Construction and Optimization of Engineered Saccharomyces cerevisiae for De Novo Synthesis of Phloretin and Its Derivatives

IF 5.7 1区 农林科学 Q1 AGRICULTURE, MULTIDISCIPLINARY
Yumei Han, Zetian Qiu, Shiqi Ji, Guang-Rong Zhao
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Abstract

Phloretin and its derivatives are dihydrochalcone compounds with diverse pharmacological properties and biological activities, offering significant potential for applications in the food and pharmaceutical industries. Due to their structural similarity to flavonoids, their extraction and isolation were highly challenging. Although the biosynthesis of phloretin via three distinct pathways has been reported, a systematic comparison within the same host has yet to be conducted. In this study, we employed rational design and synthetic biology approaches to engineer Saccharomyces cerevisiae for de novo synthesis of phloretin and its derivatives. We constructed and evaluated three biosynthetic pathways for phloretin in S. cerevisiae, demonstrating that effective phloretin synthesis is achievable only via the p-coumaryl-CoA pathway. Additionally, by optimizing enzyme screening, strain engineering, and coordinating heterologous pathways with endogenous metabolism, we achieved the highest reported de novo titer of 287.2 mg/L for phloretin, 184.6 mg/L for phlorizin, 103.1 mg/L for trilobatin, and 164.5 mg/L for nothofagin and the first-time synthesis of 4-methylphloretin and hesperetin dihydrochalcone. This study was committed to addressing the growing demand for dihydrochalcones while laying the foundation for the biosynthesis of more complex derivatives.

Abstract Image

重新合成根皮素及其衍生物的工程酿酒酵母的构建与优化
根皮素及其衍生物是具有多种药理特性和生物活性的二氢查尔酮类化合物,在食品和制药工业中具有巨大的应用潜力。由于其结构与黄酮类化合物相似,其提取和分离具有很大的挑战性。虽然已经报道了根皮素通过三种不同途径的生物合成,但尚未在同一宿主内进行系统比较。在本研究中,我们采用合理设计和合成生物学的方法对酿酒酵母进行工程改造,以重新合成根皮素及其衍生物。我们构建并评估了葡萄球菌根皮素的三种生物合成途径,证明了根皮素的有效合成只能通过对香豆醇-辅酶a途径实现。此外,通过优化酶筛选、菌株工程和协调外源途径与内源代谢,我们获得了报道的最高从头效价:根黄素287.2 mg/L、根黄素184.6 mg/L、三叶叶苷103.1 mg/L、无烟金164.5 mg/L,并首次合成了4-甲基根黄素和橙皮素二氢查尔酮。本研究致力于解决对二氢查尔酮日益增长的需求,同时为更复杂的衍生物的生物合成奠定基础。
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来源期刊
Journal of Agricultural and Food Chemistry
Journal of Agricultural and Food Chemistry 农林科学-农业综合
CiteScore
9.90
自引率
8.20%
发文量
1375
审稿时长
2.3 months
期刊介绍: The Journal of Agricultural and Food Chemistry publishes high-quality, cutting edge original research representing complete studies and research advances dealing with the chemistry and biochemistry of agriculture and food. The Journal also encourages papers with chemistry and/or biochemistry as a major component combined with biological/sensory/nutritional/toxicological evaluation related to agriculture and/or food.
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