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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2023, Vol. 43 Issue (9): 93-104    DOI: 10.13523/j.cb.2304014
综述     
细胞区室化调控萜类化合物微生物合成*
万娅1,孟栋1,李金玲1,李春1,2,王颖1,**()
1 北京理工大学医药分子科学与制剂工程工信部重点实验室 北京理工大学化学与化工学院 生物化工研究所 北京 100081
2 清华大学化学工程系 北京 100084
Research Progress of Subcellular Compartmentalization Regulation of Microbial Synthesis of Terpenes
WAN Ya1,MENG Dong1,LI Jin-ling1,LI Chun1,2,WANG Ying1,**()
1 Key Laboratory of Medicinal Molecule Science and Pharmaceutical Engineering of Ministry of Industry and Information Technology, Institute of Biochemical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, China
2 Department of Chemical Engineering, Tsinghua University, Beijing 100084, China
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摘要：

萜类化合物具有抗炎、抗氧化、抑制肿瘤细胞增殖等药学活性,在医药行业应用广泛。近年来,利用微生物合成萜类化合物受到广泛关注。在微生物中高效合成萜类化合物离不开代谢途径的调控与优化,其中细胞区室化是常用的调控策略之一,在微生物细胞工厂的构建中发挥着重要作用。代谢途径的细胞区室化具有许多优点,如增加酶和底物的局部浓度,抑制其向副产物转移和减少有毒中间体积累等,可实现萜类化合物的高效合成。近年来利用细胞区室化在微生物中合成萜类化合物的研究逐步展开,但目前对于区室化工程在构建细胞工厂中的应用总结较少。因此,围绕代谢途径区室化的作用,各种细胞器的生理特性及其在调控萜类化合物微生物合成中的应用进行了综述,讨论细胞区室化调控策略的发展、存在的问题及前景,以期为萜类化合物的高效微生物合成提供参考。
关键词： 细胞区室化;  萜类化合物;  细胞器工程;  代谢工程    
Abstract:

Plant-derived terpenoids exhibit pharmacological activities such as anti-inflammatory and antioxidant effects, and inhibition of tumor cell proliferation, making them widely used in medicine. In recent years, microbial cell factories have gained significant attention for the synthesis of terpenoids. Efficient terpenoid synthesis in microorganisms requires regulation and optimization of metabolic athways. Subcellular compartmentalization is a common regulatory strategy that plays an essential role in constructing microbial cell factories. Subcellular compartmentalization of metabolic pathways enhances the concentration of enzyme and substrate, inhibits the transfer of metabolic flux towards by-products, reduces accumulation of toxic intermediates, and enables efficient terpenoid synthesis. Although the research on the synthesis of terpenoids using compartmentalization has been carried out, there is currently limited information summarizing its application in microbial cell factory construction. Therefore, this review summarizes the physiological characteristics of various organelles and their applications in regulating terpenoid synthesis. It also discusses the development of regulatory strategies, existing problems, and prospects of subcellular compartmentalization, aiming to provide references for the efficient biosynthesis of terpenoids.
Key words: Subcellular compartments    Terpenoids    Organelle engineering    Metabolic engineering
收稿日期: 2023-04-06 出版日期: 2023-10-08
ZTFLH:  Q819  
基金资助: * 国家自然科学基金(22078020);国家重点研发计划(2019YFA0905700)
通讯作者: ** 电子信箱:wy2015@bit.edu.cn   
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万娅
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引用本文:

万娅, 孟栋, 李金玲, 李春, 王颖. 细胞区室化调控萜类化合物微生物合成*[J]. 中国生物工程杂志, 2023, 43(9): 93-104.

WAN Ya, MENG Dong, LI Jin-ling, LI Chun, WANG Ying. Research Progress of Subcellular Compartmentalization Regulation of Microbial Synthesis of Terpenes. China Biotechnology, 2023, 43(9): 93-104.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2304014    或    https://manu60.magtech.com.cn/biotech/CN/Y2023/V43/I9/93

图1  亚细胞结构在微生物代谢工程中的作用[9]
图2  萜类化合物的生物合成途径
细胞器 底盘细胞 调控优化策略 效果
线粒体 酿酒酵母 将类胡萝卜素生产相关的酶定位至线粒体 线粒体工程菌株的胡萝卜素产量比细胞质工程菌株提高13.82倍[41]
将α-檀香烯生物合成途径定位于线粒体 α-檀香烯产量提高3.7倍[46]
双重调控细胞质和线粒体乙酰辅酶A的利用 使异戊二烯产量与单纯线粒体工程和细胞质工程的重组菌株相比分别提高2.1倍和1.6倍[42]
过氧化物
酶体		 毕赤酵母 将IUP途径引入过氧化物酶体,结合通过细胞质和过氧化物酶体的双重调控 α-法尼烯产量是单纯过氧化物酶体和细胞质工程菌株的1.3倍和2.1倍[53]
酿酒酵母 将鲨烯合成途径定位于过氧化物酶体, β-香树脂醇产量提高2.6倍[55]
解脂耶氏酵母 将α-蛇麻烯生物合成途径重新定位至过氧化物酶体 使α-蛇麻烯产量提高到3.2 g/L[54]
脂滴 酿酒酵母 将原人参二醇合酶PPDS靶向定位至脂滴 使达玛烯二醇-II到人参二醇的转化率从17.4%提高到86.0%[60]
将合成熊果酸和齐墩果酸的关键酶定位至脂滴 熊果酸和齐墩果酸的产量提高到1 132.9 mg/L和433.9 mg/L[59]
解脂耶氏酵母 将β-胡萝卜素转化为虾青素的β-胡萝卜素酮化酶和羟化酶定位于脂滴 虾青素产量与细胞质中表达的菌株相比增加2.03倍[61]
内质网 解脂耶氏酵母 将青蒿二烯合酶定位于内质网 使青蒿二烯产量提高到71.74 mg/L[66]
质膜 大肠杆菌 将番茄红素的ε-环化酶定位于质膜 叶黄素和α-胡萝卜素产量分别达到595.3 μg/L和538.8 μg/L[71]
合成细胞器 大肠杆菌 将二磷酸异戊酯异构酶(Idi)及法尼基焦磷酸合酶(IspA)定位于无膜细胞器 与未定位的菌株相比法尼烯产量提升近4倍[82]
大肠杆菌 将番茄红素合成的关键酶定位于蛋白质笼 番茄红素产量提高8.5倍[83]
表1  细胞区室化促进萜类化合物合成的策略
[1] Pemberton T A, Chen M B, Harris G G, et al. Exploring the influence of domain architecture on the catalytic function of diterpene synthases. Biochemistry, 2017, 56(14): 2010-2023.
doi: 10.1021/acs.biochem.7b00137 pmid: 28362483
[2] Cao X, Yu W, Chen Y, et al. Engineering yeast for high-level production of diterpenoid sclareol. Metabolic Engineering, 2023, 75: 19-28.
doi: 10.1016/j.ymben.2022.11.002
[3] Ma Y S, Zu Y X, Huang S W, et al. Engineering a universal and efficient platform for terpenoid synthesis in yeast. Proceedings of the National Academy of Sciences of the United States of America, 2023, 120(1): e2207680120.
[4] Chen J, Zhang R L, Zhang G L, et al. Heterologous expression of the plant-derived astaxanthin biosynthesis pathway in Yarrowia lipolytica for glycosylated astaxanthin production. Journal of Agricultural and Food Chemistry, 2023, 71(6): 2943-2951.
doi: 10.1021/acs.jafc.2c08153
[5] Wess J, Brinek M, Boles E. Improving isobutanol production with the yeast Saccharomyces cerevisiae by successively blocking competing metabolic pathways as well as ethanol and glycerol formation. Biotechnology for Biofuels, 2019, 12(1): 1-15.
doi: 10.1186/s13068-018-1346-y
[6] Borodina I, Nielsen J. Advances in metabolic engineering of yeast Saccharomyces cerevisiae for production of chemicals. Biotechnology Journal, 2014, 9(5): 609-620.
doi: 10.1002/biot.201300445 pmid: 24677744
[7] Hammer S K, Avalos J L. Harnessing yeast organelles for metabolic engineering. Nature Chemical Biology, 2017, 13(8): 823-832.
doi: 10.1038/nchembio.2429 pmid: 28853733
[8] Jin K, Xia H Z, Liu Y F, et al. Compartmentalization and transporter engineering strategies for terpenoid synthesis. Microbial Cell Factories, 2022, 21(1): 92.
doi: 10.1186/s12934-022-01819-z pmid: 35599322
[9] Montaño López J, Duran L, Avalos J L. Physiological limitations and opportunities in microbial metabolic engineering. Nature Reviews Microbiology, 2022, 20(1): 35-48.
doi: 10.1038/s41579-021-00600-0
[10] Delatte T L, Scaiola G, Molenaar J, et al. Engineering storage capacity for volatile sesquiterpenes in Nicotiana benthamiana leaves. Plant Biotechnology Journal, 2018, 16(12): 1997-2006.
doi: 10.1111/pbi.2018.16.issue-12
[11] Wu S Q, Jiang Z D, Kempinski C, et al. Engineering triterpene metabolism in tobacco. Planta, 2012, 236(3): 867-877.
doi: 10.1007/s00425-012-1680-4 pmid: 22729821
[12] Zhao C, Kim Y, Zeng Y N, et al. Co-compartmentation of terpene biosynthesis and storage via synthetic droplet. ACS Synthetic Biology, 2018, 7(3): 774-781.
doi: 10.1021/acssynbio.7b00368
[13] Li M J, Hou F F, Wu T, et al. Recent advances of metabolic engineering strategies in natural isoprenoid production using cell factories. Natural Product Reports, 2020, 37(1): 80-99.
doi: 10.1039/c9np00016j pmid: 31073570
[14] 李然, 闫晓光, 李伟国, 等. 高效合成倍半萜酿酒酵母的构建策略. 中国生物工程杂志, 2022, 42(1/2): 14-25.
Li R, Yan X G, Li W G, et al. Strategies of engineering Saccharomyces cerevisiae for high-efficiency synthesis of sesquiterpenes. China Biotechnology, 2022, 42(1/2): 14-25.
[15] Chen M, Zhang M, Sun S, et al. A new triterpene from the fruiting bodies of Ganoderma lucidum. Acta Pharmaceutica Sinica, 2009, 44(7): 768-770.
pmid: 19806918
[16] Justicia J, Rosales A, Buñuel E, et al. Titanocene-catalyzed cascade cyclization of epoxypolyprenes: straightforward synthesis of terpenoids by free-radical chemistry. Chemistry:A European Journal, 2004, 10(7): 1778-1788.
doi: 10.1002/(ISSN)1521-3765
[17] Ye M, Gao J Q, Zhou Y J. Global metabolic rewiring of the nonconventional yeast Ogataea polymorpha for biosynthesis of the sesquiterpenoid β-elemene. Metabolic Engineering, 2023, 76: 225-231.
doi: 10.1016/j.ymben.2023.02.008
[18] Park S Y, Eun H, Lee M H, et al. Metabolic engineering of Escherichia coli with electron channelling for the production of natural products. Nature Catalysis, 2022, 5(8): 726-737.
doi: 10.1038/s41929-022-00820-4
[19] Sun W T, Xue H J, Liu H, et al. Controlling chemo- and regioselectivity of a plant P 450 in yeast cell toward rare licorice triterpenoid biosynthesis. ACS Catalysis, 2020, 10(7): 4253-4260.
doi: 10.1021/acscatal.0c00128
[20] Dai Z B, Liu Y, Sun Z T, et al. Identification of a novel cytochrome P450 enzyme that catalyzes the C-2α hydroxylation of pentacyclic triterpenoids and its application in yeast cell factories. Metabolic Engineering, 2019, 51: 70-78.
doi: S1096-7176(17)30455-X pmid: 30339834
[21] Westfall P J, Pitera D J, Lenihan J R, et al. Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109(3): E111-E118.
[22] Schempp F M, Drummond L, Buchhaupt M, et al. Microbial cell factories for the production of terpenoid flavor and fragrance compounds. Journal of Agricultural and Food Chemistry, 2018, 66(10): 2247-2258.
doi: 10.1021/acs.jafc.7b00473 pmid: 28418659
[23] McCarty N S, Ledesma-Amaro R. Synthetic biology tools to engineer microbial communities for biotechnology. Trends in Biotechnology, 2019, 37(2): 181-197.
doi: S0167-7799(18)30312-3 pmid: 30497870
[24] Chen B B, Lee H L, Heng Y C, et al. Synthetic biology toolkits and applications in Saccharomyces cerevisiae. Biotechnology Advances, 2018, 36(7): 1870-1881.
doi: 10.1016/j.biotechadv.2018.07.005
[25] Guo Q, Li Y W, Yan F, et al. Dual cytoplasmic-peroxisomal engineering for high-yield production of sesquiterpene α-humulene in Yarrowia lipolytica. Biotechnology and Bioengineering, 2022, 119(10): 2819-2830.
doi: 10.1002/bit.v119.10
[26] Wolfe K, Kamata R, Coutinho K, et al. Metabolic compartmentalization at the leading edge of metastatic cancer cells. Frontiers in Oncology, 2020, 10: 554272.
doi: 10.3389/fonc.2020.554272
[27] Ayer A, Sanwald J, Pillay B A, et al. Distinct redox regulation in sub-cellular compartments in response to various stress conditions in Saccharomyces cerevisiae. PLoS One, 2013, 8(6): e65240.
doi: 10.1371/journal.pone.0065240
[28] Kerfeld C A, Aussignargues C, Zarzycki J, et al. Bacterial microcompartments. Nature Reviews Microbiology, 2018, 16(5): 277-290.
doi: 10.1038/nrmicro.2018.10 pmid: 29503457
[29] Kerfeld C A, Sutter M. Engineered bacterial microcompartments: apps for programming metabolism. Current Opinion in Biotechnology, 2020, 65: 225-232.
doi: S0958-1669(20)30056-2 pmid: 32554213
[30] Lawrence A D, Frank S, Newnham S, et al. Solution structure of a bacterial microcompartment targeting peptide and its application in the construction of an ethanol bioreactor. ACS Synthetic Biology, 2014, 3(7): 454-465.
doi: 10.1021/sb4001118 pmid: 24933391
[31] Flamholz A I, Dugan E L, Blikstad C, et al. Functional reconstitution of a bacterial CO2 concentrating mechanism in Escherichia coli. eLife, 2020, 9: 59882.
[32] van Rossum H M, Kozak B U, Pronk J T, et al. Engineering cytosolic acetyl-coenzyme A supply in Saccharomyces cerevisiae: pathway stoichiometry, free-energy conservation and redox-cofactor balancing. Metabolic Engineering, 2016, 36: 99-115.
doi: 10.1016/j.ymben.2016.03.006
[33] Yuan J F, Ching C B. Mitochondrial acetyl-CoA utilization pathway for terpenoid productions. Metabolic Engineering, 2016, 38: 303-309.
doi: S1096-7176(16)30063-5 pmid: 27471067
[34] DeLoache W C, Russ Z N, Dueber J E. Towards repurposing the yeast peroxisome for compartmentalizing heterologous metabolic pathways. Nature Communications, 2016, 7(1): 1-11.
[35] Kim J E, Jang I S, Son S H, et al. Tailoring the Saccharomyces cerevisiae endoplasmic reticulum for functional assembly of terpene synthesis pathway. Metabolic Engineering, 2019, 56: 50-59.
doi: 10.1016/j.ymben.2019.08.013
[36] Yang K X, Qiao Y G, Li F, et al. Subcellular engineering of lipase dependent pathways directed towards lipid related organelles for highly effectively compartmentalized biosynthesis of triacylglycerol derived products in Yarrowia lipolytica. Metabolic Engineering, 2019, 55: 231-238.
doi: 10.1016/j.ymben.2019.08.001
[37] Zhang Y F, Lane S, Chen J M, et al. Xylose utilization stimulates mitochondrial production of isobutanol and 2-methyl-1-butanol in Saccharomyces cerevisiae. Biotechnology for Biofuels, 2019, 12: 223.
doi: 10.1186/s13068-019-1560-2
[38] Malina C, Larsson C, Nielsen J. Yeast mitochondria: an overview of mitochondrial biology and the potential of mitochondrial systems biology. FEMS Yeast Research, 2018, 18(5): foy040.
[39] Hu J J, Dong L X, Outten C E. The redox environment in the mitochondrial intermembrane space is maintained separately from the cytosol and matrix. The Journal of Biological Chemistry, 2008, 283(43): 29126-29134.
doi: 10.1074/jbc.M803028200
[40] Weinert B T, Iesmantavicius V, Moustafa T, et al. Acetylation dynamics and stoichiometry in Saccharomyces cerevisiae. Molecular Systems Biology, 2015, 11(10): 833.
doi: 10.15252/msb.156513 pmid: 26502892
[41] Matsumoto T, Osawa T, Taniguchi H, et al. Mitochondrial expression of metabolic enzymes for improving carotenoid production in Saccharomyces cerevisiae. Biochemical Engineering Journal, 2022, 189: 108720.
doi: 10.1016/j.bej.2022.108720
[42] Lv X M, Wang F, Zhou P P, et al. Dual regulation of cytoplasmic and mitochondrial acetyl-CoA utilization for improved isoprene production in Saccharomyces cerevisiae. Nature Communications, 2016, 7(1): 1-12.
[43] Mitrofan L M, Pelkonen J, Mönkkönen J. The level of ATP analog and isopentenyl pyrophosphate correlates with zoledronic acid-induced apoptosis in cancer cells in vitro. Bone, 2009, 45(6): 1153-1160.
doi: 10.1016/j.bone.2009.08.010 pmid: 19699819
[44] Mönkkönen H, Auriola S, Lehenkari P, et al. A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates. British Journal of Pharmacology, 2006, 147(4): 437-445.
pmid: 16402039
[45] Zhu Z T, Du M M, Gao B, et al. Metabolic compartmentalization in yeast mitochondria: burden and solution for squalene overproduction. Metabolic Engineering, 2021, 68: 232-245.
doi: 10.1016/j.ymben.2021.10.011
[46] Dong C, Shi Z W, Huang L, et al. Cloning and characterization of a panel of mitochondrial targeting sequences for compartmentalization engineering in Saccharomyces cerevisiae. Biotechnology and Bioengineering, 2021, 118(11): 4269-4277.
doi: 10.1002/bit.v118.11
[47] Zhou Y J, Buijs N A, Zhu Z W, et al. Harnessing yeast peroxisomes for biosynthesis of fatty-acid-derived biofuels and chemicals with relieved side-pathway competition. Journal of the American Chemical Society, 2016, 138(47): 15368-15377.
pmid: 27753483
[48] Lajus S, Dusséaux S, Verbeke J, et al. Engineering the yeast Yarrowia lipolytica for production of polylactic acid homopolymer. Frontiers in Bioengineering and Biotechnology, 2020, 8: 954.
doi: 10.3389/fbioe.2020.00954
[49] Breitling R, Sharif O, Hartman M L, et al. Loss of compartmentalization causes misregulation of lysine biosynthesis in peroxisome-deficient yeast cells. Eukaryotic Cell, 2002, 1(6): 978-986.
doi: 10.1128/EC.1.6.978-986.2002 pmid: 12477798
[50] Liu F, Liu S C, Qi Y K, et al. Enhancing Trans-nerolidol productivity in Yarrowia lipolytica by improving precursor supply and optimizing nerolidol synthase activity. Journal of Agricultural and Food Chemistry, 2022, 70(48): 15157-15165.
doi: 10.1021/acs.jafc.2c05847
[51] Gao N, Gao J Q, Yu W, et al. Spatial-temporal regulation of fatty alcohol biosynthesis in yeast. Biotechnology for Biofuels, 2022, 15: 141.
[52] Grewal P S, Samson J A, Baker J J, et al. Peroxisome compartmentalization of a toxic enzyme improves alkaloid production. Nature Chemical Biology, 2021, 17(1): 96-103.
doi: 10.1038/s41589-020-00668-4 pmid: 33046851
[53] Liu H, Chen S L, Xu J Z, et al. Dual regulation of cytoplasm and peroxisomes for improved Α-farnesene production in recombinant Pichia pastoris. ACS Synthetic Biology, 2021, 10(6): 1563-1573.
doi: 10.1021/acssynbio.1c00186
[54] Guo Q, Shi T Q, Peng Q Q, et al. Harnessing Yarrowia lipolytica peroxisomes as a subcellular factory for α-humulene overproduction. Journal of Agricultural and Food Chemistry, 2021, 69(46): 13831-13837.
doi: 10.1021/acs.jafc.1c05897 pmid: 34751575
[55] Du M M, Zhu Z T, Zhang G G, et al. Engineering Saccharomyces cerevisiae for hyperproduction of β-amyrin by mitigating the inhibition effect of squalene on β-amyrin synthase. Journal of Agricultural and Food Chemistry, 2022, 70(1): 229-237.
doi: 10.1021/acs.jafc.1c06712
[56] Sibirny A A. Yeast peroxisomes: structure, functions and biotechnological opportunities. FEMS Yeast Research, 2016, 16(4): fow038.
doi: 10.1093/femsyr/fow038
[57] Liu Y H, Zhang J, Li Q B, et al. Engineering Yarrowia lipolytica for the sustainable production of β-farnesene from waste oil feedstock. Biotechnology for Biofuels and Bioproducts, 2022, 15(1): 101.
doi: 10.1186/s13068-022-02201-2
[58] Gajdoš P, Ledesma-Amaro R, Nicaud J M, et al. Overexpression of diacylglycerol acyltransferase in Yarrowia lipolytica affects lipid body size, number and distribution. FEMS Yeast Research, 2016, 16(6): fow062.
doi: 10.1093/femsyr/fow062
[59] Jin K, Shi X, Liu J H, et al. Combinatorial metabolic engineering enables the efficient production of ursolic acid and oleanolic acid in Saccharomyces cerevisiae. Bioresource Technology, 2023, 374: 128819.
doi: 10.1016/j.biortech.2023.128819
[60] Shi Y S, Wang D, Li R S, et al. Engineering yeast subcellular compartments for increased production of the lipophilic natural products ginsenosides. Metabolic Engineering, 2021, 67: 104-111.
doi: 10.1016/j.ymben.2021.06.002 pmid: 34153454
[61] Ma Y S, Li J B, Huang S W, et al. Targeting pathway expression to subcellular organelles improves astaxanthin synthesis in Yarrowia lipolytica. Metabolic Engineering, 2021, 68: 152-161.
doi: 10.1016/j.ymben.2021.10.004
[62] Yu Y, Rasool A, Liu H R, et al. Engineering Saccharomyces cerevisiae for high yield production of α-amyrin via synergistic remodeling of α-amyrin synthase and expanding the storage pool. Metabolic Engineering, 2020, 62: 72-83.
doi: 10.1016/j.ymben.2020.08.010
[63] Ma T, Shi B, Ye Z L, et al. Lipid engineering combined with systematic metabolic engineering of Saccharomyces cerevisiae for high-yield production of lycopene. Metabolic Engineering, 2019, 52: 134-142.
doi: 10.1016/j.ymben.2018.11.009
[64] Li M, Zhou P P, Chen M K, et al. Spatiotemporal regulation of astaxanthin synthesis in S. cerevisiae. ACS Synthetic Biology, 2022, 11(8): 2636-2649.
doi: 10.1021/acssynbio.2c00044
[65] Hu Z H, He B, Ma L, et al. Recent advances in ergosterol biosynthesis and regulation mechanisms in Saccharomyces cerevisiae. Indian Journal of Microbiology, 2017, 57(3): 270-277.
doi: 10.1007/s12088-017-0657-1
[66] Marsafari M, Azi F, Dou S H, et al. Modular co-culture engineering of Yarrowia lipolytica for amorphadiene biosynthesis. Microbial Cell Factories, 2022, 21(1): 279.
doi: 10.1186/s12934-022-02010-0 pmid: 36587216
[67] Murakami S, Shimamoto T, Nagano H, et al. Producing human ceramide-NS by metabolic engineering using yeast Saccharomyces cerevisiae. Scientific Reports, 2015, 5(1): 1-11.
[68] Schuck S, Prinz W A, Thorn K S, et al. Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response. The Journal of Cell Biology, 2009, 187(4): 525-536.
doi: 10.1083/jcb.200907074
[69] Arendt P, Miettinen K, Pollier J, et al. An endoplasmic reticulum-engineered yeast platform for overproduction of triterpenoids. Metabolic Engineering, 2017, 40: 165-175.
doi: S1096-7176(16)30237-3 pmid: 28216107
[70] Shi Y T, Dong T Y, Zeng B X, et al. Production of plant sesquiterpene lactone parthenolide in the yeast cell factory. ACS Synthetic Biology, 2022, 11(7): 2473-2483.
doi: 10.1021/acssynbio.2c00132 pmid: 35723427
[71] Bian Q, Zhou P P, Yao Z, et al. Heterologous biosynthesis of lutein in S. cerevisiae enabled by temporospatial pathway control. Metabolic Engineering, 2021, 67: 19-28.
doi: 10.1016/j.ymben.2021.05.008 pmid: 34077803
[72] Ye L J, Zhu X N, Wu T, et al. Optimizing the localization of astaxanthin enzymes for improved productivity. Biotechnology for Biofuels, 2018, 11(1): 1-9.
doi: 10.1186/s13068-017-1003-x
[73] Meng Y H, Shao X X, Wang Y, et al. Extension of cell membrane boosting squalene production in the engineered Escherichia coli. Biotechnology and Bioengineering, 2020, 117(11): 3499-3507.
doi: 10.1002/bit.v117.11
[74] Wu T, Ye L J, Zhao D D, et al. Membrane engineering - A novel strategy to enhance the production and accumulation of β-carotene in Escherichia coli. Metabolic Engineering, 2017, 43: 85-91.
doi: 10.1016/j.ymben.2017.07.001
[75] Wu T, Li S W, Ye L J, et al. Engineering an artificial membrane vesicle trafficking system (AMVTS) for the excretion of β-carotene in Escherichia coli. ACS Synthetic Biology, 2019, 8(5): 1037-1046.
doi: 10.1021/acssynbio.8b00472
[76] Arhar S, Natter K. Common aspects in the engineering of yeasts for fatty acid- and isoprene-based products. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2019, 1864(12): 158513.
doi: 10.1016/j.bbalip.2019.08.009
[77] Csáky Z, Garaiová M, Kodedová M, et al. Squalene lipotoxicity in a lipid droplet-less yeast mutant is linked to plasma membrane dysfunction. Yeast, 2020, 37(1): 45-62.
doi: 10.1002/yea.v37.1
[78] Hong J, Park S H, Kim S, et al. Efficient production of lycopene in Saccharomyces cerevisiae by enzyme engineering and increasing membrane flexibility and NAPDH production. Applied Microbiology and Biotechnology, 2019, 103(1): 211-223.
doi: 10.1007/s00253-018-9449-8
[79] Zhang J L, Bai Q Y, Peng Y Z, et al. High production of triterpenoids in Yarrowia lipolytica through manipulation of lipid components. Biotechnology for Biofuels, 2020, 13: 133.
doi: 10.1186/s13068-020-01773-1
[80] Wei S P, Qian Z G, Hu C F, et al. Formation and functionalization of membraneless compartments in Escherichia coli. Nature Chemical Biology, 2020, 16(10): 1143-1148.
doi: 10.1038/s41589-020-0579-9
[81] Zhao E M, Suek N, Wilson M Z, et al. Light-based control of metabolic flux through assembly of synthetic organelles. Nature Chemical Biology, 2019, 15(6): 589-597.
doi: 10.1038/s41589-019-0284-8 pmid: 31086330
[82] Wang Y, Liu M, Wei Q X, et al. Phase-separated multienzyme compartmentalization for terpene biosynthesis in a prokaryote. Angewandte Chemie International Edition, 2022, 61(29): e202203909.
[83] Kang W, Ma X, Kakarla D, et al. Organizing enzymes on self-assembled protein cages for cascade reactions. Angewandte Chemie International Edition, 2022, 61(52): e202214001.
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