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Review Articles

Metabolic engineering of Yarrowia lipolytica for terpenoids production: advances and perspectives

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Pages 618-633 | Received 19 Feb 2021, Accepted 08 Jun 2021, Published online: 29 Jul 2021

References

  • Gershenzon J, Dudareva N. The function of terpene natural products in the natural world. Nat Chem Biol. 2007;3(7):408–414.
  • Christianson DW. Structural and chemical biology of terpenoid cyclases. Chem Rev. 2017;117(17):11570–11648.
  • Pichersky E, Raguso RA. Why do plants produce so many terpenoid compounds? New Phytol. 2018;220(3):692–702.
  • Martin VJJ, Pitera DJ, Withers ST, et al. Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nat Biotechnol. 2003;21(7):796–802.
  • Wang CL, Liwei M, Park JB, et al. Microbial platform for terpenoid production: Escherichia coli and yeast. Front Microbiol. 2018;9:2460.
  • Chang MCY, Eachus RA, Trieu W, et al. Engineering Escherichia coli for production of functionalized terpenoids using plant P450s. Nat Chem Biol. 2007;3(5):274–277.
  • De Mey M, De Maeseneire S, Soetaert W, et al. Minimizing acetate formation in E. coli fermentations. J Ind Microbiol Biotechnol. 2007;34(11):689–700.
  • Immethun CM, Hoynes-O'Connor AG, Balassy A, et al. Microbial production of isoprenoids enabled by synthetic biology. Front Microbiol. 2013;4:75.
  • Moser S, Pichler H. Identifying and engineering the ideal microbial terpenoid production host. Appl Microbiol Biotechnol. 2019;103(14):5501–5516.
  • Nielsen J. Synthetic biology for engineering acetyl coenzyme A metabolism in yeast. mBio. 2014;5(6):e02153.
  • Palmer CM, Alper HS. Expanding the chemical palette of industrial microbes: metabolic engineering for type III PKS-derived polyketides. Biotechnol J. 2019;14(1):e1700463.
  • Dai ZJ, Huang M, Chen Y, et al. Global rewiring of cellular metabolism renders Saccharomyces cerevisiae Crabtree negative. Nat Commun. 2018;9(1):3059.
  • Madzak C. Yarrowia lipolytica: recent achievements in heterologous protein expression and pathway engineering. Appl Microbiol Biotechnol. 2015;99(11):4559–4577.
  • Vandermies M, Fickers P. Bioreactor-scale strategies for the production of recombinant protein in the yeast Yarrowia lipolytica. Microorganisms. 2019;7(2):40.
  • Ma JB, Gu Y, Marsafari M, et al. Synthetic biology, systems biology, and metabolic engineering of Yarrowia lipolytica toward a sustainable biorefinery platform. J Ind Microbiol Biotechnol. 2020;47(9-10):845–862.
  • Fickers P, Cheng HR, Sze Ki Lin C. Sugar alcohols and organic acids synthesis in Yarrowia lipolytica: where are we? Microorganisms. 2020;8(4):574.
  • Xu YR, Chi P, Bilal M, et al. Biosynthetic strategies to produce xylitol: an economical venture. Appl Microbiol Biotechnol. 2019;103(13):5143–5160.
  • Wang JP, Ledesma-Amaro R, Wei YJ, et al. Metabolic engineering for increased lipid accumulation in Yarrowia lipolytica - A Review. Bioresour Technol. 2020;313:123707.
  • Kothri M, Mavrommati M, Elazzazy AM, et al. Microbial sources of polyunsaturated fatty acids (PUFAs) and the prospect of organic residues and wastes as growth media for PUFA-producing microorganisms. FEMS Microbiol Lett. 2020;367(5):fnaa028.
  • Yan Q, Pfleger BF. Revisiting metabolic engineering strategies for microbial synthesis of oleochemicals. Metab Eng. 2020;58:35–46.
  • Spagnuolo M, Yaguchi A, Blenner M. Oleaginous yeast for biofuel and oleochemical production. Curr Opin Biotechnol. 2019;57:73–81.
  • Muhammad A, Feng XD, Rasool A, et al. Production of plant natural products through engineered Yarrowia lipolytica. Biotechnol Adv. 2020;43:107555.
  • Groenewald M, Boekhout T, Neuveglise C, et al. Yarrowia lipolytica: safety assessment of an oleaginous yeast with a great industrial potential. Crit Rev Microbiol. 2014;40(3):187–206.
  • Liu H, Marsafari M, Wang F, et al. Engineering acetyl-CoA metabolic shortcut for eco-friendly production of polyketides triacetic acid lactone in Yarrowia lipolytica. Metab Eng. 2019;56:60–68.
  • Lv YK, Marsafari M, Koffas M, et al. Optimizing oleaginous yeast cell factories for flavonoids and hydroxylated flavonoids biosynthesis. ACS Synth Biol. 2019;8(11):2514–2523.
  • Markham KA, Palmer CM, Chwatko M, et al. Rewiring Yarrowia lipolytica toward triacetic acid lactone for materials generation. Proc Natl Acad Sci U S A. 2018;115(9):2096–2101.
  • Ma YR, Wang KF, Wang WJ, et al. Advances in the metabolic engineering of Yarrowia lipolytica for the production of terpenoids. Bioresour Technol. 2019;281:449–456.
  • Arnesen JA, Kildegaard KR, Pastor MC, et al. Yarrowia lipolytica strains engineered for the production of terpenoids. Front Bioeng Biotechnol. 2020;8:945.
  • Worland AM, Czajka JJ, Li Y, et al. Biosynthesis of terpene compounds using the non-model yeast Yarrowia lipolytica: grand challenges and a few perspectives. Curr Opin Biotechnol. 2020;64:134–140.
  • Vranova E, Coman D, Gruissem W. Network analysis of the MVA and MEP pathways for isoprenoid synthesis. Annu Rev Plant Biol. 2013;64(1):665–700.
  • Kirby J, Keasling JD. Metabolic engineering of microorganisms for isoprenoid production. Nat Prod Rep. 2008;25(4):656–661.
  • Cao X, Lv YB, Chen J, et al. Metabolic engineering of oleaginous yeast Yarrowia lipolytica for limonene overproduction. Biotechnol Biofuels. 2016;9:214.
  • Cheng BQ, Wei LJ, Lv YB, et al. Elevating limonene production in oleaginous yeast Yarrowia lipolytica via genetic engineering of limonene biosynthesis pathway and optimization of medium composition. Biotechnol Bioproc E. 2019;24(3):500–506.
  • Pang YR, Zhao YK, Li SL, et al. Engineering the oleaginous yeast Yarrowia lipolytica to produce limonene from waste cooking oil. Biotechnol Biofuels. 2019;12:241.
  • Yao F, Liu SC, Wang DN, et al. Engineering oleaginous yeast Yarrowia lipolytica for enhanced limonene production from xylose and lignocellulosic hydrolysate. FEMS Yeast Res. 2020;20(6):foaa046.
  • Cao X, Wei LJ, Lin JY, et al. Enhancing linalool production by engineering oleaginous yeast Yarrowia lipolytica. Bioresour Technol. 2017;245(Pt B):1641–1644.
  • Wei LJ, Zhong YT, Nie MY, et al. Biosynthesis of α-pinene by genetically engineered Yarrowia lipolytica from low-cost renewable feedstocks. J Agric Food Chem. 2021;69(1):275–285.
  • Rolf J, Julsing MK, Rosenthal K, et al. A gram-scale limonene production process with engineered Escherichia coli. Molecules. 2020;25(8):1881.
  • Dusseaux S, Wajn WT, Liu YX, et al. Transforming yeast peroxisomes into microfactories for the efficient production of high-value isoprenoids. Proc Natl Acad Sci U S A. 2020;117(50):31789–31799.
  • Guo XY, Sun J, Li DS, et al. Heterologous biosynthesis of (+)-nootkatone in unconventional yeast Yarrowia lipolytica. Biochem Eng J. 2018;137:125–131.
  • Jia D, Xu S, Sun J, et al. Yarrowia lipolytica construction for heterologous synthesis of α-santalene and fermentation optimization. Appl Microbiol Biotechnol. 2019;103(8):3511–3520.
  • Marsafari M, Xu P, Debottlenecking mevalonate pathway for antimalarial drug precursor amorphadiene biosynthesis in Yarrowia lipolytica. Metab Eng Commun. 2020;10:e00121.
  • Yang X, Nambou K, Wei LJ, et al. Heterologous production of α-farnesene in metabolically engineered strains of Yarrowia lipolytica. Bioresour Technol. 2016;216:1040–1048.
  • Liu YH, Jiang X, Cui ZY, et al. Engineering the oleaginous yeast Yarrowia lipolytica for production of α-farnesene. Biotechnol Biofuels. 2019;12:296.
  • Zhao YK, Zhu K, Li J, et al. High-efficiency production of bisabolene from waste cooking oil by metabolically engineered Yarrowia lipolytica. Microb Biotechnol. 2021:1–17.
  • Ma YR, Li WJ, Mai J, et al. Engineering Yarrowia lipolytica for sustainable production of the chamomile sesquiterpene (−)-α-bisabolol. Green Chem. 2021;23(2):780–787.
  • You SP, Yin QD, Zhang JY, et al. Utilization of biodiesel by-product as substrate for high-production of β-farnesene via relatively balanced mevalonate pathway in Escherichia coli. Bioresour Technol. 2017;243:228–236.
  • Meadows AL, Hawkins KM, Tsegaye Y, et al. Rewriting yeast central carbon metabolism for industrial isoprenoid production. Nature. 2016;537(7622):694–697.
  • Wu YF, Xu S, Gao X, et al. Enhanced protopanaxadiol production from xylose by engineered Yarrowia lipolytica. Microb Cell Fact. 2019;18(1):83.
  • Li DS, Wu YF, Zhang CB, et al. Production of triterpene ginsenoside compound K in the non-conventional yeast Yarrowia lipolytica. J Agric Food Chem. 2019;67(9):2581–2588.
  • Li DS, Wu YF, Wei PP, et al. Metabolic engineering of Yarrowia lipolytica for heterologous oleanolic acid production. Cheml Eng Sci. 2020;218:115529.
  • Zhang JL, Bai QY, Peng YZ, et al. High production of triterpenoids in Yarrowia lipolytica through manipulation of lipid components. Biotechnol Biofuels. 2020;13:133.
  • Sun J, Zhang CB, Nan WH, et al. Glycerol improves heterologous biosynthesis of betulinic acid in engineered Yarrowia lipolytica. Chem Eng Sci. 2019;196:82–90.
  • Jin CC, Zhang JL, Song H, et al. Boosting the biosynthesis of betulinic acid and related triterpenoids in Yarrowia lipolytica via multimodular metabolic engineering. Microb Cell Fact. 2019;18(1):77.
  • Huang YY, Jian XX, Lv YB, et al. Enhanced squalene biosynthesis in Yarrowia lipolytica based on metabolically engineered acetyl-CoA metabolism. J Biotechnol. 2018;281:106–114.
  • Liu H, Wang F, Deng L, et al. Genetic and bioprocess engineering to improve squalene production in Yarrowia lipolytica. Bioresour Technol. 2020;317:123991.
  • Meng YH, Shao XX, Wang Y, et al. Extension of cell membrane boosting squalene production in the engineered Escherichia coli. Biotechnol Bioeng. 2020;117(11):3499–3507.
  • Han JY, Seo SH, Song JM, et al. High-level recombinant production of squalene using selected Saccharomyces cerevisiae strains. J Ind Microbiol Biotechnol. 2018;45(4):239–251.
  • Nambou K, Jian XX, Zhang XK, et al. Flux balance analysis inspired bioprocess upgrading for lycopene production by a metabolically engineered strain of Yarrowia lipolytica. Metabolites. 2015;5(4):794–813.
  • Schwartz C, Frogue K, Misa J, et al. Host and pathway engineering for enhanced lycopene biosynthesis in Yarrowia lipolytica. Front Microbiol. 2017;8:2233.
  • Liu D, Liu H, Qi H, et al. Constructing yeast chimeric pathways to boost lipophilic terpene synthesis. ACS Synth Biol. 2019;8(4):724–733.
  • Zhang XK, Nie MY, Chen J, et al. Multicopy integrants of crt genes and co-expression of AMP deaminase improve lycopene production in Yarrowia lipolytica. J Biotechnol. 2019;289:46–54.
  • Luo ZS, Liu N, Lazar Z, et al. Enhancing isoprenoid synthesis in Yarrowia lipolytica by expressing the isopentenol utilization pathway and modulating intracellular hydrophobicity. Metab Eng. 2020;61:344–351.
  • Gao SL, Tong YY, Zhu L, et al. Production of β-carotene by expressing a heterologous multifunctional carotene synthase in Yarrowia lipolytica. Biotechnol Lett. 2017;39(6):921–927.
  • Gao SL, Tong YY, Zhu L, et al. Iterative integration of multiple-copy pathway genes in Yarrowia lipolytica for heterologous β-carotene production. Metab Eng. 2017;41:192–201.
  • Larroude M, Celinska E, Back A, et al. A synthetic biology approach to transform Yarrowia lipolytica into a competitive biotechnological producer of β-carotene. Biotechnol Bioeng. 2018;115(2):464–472.
  • Zhang XK, Wang DN, Chen J, et al. Metabolic engineering of β-carotene biosynthesis in Yarrowia lipolytica. Biotechnol Lett. 2020;42(6):945–956.
  • Qiang S, Wang J, Xiong XC, et al. Promoting the synthesis of precursor substances by overexpressing hexokinase (Hxk) and hydroxymethylglutaryl-CoA synthase (Erg13) to elevate β-carotene production in engineered Yarrowia lipolytica. Front Microbiol. 2020;11:1346.
  • Kildegaard KR, Adiego-Perez B, Belda DD, et al. Engineering of Yarrowia lipolytica for production of astaxanthin. Synth Syst Biotechnol. 2017;2(4):287–294.
  • Tramontin LRR, Kildegaard KR, Sudarsan S, et al. Enhancement of astaxanthin biosynthesis in oleaginous yeast Yarrowia lipolytica via microalgal pathway. Microorganisms. 2019;7(10):472.
  • Czajka JJ, Kambhampati S, Tang YJ, et al. Application of stable isotope tracing to elucidate metabolic dynamics during Yarrowia lipolytica α-ionone fermentation. iScience. 2020;23(2):100854.
  • Czajka JJ, Nathenson JA, Benites VT, et al. Engineering the oleaginous yeast Yarrowia lipolytica to produce the aroma compound β-ionone. Microb Cell Fact. 2018;17(1):136.
  • Lu YP, Yang QY, Lin ZL, et al. A modular pathway engineering strategy for the high-level production of β-ionone in Yarrowia lipolytica. Microb Cell Fact. 2020;19(1):49.
  • Yang JM, Guo LZ, Biosynthesis of β-carotene in engineered E. coli using the MEP and MVA pathways. Microb Cell Fact. 2014;13:160.
  • Sun L, Atkinson CA, Lee YG, et al. High-level β-carotene production from xylose by engineered Saccharomyces cerevisiae without overexpression of a truncated HMG1 (tHMG1). Biotechnol Bioeng. 2020;117(11):3522–3532.
  • Spagnuolo M, Hussain MS, Gambill L, et al. Alternative substrate metabolism in Yarrowia lipolytica. Front Microbiol. 2018;9:1077.
  • Iida T, Sumita T, Ohta A, et al. The cytochrome P450ALK multigene family of an n-alkane-assimilating yeast, Yarrowia lipolytica: cloning and characterization of genes coding for new CYP52 family members. Yeast. 2000;16(12):1077–1087.
  • Mirończuk AM, Rzechonek DA, Biegalska A, et al. A novel strain of Yarrowia lipolytica as a platform for value-added product synthesis from glycerol. Biotechnol Biofuels. 2016;9(1):180.
  • Jeffries TW. Emerging technology for fermenting D-xylose. Trends Biotechnol. 1985;3(8):208–212.
  • Ledesma-Amaro R, Lazar Z, Rakicka M, et al. Metabolic engineering of Yarrowia lipolytica to produce chemicals and fuels from xylose. Metab Eng. 2016;38:115–124.
  • Li HB, Alper HS. Enabling xylose utilization in Yarrowia lipolytica for lipid production. Biotechnol J. 2016;11(9):1230–1240.
  • Lazar Z, Dulermo T, Neuveglise C, et al. Hexokinase-a limiting factor in lipid production from fructose in Yarrowia lipolytica. Metab Eng. 2014;26:89–99.
  • Dulermo T, Lazar Z, Dulermo R, et al. Analysis of ATP-citrate lyase and malic enzyme mutants of Yarrowia lipolytica points out the importance of mannitol metabolism in fatty acid synthesis. Biochim Biophys Acta. 2015;1851(9):1107–1117.
  • Burg JS, Espenshade PJ. Regulation of HMG-CoA reductase in mammals and yeast. Prog Lipid Res. 2011;50(4):403–410.
  • Zhao FL, Bai P, Liu T, et al. Optimization of a cytochrome P450 oxidation system for enhancing protopanaxadiol production in Saccharomyces cerevisiae. Biotechnol Bioeng. 2016;113(8):1787–1795.
  • Zhang Y, Wang Y, Yao MD, et al. Improved campesterol production in engineered Yarrowia lipolytica strains. Biotechnol Lett. 2017;39(7):1033–1039.
  • Zhou YJ, Gao W, Rong QX, et al. Modular pathway engineering of diterpenoid synthases and the mevalonic acid pathway for miltiradiene production. J Am Chem Soc. 2012;134(6):3234–3241.
  • Tanaka S, Tani M. Mannosylinositol phosphorylceramides and ergosterol coodinately maintain cell wall integrity in the yeast Saccharomyces cerevisiae. Febs J. 2018;285(13):2405–2427.
  • Mori K, Iwama R, Kobayashi S, et al. Transcriptional repression by glycerol of genes involved in the assimilation of n-alkanes and fatty acids in yeast Yarrowia lipolytica. FEMS Yeast Res. 2013;13(2):233–240.
  • Qiao KJ, Wasylenko TM, Zhou K, et al. Lipid production in Yarrowia lipolytica is maximized by engineering cytosolic redox metabolism. Nat Biotechnol. 2017;35(2):173–177.
  • Liu H, Marsafari M, Deng L, et al. Understanding lipogenesis by dynamically profiling transcriptional activity of lipogenic promoters in Yarrowia lipolytica. Appl Microbiol Biotechnol. 2019;103(7):3167–3179.
  • Workman M, Holt P, Thykaer J. Comparing cellular performance of Yarrowia lipolytica during growth on glucose and glycerol in submerged cultivations. AMB Express. 2013;3(1):58.
  • Zhang M, Gu L, Cheng C, et al. Recent advances in microbial production of mannitol: utilization of low-cost substrates, strain development and regulation strategies. World J Microbiol Biotechnol. 2018;34(3):41.
  • Wei LJ, Kwak S, Liu JJ, et al. Improved squalene production through increasing lipid contents in Saccharomyces cerevisiae. Biotechnol Bioeng. 2018;115(7):1793–1800.
  • Xu P, Qiao KJ, Ahn WS, et al. Engineering Yarrowia lipolytica as a platform for synthesis of drop-in transportation fuels and oleochemicals. Proc Natl Acad Sci U S A. 2016;113(39):10848–10853.
  • Matthaus F, Ketelhot M, Gatter M, et al. Production of lycopene in the non-carotenoid-producing yeast Yarrowia lipolytica. Appl Environ Microbiol. 2014;80(5):1660–1669.
  • Brennan TCR, Turner CD, Kromer JO, et al. Alleviating monoterpene toxicity using a two-phase extractive fermentation for the bioproduction of jet fuel mixtures in Saccharomyces cerevisiae. Biotechnol Bioeng. 2012;109(10):2513–2522.
  • Zhao C, Gao Q, Chen J, et al. Metabolomic changes and metabolic responses to expression of heterologous biosynthetic genes for lycopene production in Yarrowia lipolytica. J Biotechnol. 2017;251:174–185.
  • Zhao C, Yang Y, Wei LF, et al. Simultaneous determination of intracellular nucleotides and coenzymes in Yarrowia lipolytica producing lipid and lycopene by capillary zone electrophoresis. J Chromatogr A. 2017;1514:120–126.
  • Le Guen T, Ragu S, Guirouilh-Barbat J, et al. Role of the double-strand break repair pathway in the maintenance of genomic stability. Mol Cell Oncol. 2015;2(1):e968020.
  • Kretzschmar A, Otto C, Holz M, et al. Increased homologous integration frequency in Yarrowia lipolytica strains defective in non-homologous end-joining. Curr Genet. 2013;59(1-2):63–72.
  • Abdel-Mawgoud AM, Stephanopoulos G. Improving CRISPR/Cas9-mediated genome editing efficiency in Yarrowia lipolytica using direct tRNA-sgRNA fusions. Metab Eng. 2020;62:106–115.
  • van Rossum HM, Kozak BU, Pronk JT, et al. Engineering cytosolic acetyl-coenzyme A supply in Saccharomyces cerevisiae: pathway stoichiometry, free-energy conservation and redox-cofactor balancing. Metab Eng. 2016;36:99–115.
  • Hartline CJ, Schmitz AC, Han Y, et al. Dynamic control in metabolic engineering: theories, tools, and applications. Metab Eng. 2021;63:126–140.
  • Lv YK, Gu Y, Xu JL, et al. Coupling metabolic addiction with negative autoregulation to improve strain stability and pathway yield. Metab Eng. 2020;61:79–88.
  • Keeling CI, Bohlmann J, Genes, enzymes and chemicals of terpenoid diversity in the constitutive and induced defence of conifers against insects and pathogens. New Phytol. 2006;170(4):657–675.
  • Sun WT, Qin L, Xue HJ, et al. Novel trends for producing plant triterpenoids in yeast. Crit Rev Biotechnol. 2019;39(5):618–632.
  • Zhou F, Pichersky E, More is better: the diversity of terpene metabolism in plants. Curr Opin Plant Biol. 2020;55:1–10.