文献类型：期刊文献

英文题名：Combinatorial metabolic engineering of Yarrowia lipolytica for high-level production of the plant-derived diterpenoid sclareol

作者：Chen, Jiang[1];Huang, Longzheng[1];Ye, Bang-Ce[1,2];Zhou, Ying[1]

机构：[1]East China Univ Sci & Technol, Lab Biosyst & Microanal, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]Zhejiang Univ Technol, Coll Pharmaceut Sci, Yangtze River Delta Reg Green Pharmaceut, Collaborat Innovat Ctr,Inst Engn Biol & Hlth, Hangzhou 310014, Zhejiang, Peoples R China

年份：2025

卷号：24

期号：1

外文期刊名：MICROBIAL CELL FACTORIES

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001489366300001)】；

基金：This work was supported by Shanghai Municipal Science and Technology Major Project. We sincerely thank Prof. Xiaojun Ji from Nanjing Tech University for strain Y. lipolytica Po1f-tHEI gifted to us.

语种：英文

外文关键词：Sclareol; GGPP; Diterpenoids; Yarrowia lipolytica; Synthetic biology

摘要：BackgroundSclareol, a diterpene alcohol derived from Salvia sclarea, is primarily used in the synthesis of ambrox, an alternative to the expensive spice ambergris. However, commercial production of sclareol from plant extraction is costly and environmentally problematic, limiting its scalability. Recent advances in synthetic biology have enabled the construction of efficient cell factories for sclareol synthesis, offering a more sustainable solution.ResultsIn this study, we engineered Yarrowia lipolytica to produce sclareol by integrating genes encoding (13E)-8 alpha-hydroxylabden-15-yl diphosphate synthase (LPPS) and sclareol synthase (SCS). Sclareol titers were further enhanced through the fusion of SsSCS and SsLPPS proteins, as well as multi-copy gene integration. To increase the precursor geranylgeranyl diphosphate (GGPP), we overexpressed various geranylgeranyl diphosphate synthases (GGS1), resulting in significant accumulation of GGPP. Additionally, optimization of the mevalonate pathway, coupled with the downregulation of lipid synthesis and upregulation of lipid degradation, directed more acetyl CoA towards sclareol production.ConclusionsIn this study, we reprogrammed the metabolism of Y. lipolytica by combinatorial metabolic engineering with a sclareol titer of 2656.20 +/- 91.30 mg/L in shake flasks. Our findings provide a viable strategy for utilizing Y. lipolytica as a microbial cell factory to produce sclareol.