Microbe Engineering to Provide Drimane-Type Building Blocks for Chiral Pool Synthesis of Meroterpenoids

IF 16.1 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Wenyu Du, Zhongyu Cheng, Xingming Pan, Chenhao Liu, Mingyu Yue, Tianhao Li, Zhixi Xiao, Lu-Lu Li, Xuelan Zeng, Xiaoxu Lin, Prof. Fuzhuo Li, Prof. Liao-Bin Dong
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Abstract

Drimane-type merosesquiterpenoids (DMT) are a class of natural products with diverse structures and broad biological activity. Classical DMT synthesis relies on atom-inefficient plant-derived chiral pool building blocks, while alternative drimane-type building blocks such as drimenol and albicanol offer more direct routes but face production challenges. In this study, we engineered a microbial platform for efficient production of these building blocks. By optimizing the PhoN-IPK system through rational engineering and incorporating a Nudix hydrolase, we achieved a drimenol production of 398 mg/L and high albicanol titers of 1805 mg/L in shake flasks and 3.5 g/L in a bioreactor. Structural analysis and molecular dynamics simulations of the engineered PhoN provided insights into its improved catalytic efficiency. We demonstrated the utility of this platform by synthesizing several DMT using albicanol as the starting material, reducing the number of synthetic steps and improving overall efficiency as compared to classical approaches.

Abstract Image

微生物工程为手性池合成巯基萜类化合物提供驱动力型构建块
Drimane-type merosesquiterpenoids (DMT)是一类结构多样、具有广泛生物活性的天然产物。经典的DMT合成依赖于原子效率低下的植物性手性池构建块,而替代的驱动型构建块,如drimenol和albicanol提供了更直接的途径,但面临生产挑战。在这项研究中,我们设计了一个微生物平台来有效地生产这些构建模块。通过合理的工程设计优化PhoN-IPK系统,并加入Nudix水解酶,我们获得了398 mg/L的醇醇产量和1805 mg/L的高白醇滴度,在摇瓶和生物反应器中分别为3.5 g/L。通过结构分析和分子动力学模拟,可以了解到改造后的PhoN催化效率的提高。我们通过使用白醇作为起始材料合成几种DMT来证明该平台的实用性,与传统方法相比,减少了合成步骤的数量并提高了整体效率。
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来源期刊
CiteScore
26.60
自引率
6.60%
发文量
3549
审稿时长
1.5 months
期刊介绍: Angewandte Chemie, a journal of the German Chemical Society (GDCh), maintains a leading position among scholarly journals in general chemistry with an impressive Impact Factor of 16.6 (2022 Journal Citation Reports, Clarivate, 2023). Published weekly in a reader-friendly format, it features new articles almost every day. Established in 1887, Angewandte Chemie is a prominent chemistry journal, offering a dynamic blend of Review-type articles, Highlights, Communications, and Research Articles on a weekly basis, making it unique in the field.
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