上海交通大学生命科学技术学院,微生物代谢国家重点实验室,教育部代谢与发育科学国际合作联合实验室,上海 200240
[ "杨璐(1993—),女,博士研究生。研究方向为杂环类生物碱的生物合成研究及酶工程改造。E-mail:yl2020@sjtu.edu.cn" ]
[ "瞿旭东(1980—),男,教授,博士生导师。研究方向为生物合成与生物催化。E-mail:quxd19@sjtu.edu.cn" ]
收稿:2021-05-01,
修回:2021-07-27,
纸质出版:2022-06-30
移动端阅览
杨璐, 瞿旭东. 亚胺还原酶在手性胺合成中的应用[J]. 合成生物学, 2022, 3(3): 516-529
YANG Lu, QU Xudong. Application of imine reductase in the synthesis of chiral amines[J]. Synthetic Biology Journal, 2022, 3(3): 516-529
杨璐, 瞿旭东. 亚胺还原酶在手性胺合成中的应用[J]. 合成生物学, 2022, 3(3): 516-529 DOI: 10.12211/2096-8280.2021-054.
YANG Lu, QU Xudong. Application of imine reductase in the synthesis of chiral amines[J]. Synthetic Biology Journal, 2022, 3(3): 516-529 DOI: 10.12211/2096-8280.2021-054.
手性胺存在于许多生物活性物质中,是重要的手性助剂,同时也是合成天然产物及手性药物的关键中间体。2019年零售额前200名的药物中,含有手性胺结构的药物超过三成,因此发展高效、便捷合成手性胺化合物的方法是研究的重要方向。通过酶催化方法制备手性胺化合物,因具有高效性、环境友好性、经济效率高等优点,获得了学术界及工业界的广泛关注。本文所综述的亚胺还原酶(IREDs)是一类NAD(P)H依赖的氧化还原酶,可催化亚胺的不对称还原合成手性胺。IREDs具有催化效率高、区域及立体选择性强等优异的特性,在众多合成手性胺方法中脱颖而出,吸引了科研工作者的研究目光。近年来,随着生物信息学、结构生物学、高通量筛选方法的飞速发展和数据库的不断扩充,鉴定了许多不同功能的IRED,并在IRED的发现、分子改造、底物谱扩展和多酶级联应用等方面均取得了显著的成果,其中不乏一些具有工业应用价值。本文概述了IRED的结构特征及作用机理,着重介绍了IRED的分子改造和在多酶串联反应中的应用,以及在不对称催化手性胺生物合成中遇到的瓶颈、获得的突破和进展。此外还对酶法合成手性胺化合物实现工业化生产所面临的挑战及巨大潜力,以及新颖的人工生物合成途径设计对克服这些挑战的重要性进行了展望。
Ch
iral amines with bioactivities are important chiral auxiliaries
and also key intermediates for the synthesis of many natural products and chiral drugs. Among the top 200 drugs for market revenues in 2019
more than 30% contain chiral amine structures. Therefore
the development of efficient and effective methods to synthesize chiral amine compounds is of interest for research. Due to its high efficiency
environmental friendliness and economic competitiveness
more attention has been paid on the enzyme-catalyzed production of chiral amines by academia and industry. Imine reductases (IREDs) reviewed in this article are a class of NAD(P) H-dependent oxidoreductases that catalyze asymmetric reduction of imines to chiral amines. The reduction of C
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1.86266661
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4.48733330
N bonds constitutes a physiological reaction present in a number of biosynthetic pathways
leading to a variety of metabolites. The imine reductases have excellent characteristics such as high catalytic efficiency
strong regioselectivity and stereoselectivity
etc
.
which stand out among many other methods for the synthesis of chiral amines
and attract attention and enthusiasm of many researchers. In the past decade
with the rapid development of bioinformatics
structural biology
high-throughput screening approaches and the continuous expansion of the gene databases
many imine reductases with different functions have been identified. Significant achievements have b
een made in the discovery of IREDs
protein engineering and multi-enzyme cascade applications
among which some successful modification cases have industrial application potentials. This review summarizes the structural characteristics
catalytic mechanisms and applications of IREDs
with emphasis on their protein engineering and applications in multi-enzyme cascade reactions
as well as the bottleneck
breakthrough and progress in asymmetric catalytic chiral amine biosynthesis. In addition
the challenges and potentials of the enzymatic synthesis of chiral amine compounds for industrial production
and the importance of novel artificial biosynthesis pathway design to overcome these challenges are highlighted.
2
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