Synthesizing ginsenoside Rh2 in Saccharomyces cerevisiae cell factory at high-efficiency

原人参二醇 酵母 化学 发酵 底盘 酿酒酵母 人参皂甙 人参 代谢工程 苷元 生物化学 糖苷 立体化学 替代医学 病理 工程类 医学 结构工程
作者
Pingping Wang,Wei Wei,Wei Ye,Xiaodong Li,Wenfang Zhao,Chengshuai Yang,Chaojing Li,Xing Yan,Zhihua Zhou
出处
期刊:Cell discovery [Springer Nature]
卷期号:5 (1) 被引量:139
标识
DOI:10.1038/s41421-018-0075-5
摘要

Synthetic biology approach has been frequently applied to produce plant rare bioactive compounds in microbial cell factories by fermentation. However, to reach an ideal manufactural efficiency, it is necessary to optimize the microbial cell factories systemically by boosting sufficient carbon flux to the precursor synthesis and tuning the expression level and efficiency of key bioparts related to the synthetic pathway. We previously developed a yeast cell factory to produce ginsenoside Rh2 from glucose. However, the ginsenoside Rh2 yield was too low for commercialization due to the low supply of the ginsenoside aglycone protopanaxadiol (PPD) and poor performance of the key UDP-glycosyltransferase (UGT) (biopart UGTPg45) in the final step of the biosynthetic pathway. In the present study, we constructed a PPD-producing chassis via modular engineering of the mevalonic acid pathway and optimization of P450 expression levels. The new yeast chassis could produce 529.0 mg/L of PPD in shake flasks and 11.02 g/L in 10 L fed-batch fermentation. Based on this high PPD-producing chassis, we established a series of cell factories to produce ginsenoside Rh2, which we optimized by improving the C3-OH glycosylation efficiency. We increased the copy number of UGTPg45, and engineered its promoter to increase expression levels. In addition, we screened for more efficient and compatible UGT bioparts from other plant species and mutants originating from the direct evolution of UGTPg45. Combining all engineered strategies, we built a yeast cell factory with the greatest ginsenoside Rh2 production reported to date, 179.3 mg/L in shake flasks and 2.25 g/L in 10 L fed-batch fermentation. The results set up a successful example for improving yeast cell factories to produce plant rare natural products, especially the glycosylated ones.
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