微生物环氧水解酶催化机制及应用研究进展

doi:10.12211/2096-8280.2020-004

合成生物学 ›› 2020, Vol. 1 ›› Issue (5): 528-539.DOI: 10.12211/2096-8280.2020-004

微生物环氧水解酶催化机制及应用研究进展

曹菲^1,², 李永泉^1,², 毛旭明^1,²

^1.浙江大学药物生物技术研究所，浙江杭州 310058
^2.浙江省微生物生化与代谢工程重点实验室，浙江杭州 310058

收稿日期:2020-02-27 修回日期:2020-08-07 出版日期:2020-10-31 发布日期:2020-12-03
通讯作者: 李永泉,毛旭明
作者简介:作者简介:曹菲（1995—），男，博士研究生，研究方向为微生物药物生物合成、微生物天然产物生物合成的酶学机制和化学机制研究、基于合成生物学的微生物药物开发。E-mail：feecao@zju.edu.cn|李永泉（1962—），男，博士，浙江大学求是特聘教授。研究方向为微生物合成生物学、微生物次级代谢调控和微生物制药。E-mail：lyq@zju.edu.cn|毛旭明（1978—），男，博士，教授，研究方向为基于合成生物学的微生物药物开发、微生物药物生物合成的调控机制研究、基于多组学的新活性和新结构微生物天然产物挖掘、微生物天然产物生物合成的酶学机制和化学机制研究。E-mail：xmmao@zju.edu.cn
基金资助:
国家重点研发计划(2019YFA0905400)

Recent development in catalytic mechanisms and applications of microbial epoxide hydrolases

Fei CAO^1,², Yongquan LI^1,², Xuming MAO^1,²

^1.Institute of Pharmaceutical Biotechnology，Zhejiang University，Hangzhou 310058，Zhejiang，China
^2.Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering，Hangzhou 310058，Zhejiang，China

Received:2020-02-27 Revised:2020-08-07 Online:2020-10-31 Published:2020-12-03
Contact: Yongquan LI,Xuming MAO

摘要/Abstract

摘要：

微生物来源的环氧水解酶（epoxide hydrolases，EHs，EC 3.3.2.3）能不对称水解外消旋环氧化物生成手性环氧化物和邻二醇，催化效率高且区域、立体选择性强，有利于合成高纯度的手性化合物。因此，微生物EHs成为了手性药物合成的一种非常重要的生物催化剂，也是一种强有力的生物合成元件。近10年来，随着基因组学、分子生物学、化学生物学、结构生物学等技术的快速发展，研究者又从多种微生物体内发现了多种具有潜在应用价值的EHs。与此同时，研究者也对微生物来源的EHs的酶学特性、生物大分子结构与催化机理进行了深入的研究。本文介绍了几种目前研究比较透彻的EHs催化机制，并综述了近10年来最新发现的微生物来源EHs，这些EHs具备潜在的应用价值。此外，本文总结了EHs的应用进展，重点介绍了EHs在合成生物学领域的应用。利用酶的定向进化等技术提高EHs催化性能和串联多个合成元件高效合成手性产物，是当前主要的研究趋势。

关键词: 微生物, 环氧水解酶, 催化机制, 合成生物学, 手性药物

Abstract:

Microbial epoxide hydrolases (EHs, EC 3.3.2.3) catalyze the enantioselective ring opening of racemic epoxides to the chiral epoxides and vicinal diols. EHs have high catalytic efficiency and chemical-, region-, and stereo-selectivity without cofactors, and are conducive to the synthesis of high-purity chiral compounds by biotransformation. Since they were discovered, EHs have become very important catalysts and powerful biosynthetic elements for the green synthesis of chiral drugs in industry. In the last 10 years, with the rapid development of genomics, molecular biology, chemical biology and structural biology, researchers have found a variety of EHs from various microorganisms with potential applications. At the same time, researchers have also paid a lot of attention to the enzymatic properties, protein structure and catalytic mechanism of microbial EHs. This review introduces the currently well-understood catalytic mechanism of microbial EHs, such as ArEH from Agrobacterium radiobacter and limonene 1,2-EH from Rhodococcus erythropolis. Moreover, it summarizes 30+ microbial EHs with potential values, which were newly discovered in the last decade based on genome mining of microorganisms, along with the cognate biosynthetic pathways for natural product production. At least 15 crystal structures of new microbial EHs have been elucidated, helping people further understand the catalytic mechanisms at atomic levels and laying the foundation of their evolutions and applications. In addition, the applications of EHs in the field of pharmaceuticals and synthetic biology are also highlighted. Nowadays, researchers are mainly focusing on the improvement of catalytic activity, specificity and efficiency, as well as enantio-purity and yield of the products from microbial EHs with two main strategies: random or rational mutations of enzymes and strains, and artificial design of enzyme cascades within chassis cells. In the future, the synthesis of chiral drugs catalyzed by EHs will commence on the evolution of enzymatic activity, and assembly of multi-enzyme instead of single-enzyme in a cell factory for efficient biocatalysis.

Key words: microorganisms, epoxide hydrolases, catalytic mechanism, synthetic biology, chiral drugs

中图分类号:

Q 939.97

曹菲, 李永泉, 毛旭明. 微生物环氧水解酶催化机制及应用研究进展[J]. 合成生物学, 2020, 1(5): 528-539.

Fei CAO, Yongquan LI, Xuming MAO. Recent development in catalytic mechanisms and applications of microbial epoxide hydrolases[J]. Synthetic Biology Journal, 2020, 1(5): 528-539.

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微生物环氧水解酶催化机制及应用研究进展

Recent development in catalytic mechanisms and applications of microbial epoxide hydrolases

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