Abstract
As essential structural molecules of fungal cell membrane, ergosterol is not only an important component of fungal growth and stress-resistance but also a key precursor for manufacturing steroid drugs of pharmaceutical or agricultural significance. So far, ergosterol biosynthesis in yeast has been elucidated elaborately, and efforts have been made to increase ergosterol production through regulation of ergosterol metabolism and storage. Furthermore, the same intermediates shared by yeasts and animals or plants make the construction of heterologous sterol pathways in yeast a promising approach to synthesize valuable steroids, such as phytosteroids and animal steroid hormones. During these challenging processes, several obstacles have arisen and been combated with great endeavors. This paper reviews recent research progress of yeast metabolic engineering for improving the production of ergosterol and heterologous steroids. The remaining tactics are also discussed.
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Abbreviations
- 7-DHC:
-
7-Dehydrocholesterol
- CDP:
-
Cytidine diphosphate
- CDP-DAG:
-
Cytidine diphosphate-diacylglycerol
- CFP:
-
Cyan fluorescent protein
- CPR:
-
Cytochrome P450 reductase
- DAG:
-
Diacylglycerol
- DD:
-
Dammarenediol-II
- E4P:
-
Erythrose 4-phosphate
- ePTS1:
-
Enhanced efficiency PTS1
- ER:
-
Endoplasmic reticulum
- F6P:
-
Fructose-6-phosphate
- FPP:
-
Farnesyl pyrophosphate
- G6P:
-
Glucose-6-phophate
- HCVcp:
-
Hepatitis C virus core protein 118–164 amino acids
- HSDs:
-
Hydroxysteroid dehydrogenases
- LD:
-
Lipid droplet
- LDL:
-
Low-density lipoprotein
- MLS:
-
Mitochondrial leader sequence
- MVA:
-
Mevalonate
- Ole:
-
Oleosin
- PA:
-
Phosphatidic acid
- PP:
-
Pentose phosphate
- PPD:
-
Protopanaxadiol
- PPDS:
-
Protopanaxadiol synthase
- PTS:
-
Peroxisome targeted sequence
- ROS:
-
Reactive oxygen species
- SE:
-
Steryl ester
- TAG:
-
Triacylglycerols
References
Abramova NE, Cohen BD, Sertil O, Kapoor R, Davies KJA, Lowry CV (2001) Regulatory mechanisms controlling expression of the DAN/TIR mannoprotein genes during anaerobic remodeling of the cell wall in Saccharomyces cerevisiae. Genetics 157(3):1169–1177. https://doi.org/10.1093/genetics/157.3.1169
Adeyo O, Horn PJ, Lee SK, Binns DD, Chandrahas A, Chapman KD, Goodman JM (2011) The yeast lipin orthologue Pah1p is important for biogenesis of lipid droplets. J Cell Biol 192(6):1043–1055. https://doi.org/10.1083/jcb.201010111
Aguilera F, Peinado RA, Millan C, Ortega JM, Mauricio JC (2006) Relationship between ethanol tolerance, H+-ATPase activity and the lipid composition of the plasma membrane in different wine yeast strains. Int J Food Microbiol 110(1):34–42. https://doi.org/10.1016/j.ijfoodmicro.2006.02.002
Arendt P, Miettinen K, Pollier J, De Rycke R, Callewaert N, Goossens A (2017) An endoplasmic reticulum-engineered yeast platform for overproduction of triterpenoids. Metab Eng 40:165–175. https://doi.org/10.1016/j.ymben.2017.02.007
Avalos JL, Fink GR, Stephanopoulos G (2013) Compartmentalization of metabolic pathways in yeast mitochondria improves the production of branched-chain alcohols. Nat Biotechnol 31(4):335–341. https://doi.org/10.1038/nbt.2509
Baek M, DiMaio F, Anishchenko I, Dauparas J, Ovchinnikov S, Lee GR, Wang J et al (2021) Accurate prediction of protein structures and interactions using a three-track neural network. Science 373(6557):871–876. https://doi.org/10.1126/science.abj8754
Bajguz A (2011) Brassinosteroids—occurence and chemical structures in plants Brassinosteroids: a class of plant hormone. Springer, New York
Barba G, Harper F, Harada T, Kohara M, Goulinet S, Matsuura Y, Eder G et al (1997) Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. Proc Natl Acad Sci USA 94(4):1200–1205. https://doi.org/10.1073/pnas.94.4.1200
Bauman KD, Butler KS, Moore BS, Chekan JR (2021) Genome mining methods to discover bioactive natural products. Nat Prod Rep 38(11):2100–2129. https://doi.org/10.1039/d1np00032b
Bernstein JJJ, Holt GB, Bernstein J (2019) Price dispersion of generic medications. PLoS ONE. https://doi.org/10.1371/journal.pone.0225280
Brower V (2008) Back to nature: extinction of medicinal plants threatens drug discovery. J Natl Cancer Inst 100(12):838–839. https://doi.org/10.1093/jnci/djn199
Cameron DE, Bashor CJ, Collins JJ (2014) A brief history of synthetic biology. Nat Rev Microbiol 12(5):381–390. https://doi.org/10.1038/nrmicro3239
Carman GM, Han GS (2019) Fat-regulating phosphatidic acid phosphatase: a review of its roles and regulation in lipid homeostasis. J Lipid Res 60(1):2–6. https://doi.org/10.1194/jlr.S087452
Cravens A, Payne J, Smolke CD (2019) Synthetic biology strategies for microbial biosynthesis of plant natural products. Nat Commun. https://doi.org/10.1038/s41467-019-09848-w
de Ruijter JC, Koskela EV, Frey AD (2016) Enhancing antibody folding and secretion by tailoring the Saccharomyces cerevisiae endoplasmic reticulum. Microb Cell Fact 15:87. https://doi.org/10.1186/s12934-016-0488-5
DeLoache WC, Russ ZN, Dueber JE (2016) Towards repurposing the yeast peroxisome for compartmentalizing heterologous metabolic pathways. Nat Commun 7:11152. https://doi.org/10.1038/ncomms11152
Ehrenworth AM, Haines MA, Wong A, Peralta-Yahya P (2017) Quantifying the efficiency of Saccharomyces cerevisiae translocation tags. Biotechnol Bioeng 114(11):2628–2636. https://doi.org/10.1002/bit.26376
Emmerstorfer A, Wimmer-Teubenbacher M, Wriessnegger T, Leitner E, Muller M, Kaluzna I, Schurmann M et al (2015) Over-expression of ICE2 stabilizes cytochrome P450 reductase in Saccharomyces cerevisiae and Pichia pastoris. Biotechnol J 10(4):623-U345. https://doi.org/10.1002/biot.201400780
Farhi M, Marhevka E, Masci T, Marcos E, Eyal Y, Ovadis M, Abeliovich H, Vainstein A (2011) Harnessing yeast subcellular compartments for the production of plant terpenoids. Metab Eng 13(5):474–481. https://doi.org/10.1016/j.ymben.2011.05.001
Fernandez-Cabezon L, Galan B, Garcia JL (2018) New insights on steroid biotechnology. Front Microbiol. https://doi.org/10.3389/fmicb.2018.00958
Gao Q, Goodman JM (2015) The lipid droplet-a well-connected organelle. Front Cell Dev Biol 3:49. https://doi.org/10.3389/fcell.2015.00049
Gao Q, Binns DD, Kinch LN, Grishin NV, Ortiz N, Chen X, Goodman JM (2017) Pet10p is a yeast perilipin that stabilizes lipid droplets and promotes their assembly. J Cell Biol 216(10):3199–3217. https://doi.org/10.1083/jcb.201610013
Gu YA, Jiao X, Ye LD, Yu HW (2021) Metabolic engineering strategies for de novo biosynthesis of sterols and steroids in yeast. Bioresour Bioprocess. https://doi.org/10.1186/s40643-021-00460-9
Guerfal M, Claes K, Knittelfelder O, De Rycke R, Kohlwein SD, Callewaert N (2013) Enhanced membrane protein expression by engineering increased intracellular membrane production. Microb Cell Fact 12:122. https://doi.org/10.1016/j.nbt.2014.05.1750
Guo XY, Sun J, Li DS, Lu WY (2018) Heterologous biosynthesis of (+)-nootkatone in unconventional yeast Yarrowia lipolytica. Biochem Eng J 137:125–131. https://doi.org/10.1016/j.bej.2018.05.023
Guo XJ, Yao MD, Xiao WH, Wang Y, Zhao GR, Yuan YJ (2021) Compartmentalized Reconstitution of Post-squalene Pathway for 7-Dehydrocholesterol Overproduction in Saccharomyces cerevisiae. Front Microbiol 12:663973. https://doi.org/10.3389/fmicb.2021.663973
Hammer SK, Avalos JL (2017) Harnessing yeast organelles for metabolic engineering. Nat Chem Biol 13(8):823–832. https://doi.org/10.1038/nchembio.2429
Han GS, Wu WI, Carman GM (2006) The Saccharomyces cerevisiae lipin homolog is a Mg2+-dependent phosphatidate phosphatase enzyme. J Biol Chem 281(14):9210–9218. https://doi.org/10.1074/jbc.M600425200
Hayat S, Ahmad A (2011) Brassinosteroids: a class of plant hormone. Springer, Aligarh
He XP, Zhang BR, Tan HR (2003) Overexpression of a sterol C-24(28) reductase increases ergosterol production in Saccharomyces cerevisiae. Biotechnol Lett 25(10):773–778. https://doi.org/10.1023/A:1023572403185
He XP, Guo XN, Liu N, Zhang BR (2007) Ergosterol production from molasses by genetically modified Saccharomyces cerevisiae. Appl Microbiol Biotechnol 75(1):55–60. https://doi.org/10.1007/s00253-006-0807-6
Henry SA, Kohlwein SD, Carman GM (2012) Metabolism and regulation of glycerolipids in the yeast Saccharomyces cerevisiae. Genetics 190(2):317–349. https://doi.org/10.1534/genetics.111.130286
Heyken WT, Repenning A, Kumme J, Schuller HJ (2005) Constitutive expression of yeast phospholipid biosynthetic genes by variants of Ino2 activator defective for interaction with Opi1 repressor. Mol Microbiol 56(3):696–707. https://doi.org/10.1111/j.1365-2958.2004.04499.x
Hong J, Park SH, Kim S, Kim SW, Hahn JS (2019) Efficient production of lycopene in Saccharomyces cerevisiae by enzyme engineering and increasing membrane flexibility and NAPDH production. Appl Microbiol Biotechnol 103(1):211–223. https://doi.org/10.1007/s00253-018-9449-8
Hou J, Lages NF, Oldiges M, Vemuri GN (2009) Metabolic impact of redox cofactor perturbations in Saccharomyces cerevisiae. Metab Eng 11(4–5):253–261. https://doi.org/10.1016/j.ymben.2009.05.001
Hu ZH, He B, Ma L, Sun YL, Niu YL, Zeng B (2017) Recent advances in ergosterol biosynthesis and regulation mechanisms in Saccharomyces cerevisiae. Indian J Microbiol 57(3):270–277. https://doi.org/10.1007/s12088-017-0657-1
Hurt EC, Pesoldhurt B, Suda K, Oppliger W, Schatz G (1985) The 1st 12 amino-acids (less than half of the pre-sequence) of an imported mitochondrial protein can direct mouse cytosolic dihydrofolate-reductase into the yeast mitochondrial matrix. EMBO J 4(8):2061–2068. https://doi.org/10.1002/j.1460-2075.1985.tb03892.x
Jacquier N, Schneiter R (2012) Mechanisms of sterol uptake and transport in yeast. J Steroid Biochem Mol Biol 129(1–2):70–78. https://doi.org/10.1016/j.jsbmb.2010.11.014
Joshi AS, Cohen S (2019) Lipid droplet and peroxisome biogenesis: do they go hand-in-hand? Front Cell Dev Biol 7:92. https://doi.org/10.3389/fcell.2019.00092
Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K et al (2021) Highly accurate protein structure prediction with AlphaFold. Nature 596(7873):583–589. https://doi.org/10.1038/s41586-021-03819-2
Khripach VA, Zhabinskii VN, Ermolovich YV (2015) Synthetic aspects of Brassinosteroids. Stud Nat Prod Chem 44:309–352
Kim JE, Jang IS, Sung BH, Kim SC, Lee JY (2018) Rerouting of NADPH synthetic pathways for increased protopanaxadiol production in Saccharomyces cerevisiae. Sci Rep 8:15820. https://doi.org/10.1038/s41598-018-34210-3
Kim JE, Jang IS, Son SH, Ko YJ, Cho BK, Kim SC, Lee JY (2019) Tailoring the Saccharomyces cerevisiae endoplasmic reticulum for functional assembly of terpene synthesis pathway. Metab Eng 56:50–59. https://doi.org/10.1016/j.ymben.2019.08.013
Kim GB, Kim WJ, Kim HU, Lee SY (2020) Machine learning applications in systems metabolic engineering. Curr Opin Biotechnol 64:1–9. https://doi.org/10.1016/j.copbio.2019.08.010
Klug L, Daum G (2014) Yeast lipid metabolism at a glance. FEMS Yeast Res 14(3):369–388. https://doi.org/10.1111/1567-1364.12141
Kristan K, Rizner TL (2012) Steroid-transforming enzymes in fungi. J Steroid Biochem Mol Biol 129(1–2):79–91. https://doi.org/10.1016/j.jsbmb.2011.08.012
Kurihara T, Ueda M, Kanayama N, Kondo J, Teranishi Y, Tanaka A (1992) Peroxisomal acetoacetyl-coa thiolase of an N-alkane-utilizing yeast Candida tropicalis. Eur J Biochem 210(3):999–1005. https://doi.org/10.1111/j.1432-1033.1992.tb17505.x
Lee CM, Sedman J, Neupert W, Stuart RK (1999) The DNA helicase, Hmi1p, is transported into mitochondria by a C-terminal cleavable targeting signal. J Biol Chem 274(30):20937–20942. https://doi.org/10.1074/jbc.274.30.20937
Li DS, Wu YF, Zhang CB, Sun J, Zhou ZJ, Lu WY (2019) Production of Triterpene Ginsenoside compound K in the non-conventional yeast Yarrowia lipolytica. J Agric Food Chem 67(9):2581–2588. https://doi.org/10.1021/acs.jafc.9b00009
Li Z, Jiang YY, Guengerich FP, Ma L, Li SY, Zhang W (2020) Engineering cytochrome P450 enzyme systems for biomedical and biotechnological applications. J Biol Chem 295(3):833–849. https://doi.org/10.1074/jbc.REV119.008758
Li CQ, Lei HM, Hu QY, Li GH, Zhao PJ (2021) Recent advances in the synthetic biology of natural drugs. Front Bioeng Biotechnol 9:691152. https://doi.org/10.3389/fbioe.2021.691152
Lin JL, Zhu J, Wheeldon I (2017) Synthetic protein scaffolds for biosynthetic pathway colocalization on lipid droplet membranes. ACS Synth Biol 6(8):1534–1544. https://doi.org/10.1021/acssynbio.7b00041
Liu JF, Xia JJ, Nie KL, Wang F, Deng L (2019) Outline of the biosynthesis and regulation of ergosterol in yeast. World J Microbiol Biotechnol 35(7):98. https://doi.org/10.1007/s11274-019-2673-2
Liu GS, Li T, Zhou W, Jiang M, Tao XY, Liu M, Zhao M et al (2020) The yeast peroxisome: a dynamic storage depot and subcellular factory for squalene overproduction. Metab Eng 57:151–161. https://doi.org/10.1016/j.ymben.2019.11.001
Lobs AK, Schwartz C, Thorwall S, Wheeldon I (2018) Highly multiplexed CRISPRi repression of respiratory functions enhances mitochondrial localized ethyl acetate biosynthesis in Kluyveromyces marxianus. ACS Synth Biol 7(11):2647–2655. https://doi.org/10.1021/acssynbio.8b00331
Loewen CJR, Gaspar ML, Jesch SA, Delon C, Ktistakis NT, Henry SA, Levine TP (2004) Phospholipid metabolism regulated by a transcription factor sensing phosphatidic acid. Science 304(5677):1644–1647. https://doi.org/10.1126/science.1096083
Ma BX, Ke X, Tang XL, Zheng RC, Zheng YG (2018) Rate-limiting steps in the Saccharomyces cerevisiae ergosterol pathway: towards improved ergosta-5,7-dien-3 beta-ol accumulation by metabolic engineering. World J Microbiol Biotechnol 34(4):55. https://doi.org/10.1007/s11274-018-2440-9
Ma T, Shi B, Ye ZL, Li XW, Liu M, Chen Y, Xia J, Nielsen J, Deng ZX, Liu TG (2019) Lipid engineering combined with systematic metabolic engineering of Saccharomyces cerevisiae for high-yield production of lycopene. Metab Eng 52:134–142. https://doi.org/10.1016/j.ymben.2018.11.009
Malina C, Larsson C, Nielsen J (2018) Yeast mitochondria: an overview of mitochondrial biology and the potential of mitochondrial systems biology. Fems Yeast Res 18(5):foy040. https://doi.org/10.1093/femsyr/foy040
Meadows AL, Hawkins KM, Tsegaye Y, Antipov E, Kim Y, Raetz L, Dahl RH et al (2016) Rewriting yeast central carbon metabolism for industrial isoprenoid production. Nature 537(7622):694–697. https://doi.org/10.1038/nature19769
Meinecke M, Cizmowski C, Schliebs W, Kruger V, Beck S, Wagner R, Erdmann R (2010) The peroxisomal importomer constitutes a large and highly dynamic pore. Nat Cell Biol 12(3):273-U268. https://doi.org/10.1038/ncb2027
Milla P, Athenstaedt K, Viola F, Oliaro-Bosso S, Kohlwein SD, Daum G, Balliano G (2002) Yeast oxidosqualene cyclase (Erg7p) is a major component of lipid particles. J Biol Chem 277(4):2406–2412. https://doi.org/10.1074/jbc.M104195200
Moreau RA, Nystrom L, Whitaker BD, Winkler-Moser JK, Baer DJ, Gebauer SK, Hicks KB (2018) Phytosterols and their derivatives: structural diversity, distribution, metabolism, analysis, and health-promoting uses. Prog Lipid Res 70:35–61. https://doi.org/10.1016/j.plipres.2018.04.001
Muhlenhoff U, Lill R (2000) Biogenesis of iron-sulfur proteins in eukaryotes: a novel task of mitochondria that is inherited from bacteria. BBA-Bioenergetics 1459(2–3):370–382. https://doi.org/10.1016/S0005-2728(00)00174-2
Nes WD (2011) Biosynthesis of cholesterol and other sterols. Chem Rev 111(10):6423–6451. https://doi.org/10.1021/cr200021m
Nowrouzi B, Rios-Solis L (2021) Redox metabolism for improving whole-cell P450-catalysed terpenoid biosynthesis. Crit Rev Biotechnol. https://doi.org/10.1080/07388551.2021.1990210
Olin-Sandoval V, Yu JSL, Miller-Fleming L, Alam MT, Kamrad S, Correia-Melo C, Haas R et al (2019) Lysine harvesting is an antioxidant strategy and triggers underground polyamine metabolism. Nature 572(7768):249–253. https://doi.org/10.1038/s41586-019-1442-6
Olzmann JA, Carvalho P (2019) Dynamics and functions of lipid droplets. Nat Rev Mol Cell Biol 20(3):137–155. https://doi.org/10.1038/s41580-018-0085-z
Ott RG, Athenstaedt K, Hrastnik C, Leitner E, Bergler H, Daum G (2005) Flux of sterol intermediates in a yeast strain deleted of the lanosterol C-14 dernethylase Erg11p. BBA-Mol Cell Biol Lett 1735(2):111–118. https://doi.org/10.1016/j.bbalip.2005.05.003
Outten CE, Culotta VC (2003) A novel NADH kinase is the mitochondrial source of NADPH in Saccharomyces cerevisiae. EMBO J 22(9):2015–2024. https://doi.org/10.1093/emboj/cdg211
Papagiannidis D, Bircham PW, Luchtenborg C, Pajonk O, Ruffini G, Brugger B, Schuck S (2021) Ice2 promotes ER membrane biogenesis in yeast by inhibiting the conserved lipin phosphatase complex. EMBO J 40(22):e107958. https://doi.org/10.15252/embj.2021107958
Ramprasath VR, Awad AB (2015) Role of phytosterols in cancer prevention and treatment. J AOAC Int 98(3):735–738. https://doi.org/10.5740/jaoacint.SGERamprasath
Rocha VZ, Ras RT, Gagliardi AC, Mangili LC, Trautwein EA, Santos RD (2016) Effects of phytosterols on markers of inflammation: a systematic review and meta-analysis. Atherosclerosis 248:76–83. https://doi.org/10.1016/j.atherosclerosis.2016.01.035
Rucktaschel R, Girzalsky W, Erdmann R (2011) Protein import machineries of peroxisomes. BBA-Biomembranes 1808(3):892–900. https://doi.org/10.1016/j.bbamem.2010.07.020
Schuckel J, Rylott EL, Grogan G, Bruce NC (2012) A gene-fusion approach to enabling plant cytochromes P450 for biocatalysis. ChemBioChem 13(18):2758–2763. https://doi.org/10.1002/cbic.201200572
Shi SB, Chen Y, Siewers V, Nielsen J (2014) Improving production of malonyl coenzyme A-derived metabolites by abolishing Snf1-dependent regulation of Acc1. Mbio 5(3):e01130-e11114. https://doi.org/10.1128/mBio.01130-14
Shi YS, Wang D, Li RS, Huang LQ, Dai ZB, Zhang XL (2021) Engineering yeast subcellular compartments for increased production of the lipophilic natural products ginsenosides. Metab Eng 67:104–111. https://doi.org/10.1016/j.ymben.2021.06.002
Su WM, Han GS, Carman GM (2014) Yeast Nem1-Spo7 protein phosphatase activity on Pah1 phosphatidate phosphatase is specific for the Pho85-Pho80 protein kinase phosphorylation sites. J Biol Chem 289(50):34699–34708. https://doi.org/10.1074/jbc.M114.614883
Su W, Xiao WH, Wang Y, Liu D, Zhou X, Yuan YJ (2015) Alleviating redox imbalance enhances 7-dehydrocholesterol production in engineered Saccharomyces cerevisiae. PLoS ONE 10(6):e0130840. https://doi.org/10.1371/journal.pone.0130840
Sun J, Zhang CB, Nan WH, Li DS, Ke D, Lu WY (2019) Glycerol improves heterologous biosynthesis of betulinic acid in engineered Yarrowia lipolytica. Chem Eng Sci 196:82–90. https://doi.org/10.1016/j.ces.2018.10.052
Sun ZJ, Lian JZ, Zhu L, Jiang YQ, Li GS, Xue HL, Wu MB, Yang LR, Lin JP (2021) Combined biosynthetic pathway engineering and storage pool expansion for high-level production of ergosterol in industrial Saccharomyces cerevisiae. Front Bioeng Biotechnol 9:681666. https://doi.org/10.3389/fbioe.2021.681666
Thodey K, Galanie S, Smolke CD (2014) A microbial biomanufacturing platform for natural and semisynthetic opioids. Nat Chem Biol 10(10):837–844. https://doi.org/10.1038/NCHEMBIO.1613
Urlacher VB, Girhard M (2012) Cytochrome P450 monooxygenases: an update on perspectives for synthetic application. Trends Biotechnol 30(1):26–36. https://doi.org/10.1016/j.tibtech.2011.06.012
Vemuri GN, Eiteman MA, McEwen JE, Olsson L, Nielsen J (2007) Increasing NADH oxidation reduces overflow metabolism in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 104(7):2402–2407. https://doi.org/10.1073/pnas.0607469104
Volkman JK (2003) Sterols in microorganisms. Appl Microbiol Biotechnol 60(5):495–506. https://doi.org/10.1007/s00253-002-1172-8
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
Wang CW (2015) Lipid droplet dynamics in budding yeast. Cell Mol Life Sci 72(14):2677–2695. https://doi.org/10.1007/s00018-015-1903-5
Wang SQ, Wang T, Liu JF, Deng L, Wang F (2018) Overexpression of Ecm22 improves ergosterol biosynthesis in Saccharomyces cerevisiae. Lett Appl Microbiol 67(5):484–490. https://doi.org/10.1111/lam.13061
Willer M, Rainey M, Pullen T, Stirling CJ (1999) The yeast CDC9 gene encodes both a nuclear and a mitochondrial form of DNA ligase I. Curr Biol 9(19):1085–1094. https://doi.org/10.1016/S0960-9822(99)80477-1
Wollam J, Antebi A (2011) Sterol regulation of metabolism, homeostasis, and development. Annu Rev Biochem 80(80):885–916. https://doi.org/10.1146/annurev-biochem-081308-165917
Wriessnegger T, Pichler H (2013) Yeast metabolic engineering—targeting sterol metabolism and terpenoid formation. Prog Lipid Res 52(3):277–293. https://doi.org/10.1016/j.plipres.2013.03.001
Xu SH, Li YR (2020) Yeast as a promising heterologous host for steroid bioproduction. J Ind Microbiol Biotechnol 47(9–10):829–843. https://doi.org/10.1007/s10295-020-02291-7
Xu SH, Chen C, Li YR (2020) Engineering of phytosterol-producing yeast platforms for functional reconstitution of downstream biosynthetic pathways. ACS Synth Biol 9(11):3157–3170. https://doi.org/10.1021/acssynbio.0c00417
Yao Y, Wang W, Shi W, Yan R, Zhang J, Wei G, Liu L, Che Y, An C, Gao SS (2021) Overproduction of medicinal ergot alkaloids based on a fungal platform. Metab Eng 69:198–208. https://doi.org/10.1016/j.ymben.2021.12.002
Yocum HC, Pham A, Da Silva NA (2021) Successful enzyme colocalization strategies in yeast for increased synthesis of non-native products. Front Bioeng Biotechnol 9:606795. https://doi.org/10.3389/fbioe.2021.606795
Yuan JF, Ching CB (2016) Mitochondrial acetyl-CoA utilization pathway for terpenoid productions. Metab Eng 38:303–309. https://doi.org/10.1016/j.ymben.2016.07.008
Zangar RC, Davydov DR, Verma S (2004) Mechanisms that regulate production of reactive oxygen species by cytochrome P450. Toxicol Appl Pharmacol 199(3):316–331. https://doi.org/10.1016/j.taap.2004.01.018
Zehmer JK, Bartz R, Liu PS, Anderson RGW (2008) Identification of a novel N-terminal hydrophobic sequence that targets proteins to lipid droplets. J Cell Sci 121(11):1852–1860. https://doi.org/10.1242/jcs.012013
Zhao X, Shi F, Zhan W (2015) Overexpression of ZWF1 and POS5 improves carotenoid biosynthesis in recombinant Saccharomyces cerevisiae. Lett Appl Microbiol 61(4):354–360. https://doi.org/10.1111/lam.12463
Zhao FL, Bai P, Liu T, Li DS, Zhang XM, Lu WY, Yuan YJ (2016) Optimization of a cytochrome P450 oxidation system for enhancing protopanaxadiol production in Saccharomyces cerevisiae. Biotechnol Bioeng 113(8):1787–1795. https://doi.org/10.1002/bit.25934
Zweytick D, Leitner E, Kohlwein SD, Yu CJ, Rothblatt J, Daum G (2000) Contribution of Are1p and Are2p to steryl ester synthesis in the yeast Saccharomyces cerevisiae. Eur J Biochem 267(4):1075–1082. https://doi.org/10.1046/j.1432-1327.2000.01103.x
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We sincerely apologize to those whose work has not been discussed or cited in this review due to space and scope limitations. This work was financially supported by National Key Research and Development Program (2019YFA0905400).
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This work was financially supported by National Key Research and Development Program (Grant No. 2019YFA0905400).
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Jiang, Yq., Lin, Jp. Recent progress in strategies for steroid production in yeasts. World J Microbiol Biotechnol 38, 93 (2022). https://doi.org/10.1007/s11274-022-03276-7
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