Reprograming the Carbon Metabolism of Yeast for Hyperproducing Mevalonate, a Building Precursor of the Terpenoid Backbone

作者：Ge Zhang, Yurui Ma, Meina Huang, Kai‐Zhi Jia, Ting Ma, Zongjie Dai, Qinhong Wang · 发表于：Journal of Agricultural and Food Chemistry · 年份：2024 · DOI：10.1021/acs.jafc.4c09874 · 被引用次数：14 · 研究领域：Microbial Metabolic Engineering and Bioproduction、Plant biochemistry and biosynthesis、Enzyme Catalysis and Immobilization

Utilization of microbial hosts to produce natural plant products is regarded as a promising and sustainable approach. However, achieving highly efficient production of terpenoids using microorganisms remains a significant challenge. Here, mevalonate, a building block of terpenoids, was used as a demo product to explore the potential metabolic constraints for terpenoid biosynthesis in Yarrowia lipolytica . First, by regulation of the expression of ERG12 and HMGR, the mevalonate titer was improved by 7660%. Subsequently, the native mevalonate pathway (MVA pathway) was enhanced, and the production of mevalonate increased to 4.16 g/L. To ensure a sufficient supply of acetyl-CoA, the citrate route and TCA cycle were simultaneously engineered, and the mevalonate titer was further improved to 5.25 g/L in shake flasks. Ultimately, the citrate overflow metabolism of Y. lipolytica was eliminated by deleting CEX1, resulting in the highest mevalonate titer of 101 g/L with a yield of 0.255 g/g of glucose in eukaryotes. These insights could be applied to the effective production of terpenoids and biochemicals derived from central carbon metabolic pathways.