Engineering budding yeast for the de novo synthesis of valuable flavanone derivatives

作     者：Zhu, Si-Yu Li, Na Liu, Zhi-Hua Yuan, Ying-Jin Li, Bing-Zhi 

作者机构：Tianjin Univ Frontiers Sci Ctr Synthet Biol Tianjin 300072 Peoples R China Tianjin Univ Sch Chem Engn & Technol Key Lab Syst Bioengn Minist Educ Tianjin 300072 Peoples R China Tianjin Univ Frontiers Res Inst Synthet Biol Tianjin 301799 Peoples R China 

出 版 物：《GREEN CHEMISTRY》 (Green Chem.)

年 卷 期：2025年第27卷第13期

页      面：3477-3493页

核心收录：

学科分类：07[理学] 0703[理学-化学] 

基　　金：National Key Research and Development Program of China [2023YFC3403500] National Key Research and Development Program of China 

主　　题：Yeast 

摘      要：Flavonoids, such as homoeriodictyol derivatives, hold significant value in nutraceuticals, foods, and pharmaceuticals. Microbial synthesis of these products has emerged as a powerful approach due to its sustainability and environmental friendliness. However, constructing microbial cell factories of homoeriodictyol derivatives is often challenged by the lack of a biosynthesis pathway and the poor performance of endogenous metabolic networks. Here, an efficient Saccharomyces cerevisiae cell factory was designed and metabolically engineered for the de novo biosynthesis of homoeriodictyol 7-O-glucoside. Relieving the feedback inhibition and overexpressing the key enzymes successfully achieved the biosynthesis of homoeriodictyol with a titer of 174.0 mg L-1. Enzyme screening strategies explored missing glycosyltransferases and unveiled the homoeriodictyol 7-O-glucoside synthesis pathway for the first time. Blocking the glycoside hydrolysis pathway improved the titer of homoeriodictyol 7-O-glucoside by a substantial 7.2-fold. Metabolically regulating NADPH regeneration reduced the intermediate accumulation by 91.3%, while strengthening uridine diphosphate-glucose and substrate supply further boosted the homoeriodictyol 7-O-glucoside production. Altogether, these advancements led to a record homoeriodictyol 7-O-glucoside titer of 600.2 mg L-1 and a yield of 12.2 mg g-1 glucose. Overall, the versatile S. cerevisiae cell factory shows the potential to synthesize homoeriodictyol 7-O-glucoside, contributing to the green and sustainable production of natural products.