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Establishing cell suitability for high-level production of licorice triterpenoids in yeast

Acta Pharmaceutica Sinica B 2024年第9期14卷 4134-4148页

作者： Wentao Sun Shengtong Wan Chuyan Liu Ruwen Wang Haocheng Zhang Lei Qin Runming Wang Bo Lv Chun Li Department of Chemical Engineering Tsinghua UniversityBeijing 100084China Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering Ministry of Industry and Information TechnologyInstitute of Biochemical EngineeringSchool of Chemistry and Chemical EngineeringBeijing Institute of TechnologyBeijing 100081China The University of Chicago ChicagoIL 60637USA Key Lab for Industrial Biocatalysis Ministry of EducationTsinghua UniversityBeijing 100084China Center for Synthetic and Systems Biology Tsinghua UniversityBeijing 100084China Institute of Biopharmaceutical and Health Engineering Tsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhen 518055China

Yeast has been an indispensable host for synthesizing complex plant-derived naturalcompounds, yet the yields remained largely constrained. This limitation mainly arises from overlookingthe importance of cell and pathway suitability during the optimization of enzymes and pathways. Herein,beyond conventional enzyme engineering, we dissected metabolic suitability with a framework forsimultaneously augmenting cofactors and carbon flux to enhance the biosynthesis of heterogenoustriterpenoids. We further developed phospholipid microenvironment engineering strategies, dramaticallyimproving yeast’s suitability for the high performance of endoplasmic reticulum (ER)-localized, ratelimitingplant P450s. Combining metabolic and microenvironment suitability by manipulating only threegenes, NHMGR (NADH-dependent HMG-CoA reductase), SIP4 (a DNA-binding transcription factor)andGPP1 (Glycerol-1-phosphate phosphohydrolase 1), we enabled the high-level production of 4.92 g/L rarelicorice triterpenoids derived from consecutive oxidation of b-amyrin by two P450 enzymes afterfermentation optimization. This production holds substantial commercial value, highlighting the criticalrole of establishing cell suitability in enhancing triterpenoid biosynthesis and offering a versatileframework applicable to various plant natural product biosynthetic pathways.

关键词： Cell suitability phospholipid microenvironment Cytochrome P450 Triterpenoids Saccharomyces cerevisiae

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