol 7:1–15

    Google Scholar 

  • Benson DA, Karsch-Mizrachi I, Lipman DJ, Ostell J, Sayers EW (2011) GenBank. Nucleic Acids Res 39:32–37

    Google Scholar 

  • Blin K, Shaw S, Steinke K, Villebro R, Ziemert N, Lee SY, Medema MH, Weber T (2019) antiSMASH 5.0: updates to the secondary metabolite genome mining pipeline. Nucleic Acids Res 47:81–87

    Google Scholar 

  • Bond CM, Tang Y (2019) Engineering Saccharomyces cerevisiae for production of simvastatin. Metab Eng 51:1–8

    CAS  PubMed  Google Scholar 

  • Brakhage AA, Schuemann J, Bergmann S, Scherlach K, Schroeckh V, Hertweck C (2008) Activation of fungal silent gene clusters: a new avenue to drug discovery. Prog Drug Res 66(1):3–12

    Google Scholar 

  • Brown S, Clastre M, Courdavault V, Connor SEO (2015) De novo production of the plant derived alkaloid strictosidine in yeast. Proc Natl Acad Sci 112:3205–3210

    CAS  PubMed  Google Scholar 

  • Brückner A, Polge C, Lentze N, Auerbach D, Schlattner U (2009) Yeast two-hybrid, a powerful tool for systems biology. Int J Mol Sci 10(6):2763–2788. https://doi.org/10.3390/ijms10062763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carroll D (2011) Genome engineering with zinc-finger nucleases. Genetics 188:773–782

    CAS  PubMed  PubMed Central  Google Scholar 

  • Challis GL (2008) Genome mining for novel natural product discovery. J Med Chem 51:2618–2628

    CAS  PubMed  Google Scholar 

  • Choi JE, Choi SH, Lee JS, Lee KC, Kang SM, Kim JI, Cjoi MS, Kim HG, Seo WT, Lee KY, Moon BC, Kang YM (2018a) Analysis of microbial communities in local cultivars of astringent persimmon (Diospyros kaki) fruits grown in Gyeongnam Province of Korea. J Environ Biol 39:237–246

    CAS  Google Scholar 

  • Choi SS, Katsuyama Y, Bai L, Deng Z, Ohnishi Y, Kim ES (2018b) Genome engineering for microbial natural product discovery. Curr Opin Microbiol 45:53–60

    CAS  PubMed  Google Scholar 

  • Curran KA, Karim AS, Gupta A, Alper HS (2013) Use of expression-enhancing terminators in Saccharomyces cerevisiae to increase mRNA half-life and improve gene expression control for metabolic engineering applications. Metab Eng 19:88–97

  • DiCarlo JE, Conley AJ, Penttila M, Jantti J, Wang HH, Church GM (2013) Yeast oligo-mediated genome engineering (YOGE). ACS Synth Biol 2:741–749

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ding MZ, Yan HF, Li LF, Zhai F, Shang LQ, Yin Z, Yuan YJ (2014) Biosynthesis of taxadiene in Saccharomyces cerevisiae: selection of geranylgeranyl diphosphate synthase directed by a computer-aided docking strategy. PLoS One 9:10

    PubMed Central  Google Scholar 

  • Eichenberger M, Lehka BJ, Folly C, Fischer D, Martens S, Simón E, Naesby M (2017) Metabolic engineering of Saccharomyces cerevisiae for de novoproduction of dihydrochalcones with known antioxidant, antidiabetic, and sweet tasting properties. Metab Eng 39:80–89

    CAS  PubMed  PubMed Central  Google Scholar 

  • Engels B, Dahm P, Jennewein S (2008) Metabolic engineering of taxadiene biosynthesis in yeast as a first step towards Taxol (Paclitaxel) production. Metab Eng 10:201–206

    CAS  PubMed  Google Scholar 

  • Fidan O, Zhan J (2015) Recent advances in engineering yeast for pharmaceutical protein production. RSC Adv:1–3

  • Fossati E, Ekins A, Narcross L, Zhu Y, Falgueyret J, Beaudoin GAW, Facchini PJ, Martin VJJ (2014) Reconstitution of a 10-gene pathway for synthesis of the plant alkaloid dihydrosanguinarine in Saccharomyces cerevisiae. Nat Commun 5:1–11

    Google Scholar 

  • Fossati E, Narcross L, Ekins A, Falgueyret J, Vincent J (2015) Synthesis of morphinan alkaloids in Saccharomyces cerevisiae. PLoS One 10:1–15

    Google Scholar 

  • Frias UA, Pereira GKB, Guazzaroni ME, Silva-Rocha R (2018) Boosting secondary metabolite production and discovery through the engineering of novel microbial biosensors. Biomed Res Int 1: 1-11. doi.org/https://doi.org/10.1155/2018/7021826

  • Galanie S, Smolke CD (2012) Optimization of yeast-based production of medicinal protoberberine alkaloids. Microb Cell Factories 14:144

    Google Scholar 

  • Galanie S, Thodey K, Trenchard IJ, Filsinger Interrante M, Smolke CD (2015) Complete biosynthesis of opioids in yeast. Science 349:1095–1100

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gao L, Cai M, Shen W, Xiao S, Zhou X, Zhang Y (2013) Engineered fungal polyketide biosynthesis in Pichia pastoris: a potential excellent host for polyketide production. Microb Cell Factories 12:77

    Google Scholar 

  • Gibson DG, Young L, Chuang RY, Venter JC, Hutchison CA, Smith HO (2009) Enzymatic assembly of DNA molecules up to several hundred kilobases. Nat Methods 6:343–345

    CAS  PubMed  Google Scholar 

  • Gilbert LA, Larson MH, Morsut L, Liu Z, Brar GA, Torres SE, Stern-Ginossar N, Brandman O, Whitehead EH, Doudna JA, Lim WA, Weissman JS, Qi LS (2013) CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154:442–451

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hara KY, Kiriyama K, Inagaki A (2012) Improvement of glutathione production by metabolic engineering the sulfate assimilation pathway of Saccharomyces cerevisiae. Appl Microbiol Biotechnol 94:1313–1319

    CAS  PubMed  Google Scholar 

  • Hara KY, Aoki N, Kobayashi J, Kiriyama K (2015) Improvement of oxidized glutathione fermentation by thiol redox metabolism engineering in Saccharomyces cerevisiae. Appl Microbiol Biotechnol 99:9771–9778

    CAS  PubMed  Google Scholar 

  • Hawkins KM, Smolke CD (2008) Production of benzylisoquinoline alkaloids in Saccharomyces cerevisiae. Nat Chem Biol 4:564–573

  • Hershkovitz V, Sela N, Salaime LT, Liu J, Kessler C, Aly R, Levy M, Wisniewski M, Droby S (2013) De-novo assembly and characterization of the transcriptome of Metschnikowia fructicola reveals differences in gene expression following interaction with Penicillium digitatum and grapefruit peel. BMC Genomics 14:168

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hoffman CS, Wood V, Fantes PA (2015) An ancient yeast for young geneticists: a primer on the Schizosaccharomyces pombe model system. Genetics 201(2):403–423. https://doi.org/10.1534/genetics.115.181503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ignea C, Ioannou E, Georgantea P, Trikka FA, Athanasakoglou A, Loupassaki S, Roussis V, Makris AM, Kampranis SC (2016) Production of the forskolin precursor 11 β-hydroxy-manoyl oxide in yeast using surrogate enzymatic activities. Microb Cell Factories 15:46

  • Jacobs JZ, Ciccaglione KM, Tournier V, Zaratiegui M (2014) Implementation of the CRISPR-Cas9 system in fission yeast. Nat Commun 5:5344

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jensen MK, Keasling JD (2015) Recent applications of synthetic biology tools for yeast metabolic engineering. FEMS Yeast Res 15:1–12

    CAS  PubMed  Google Scholar 

  • Kang YM, Choi JE, Komakech R, Park JH, Kim DW, Cho KM, Kang SM, Choi SH, Song KC, Ryu CM, Lee KC, Lee JS (2017) Characterization of a novel yeast species Metschnikowia persimmonesis KCTC 12991BP (KIOM G15050 type strain) isolated from a medicinal plant, Korean persimmon calyx (Diospyros kaki Thumb). AMB Express 7:199

    PubMed  PubMed Central  Google Scholar 

  • Kealey JT, Liu L, Santi DV, Betlach MC, Barr PJ (1998) Production of a polyketide natural product in nonpolyketide-producing prokaryotic and eukaryotic host. Proc Natl Acad Sci U S A 95:505–509

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim HU, Charusanti P, Lee SY, Weber T (2016) Metabolic engineering with systems biology tools to optimize production of prokaryotic secondary metabolites. Nat Prod Rep 33:933

    CAS  PubMed  Google Scholar 

  • Kim YS, Kweon J, Kim A, Chon JK, Yoo JY, Kim HJ, Kim S, Lee C, Jeong E, Chung E, Kim D, Lee MS, Go EM, Song HJ, Kim H, Cho N, Bang D, Kim S, Kim JS (2013) A library of TAL effector nucleases spanning the human genome. Nat Biotechnol 31(3):251–258

  • Koopman F, Beekwilder J, Crimi B, Houwelingen A, Hall RD, Bosch D, Maris AJA, Pronk JT, Daran JM (2012) De novo production of the flavonoid naringenin in engineered Saccharomyces cerevisiae. Microb Cell Factories 11:155

    CAS  Google Scholar 

  • Kurtzman CP, Piškur J (2006) Taxonomy and phylogenetic diversity among the yeasts. In: Sunnerhagen P, Piskur J (eds) Comparative genomics: using Fungi as models. Springer, Berlin, pp 29–46

    Google Scholar 

  • Larionov V, Kouprina N, Graves J, Chen XN, Korenberg J, Resnick MA (1996) Specific cloning of human DNA as yeast artificial chromosomes by transformation-associated recombination. Proc Natl Acad Sci 93:491–496

    CAS  PubMed  Google Scholar 

  • Lee SY, Kim HU (2015) Systems strategies for developing industrial microbial strains. Nat Biotechnol 33:1061–1072

    CAS  PubMed  Google Scholar 

  • Lee ME, Aswani A, Han AS, Tomlin CJ (2013) Expression-level optimization of a multi-enzyme pathway in the absence of a high-throughput assay. Nucleic Acids Res 41:22

    Google Scholar 

  • Li Y, Smolke CD (2016) Engineering biosynthesis of the anticancer alkaloid noscapine in yeast. Nat Commun 7:1–14

    Google Scholar 

  • Li M, Kildegaard KR, Chen Y, Rodriguez A, Borodina I, Nielsen J (2015) De novo production of resveratrol from glucose or ethanol by engineered Saccharomyces cerevisiae. Metab Eng 32:1–11

    PubMed  Google Scholar 

  • Li M, Schneider K, Kristensen M, Borodina I, Nielsen J (2016) Engineering yeast for high-level production of stilbenoid antioxidants. Sci Rep 6:1–8

    Google Scholar 

  • Lian J, Mishrab S, Zhao H (2018) Recent advances in metabolic engineering of Saccharomyces cerevisiae: new tools and their applications. Metab Eng 50:85–108

    CAS  PubMed  Google Scholar 

  • Liu XB, Liu M, Tao XY, Zhang ZX, Wang FQ, Wei DZ (2015) Metabolic engineering of Pichia pastoris for the production of dammarenediol-II. J Biotechnol 216:47–55

    CAS  PubMed  Google Scholar 

  • Liu X, Cheng J, Zhang G, Ding W, Duan L, Yang J, Kui L, Cheng X, Ruan J, Fan W, Chen J, Long G, Zhao Y, Cai J, Wang W, Ma Y, Dong Y, Yang S, Jiang H (2018a) Engineering yeast for the production of breviscapine by genomic analysis and synthetic biology approaches. Nat Commun 9:448

    PubMed  PubMed Central  Google Scholar 

  • Liu Y, Tu X, Xu Q, Bai KC, Liu Q, Yu J, Peng Q, Zhou X, Zhang Y, Cai M (2018b) Engineered monoculture and co-culture of methylotrophic yeast for de novo production of monacolin J and lovastatin from methanol. Metab Eng 45:189–199

    CAS  PubMed  Google Scholar 

  • Löbs AK, Schwartz C, Wheeldon I (2017) Genome and metabolic engineering in non-conventional yeasts: current advances and applications. Synth Syst Biotechnol 2(3):198–207

    PubMed  PubMed Central  Google Scholar 

  • Meyer V (2008) Genetic engineering of filamentous fungi: progress, obstacles and future trends. Biotechnol Adv 26:177–185. https://doi.org/10.1016/j.biotechadv.2007.12.001

    Article  CAS  PubMed  Google Scholar 

  • Moses T, Pollier J, Almagro L, Buyst D, Montagu MV, Pedreño MA, Martins JC, Thevelein JM, Goossens A (2014) Combinatorial biosynthesis of sapogenins and saponins in Saccharomyces cerevisiae using a C-16α hydroxylase from Bupleurum falcatum. Proc Natl Acad Sci U S A 111:1634–1639

    CAS  PubMed  PubMed Central  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

    CAS  PubMed  Google Scholar 

  • Nam KH, Chung HJ, Jeon EJ, Park MK, Yim YH, Liu JR, Park JH (2007) In vitro biosynthesis of strictosidine using lonicera japonica leaf extracts and recombinant yeast. J Plant Bio 50:315–320

    CAS  Google Scholar 

  • Nielsen AAK, Segall-Shapiro TH, Voigt CA (2013) Advances in genetic circuit design: novel biochemistries, deep part mining and precision gene expression. Curr Opin Chem Biol 17:878–892

    CAS  PubMed  Google Scholar 

  • Obst U, Lu TK, Sieber V (2017) A modular toolkit for generating Pichia pastoris secretion libraries. ACS Synth Biol 6:1016–1025. https://doi.org/10.1021/acssynbio.6b00337

    Article  CAS  PubMed  Google Scholar 

  • Orumets K, Kevvai K, Nisamedtinov I, Tamm T, Paalme T (2012) YAP1 over-expression in Saccharomyces cerevisiae enhances glutathione accumulation at its biosynthesis and substrate availability levels. Biotechnol J 7:566–568

    CAS  PubMed  Google Scholar 

  • Ozaydin B, Burd H, Lee TS, Keasling JD (2012) Carotenoid-based phenotypic screen of the yeast deletion collection reveals new genes with roles in isoprenoid production. Metab Eng 15:174–183

    PubMed  Google Scholar 

  • Paddon CJ, Westfall PJ, Pitera DJ, Benjamin K, Fisher K, McPhee D, Leavell MD, Tai A, Main A, Eng D, Polichuk DR, Teoh KH, Reed DW, Treynor T, Lenihan J, Fleck M, Bajad S, Dang G, Dengrove D, Diola D, Dorin G, Ellens KW, Fickes S, Galazzo J, Gaucher SP, Geistlinger T, Henry R, Hepp M, Horning T, Iqbal T, Jiang H, Kizer L, Lieu B, Melis D, Moss N, Regentin R, Secrest S, Tsuruta H, Vazquez R, Westblade LF, Xu L, Yu M, Zhang Y, Zhao L, Lievense J, Covello PS, Keasling JD, Reiling KK, Renninger NS, Newman JD (2013) High-level semisynthetic production of the potent antimalarial artemisinin. Nature. 496:528–532

    CAS  PubMed  Google Scholar 

  • Palmer AE, Qin Y, Park JG, McCombs JE (2011) Design and application of genetically encoded biosensors. Trends Biotechnol 29:144–152

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pena DA, Gasser B, Zanghellinia J, Steigera MG, Mattanovich D (2018) Metabolic engineering of Pichia pastoris. Metab Eng 50:2–15

    CAS  PubMed  Google Scholar 

  • Prielhofer R, Barrero JJ, Steuer S, Gassler T, Zahrl R, Baumann K, Sauer M, Mattanovich M, Gasser B, Marx H (2017) GoldenPiCS: a golden gate-derived modular cloning system for applied synthetic biology in the yeast Pichia pastoris. BMC Syst Biol 11:123

    PubMed  PubMed Central  Google Scholar 

  • Qi LS, Arkin AP (2014) A versatile framework for microbial engineering using synthetic non-coding RNAs. Nat Rev Microbiol 12:341–354

    CAS  PubMed  Google Scholar 

  • Rahmat E, Kang Y (2019) Adventitious root culture for secondary metabolite production in medicinal plants: a review. J Plant Biotechnol 46:143–157

    Google Scholar 

  • Ro DK, Paradise EM, Ouellet M, Fisher KJ, Newman KL, Ndungu JM, Ho KA, Eachus RA, Ham TS, Kirby J, Chang MCY, Withers ST, Shiba Y, Sarpong R, Keasling JD (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440:940–943

    CAS  PubMed  Google Scholar 

  • Rodriguez A, Kildegaard KR, Li M, Borodina I, Nielsen J (2015) Establishment of a yeast platform strain for production of p-coumaric acid through metabolic engineering of aromatic amino acid biosynthesis. Metab Eng 31:181–188

    CAS  PubMed  Google Scholar 

  • Rottig M, Medema MH, Blin K, Weber T, Rausch C, Kohlbacher O (2011) NRPSpredictor2: a web server for predicting NRPS adenylation domain specificity. Nucleic Acids Res 39:362–367

    Google Scholar 

  • Salis HM, Mirsky EA, Voigt CA (2009) Automated design of synthetic ribosome binding sites to control protein expression. Nat Biotechnol 27(10):946–950. https://doi.org/10.1038/nbt.1568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sander JD, Joung JK (2014) CRISPR-Cas systems for editing, regulating and targeting genomes. Nat Biotechnol 32:347–355

    CAS  PubMed  PubMed Central  Google Scholar 

  • Scalcinati G, Knuf C, Partow S (2012) Dynamic control of gene expression in Saccharomyces cerevisiae engineered for the production of plant sesquitepene α-santalene in a fed-batch mode. Metab Eng 14(2):91–103

    CAS  PubMed  Google Scholar 

  • Schreiber V, Dersch J, Puzik K, Bäcker O, Liu X, Stork S, Schulz J, Heimerl T, Klingl A, Zauner S, Maier UG (2017) The central vacuole of the diatom Phaeodactylum tricornutum: identification of new vacuolar membrane proteins and of a functional di-leucine-based targeting motif. Protist 168:271–282. https://doi.org/10.1016/j.protis.2017.03.001

    Article  CAS  PubMed  Google Scholar 

  • Shin SY, Han NS, Park YC, Kim MD, Seo JH (2011) Production of resveratrol from p-coumaric acid in recombinant Saccharomyces cerevisiae expressing 4-coumarate: coenzyme A ligase and stilbene synthase genes. Enzym Microb Technol 2011; 48:48–53

  • Shin SY, Jung SM, Kim MD, Han NS, Seo JH (2012) Production of resveratrol from tyrosine in metabolically engineered Saccharomyces cerevisiae. Enzym Microb Technol 51:211–216

    CAS  Google Scholar 

  • Siddiqui MS, Thodey K, Trenchard I, Smolke CD (2012) Advancing secondary metabolite biosynthesis in yeast with synthetic biology tools. FEMS Yeast Res 12:144–170

    CAS  PubMed  Google Scholar 

  • Sigoillot M, Brockhoff A, Lescop E, Poirier N, Meyerhof W, Briand L (2012) Optimization of the production of gurmarin, a sweet-taste-suppressing protein, secreted by the methylotrophic yeast Pichia pastoris. Appl Microbiol Biotechnol 96:1253–1263

    CAS  PubMed  Google Scholar 

  • Spohner SC, Schaum V, Quitmann H, Czermak P (2016) Kluyveromyces lactis: an emerging tool in biotechnology. J Biotechnol 222:104–116

    CAS  PubMed  Google Scholar 

  • Sugiyama M, Akase S, Nakanishi R, Kaneko Y, Harashima S (2016) Overexpression of ESBP6 improves lactic acid resistance and production in Saccharomyces cerevisiae. J Biosci Bioeng 122:415–420

    CAS  PubMed  Google Scholar 

  • Sun N, Zhao H (2013) Transcription activator-like effector nucleases (TALENs): a highly efficient and versatile tool for genome editing. Biotechnol Bioeng 110:1811–1821

    CAS  PubMed  Google Scholar 

  • Sydor T, Schaffer S, Boles E (2010) Considerable increase in resveratrol production by recombinant industrial yeast strains with use of rich medium. Appl Environ Microbiol 76:3361–3363

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tong AHY, Boone C (2006) Synthetic genetic array analysis in Saccharomyces cerevisiae. In: Xiao W (ed) Yeast Protocols. Springer Science & Business Media, pp, 171–19

  • Trenchard IJ, Siddiqui MS, Thodey K, Smolke CD (2015) De novo production of the key branch point benzylisoquinoline alkaloid reticuline in yeast. Metab Eng 31:74–83

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vogl T, Glieder A (2013) Regulation of Pichia pastoris promoters and its consequences for protein production. New Biotechnol 30:385–404

    CAS  Google Scholar 

  • Vogl T, Ahmad M, Krainer FW, Schwab H, Glieder (2015) A restriction site free cloning (RSFC) plasmid family for seamless, sequence independent cloning in Pichia pastoris. Microb Cell Factories 14:103

  • Vogl T, Sturmberger L, Kickenweiz T, Wasmayer R, Schmid C, Hatzl AM, Gerstmann MA, Pitzer J, Wagner M, Thallinger GG, Geier M, Glieder A (2016) A toolbox of diverse promoters related to methanol utilization: functionally verified parts for heterologous pathway expression in Pichia pastoris. ACS Synth Biol 5(2):172–186

    CAS  PubMed  Google Scholar 

  • Voigt O, Erpenbeck D, Wörheide G (2008) A fragmented metazoan organellar genome: the two mitochondrial chromosomes of Hydra magnipapillata. BMC Genomics 9:350

    PubMed  PubMed Central  Google Scholar 

  • Wagner JM, Alper HS (2016) Synthetic biology and molecular genetics in non-conventional yeasts: current tools and future advances. Fungal Genet Biol 89:126–136. https://doi.org/10.1016/j.fgb.2015.12.001

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Yu O (2012) Synthetic scaffolds increased resveratrol biosynthesis in engineered yeast cells. J Biotechnol 157:258–260

    CAS  PubMed  Google Scholar 

  • Wang P, Wei W, Ye W, Li X, Zhao W, Yang C, Li C, Yan X, Zhou Z (2019) Synthesizing ginsenoside Rh2 in Saccharomyces cerevisiae cell factory at high-efficiency. Cell Discov 5:5

    PubMed  PubMed Central  Google Scholar 

  • Weninger A, Glieder A, Vogl T (2015) A toolbox of endogenous and heterologous nuclear localization sequences for the methylotrophic yeast Pichia pastoris. FEMS Yeast Res 15:82

    Google Scholar 

  • Westfall PJ, Pitera DJ, Lenihan JR, Eng D, Woolard FX, Regentin R, Horning T, Tsuruta H, Melis DJ, Owens A, Fickes S, Diola D, Benjamin KR, Keasling JD, Leavell MD, McPhee DJ, Renninger NS, Newman JD, Paddon CJ (2012) Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin. Proc Natl Acad Sci 109:111–118

    Google Scholar 

  • Xie W, Lv X, Ye L, Zhou P, Yu H (2015) Construction of lycopene-overproducing Saccharomyces cerevisiae by combining directed evolution and metabolic engineering. Metab Eng 30:69–78

    CAS  PubMed  Google Scholar 

  • Xu P, Wang W, Li L, Bhan N, Zhang F, Koffas MAG (2014) Design and kinetic analysis of a hybrid promoter–regulator system for malonyl-CoA sensing in Escherichia coli. ACS Chem Biol 401(9):451–458

    Google Scholar 

  • Ye VM, Bhatia SK (2012) Metabolic engineering for the production of clinically important molecules: omega-3 fatty acids, artemisinin, and taxol. Biotechnol J 7:20–33

    CAS  PubMed  Google Scholar 

  • Yin H, Ma Y, Deng Y, Xu Z, Liu J, Zhao J, Dong J (2016) Genome shuffling of Saccharomyces cerevisiae for enhanced glutathione yield and relative gene expression analysis using fluorescent quantitation reverse transcription polymerase chain reaction. J Microbiol Methods 127:188–192

    CAS  PubMed  Google Scholar 

  • Zhao C, Gao X, Liu X, Wang Y, Yang S, Wang F, Ren Y (2016) Enhancing biosynthesis of a ginsenoside precursor by self-assembly of two key enzymes in Pichia pastoris. J Agric Food Chem 64:3380–3385

    CAS  PubMed  Google Scholar 

  • Ziemert N, Podell S, Penn K, Badger JH, Allen E, Jensen PR (2012) The natural product domain seeker NaPDoS: a phylogeny based bioinformatic tool to classify secondary metabolite gene diversity. PLoS One 7:e34064

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the Development of Foundational Techniques for the Domestic Production of Herbal Medicines (K18405), Applicational Development of Standardized Herbal Resources (KSN1911420), Development of Sustainable Application for Standard Herbal Resources (KSN2012320), Korea Institute of Oriental Medicine through the Ministry of Science and ICT, Republic of Korea.

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ER contributes for acquisition of data and writing of manuscript. YMK supports the conception, design strategies, and revising for essential intellectual content of this manuscript.

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Correspondence to Youngmin Kang.

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Rahmat, E., Kang, Y. Yeast metabolic engineering for the production of pharmaceutically important secondary metabolites. Appl Microbiol Biotechnol 104, 4659–4674 (2020). https://doi.org/10.1007/s00253-020-10587-y

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