酶促合成手性氨基酸的研究进展

王子渊; 杨立荣; 吴坚平; 郑文隆

doi:10.12211/2096-8280.2024-015

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酶促合成手性氨基酸的研究进展

特约评述 | 更新时间：2025-04-11

- 酶促合成手性氨基酸的研究进展
- A review on enzyme-catalyzed synthesis of chiral amino acids
- 合成生物学 2024年5卷第6期页码：1319-1349
- 作者机构：
  
  1.浙江大学杭州国际科创中心，生物与分子智造研究院，浙江杭州 311215
  2.浙江大学化学工程与生物工程学院，浙江杭州 310058
- 作者简介：
  
  [ "王子渊（1995—），女，博士后。研究方向为蛋白工程、生物化工。E-mail：ziyuanwang@zju.edu.cn" ]
  [ "郑文隆（1991—），男，研究员。研究方向为生物催化与转化、蛋白质智能设计等。E-mail：per@zju.edu.cn" ]
- 基金信息：
  
  国家自然科学基金(22308317);国家重点研究计划项目(2019YFA0905000);浙江省“尖兵”“领雁”研发攻关计划(2024C03013)
- DOI：10.12211/2096-8280.2024-015
  中图分类号： Q814
- 收稿：2024-02-04，
  
  修回：2024-05-16，
  
  纸质出版：2024-12-31
- 稿件说明：
移动端阅览
王子渊，杨立荣，吴坚平，郑文隆. 酶促合成手性氨基酸的研究进展［J］. 合成生物学， 2024， 5（6）： 1319-1349

WANG Ziyuan， YANG Lirong， WU Jianping， ZHENG Wenlong. A review on enzyme-catalyzed synthesis of chiral amino acids［J］. Synthetic Biology Journal， 2024， 5（6）： 1319-1349
王子渊，杨立荣，吴坚平，郑文隆. 酶促合成手性氨基酸的研究进展［J］. 合成生物学， 2024， 5（6）： 1319-1349 DOI： 10.12211/2096-8280.2024-015.

WANG Ziyuan， YANG Lirong， WU Jianping， ZHENG Wenlong. A review on enzyme-catalyzed synthesis of chiral amino acids［J］. Synthetic Biology Journal， 2024， 5（6）： 1319-1349 DOI： 10.12211/2096-8280.2024-015.

摘要

手性氨基酸是一类重要的高价值化学品，广泛应用于食品、医药、化工、农药等多个领域。手性氨基酸常用的制备方法可以分为四类，包括化学合成、蛋白质水解、发酵和酶促合成。其中，酶促合成手性氨基酸以其反应条件温和、立体选择性高、步骤简单、应用范围广等优势备受关注。近年来，得益于生物信息学和蛋白质工程等技术的快速发展，大量性能优异的酶制剂被开发，并成功应用于多种手性氨基酸的制备。本文重点综述了酶促不对称合成和去消旋化合成两种路径在手性氨基酸合成中的应用，包括关键酶制剂氨基酸脱氢酶、转氨酶、氨裂解酶、醛缩酶、氨基酸氧化酶、氨基酸脱氨酶等的开发与改造，及其在草铵膦、叔亮氨酸、西格列汀中间体等高价值手性氨基酸合成中的应用。同时，总结了酶促合成手性氨基酸领域面临的主要困境，如关键酶元件缺乏，以及野生酶非对映体选择性低、底物谱窄、催化活性低、稳定性差、反应条件局限等。最后，展望了自动化实验装置、机器学习和人工智能等前沿技术在酶改造领域的应用，以及通过反应器设计和反应过程控制，开发更为高效和环境友好的催化工艺，推动酶促合成手性氨基酸技术更广泛的工业应用。

Abstract

Chiral amino acids represent a crucial class of chiral building blocks with significant value in food

medicine

chemical industry

and agriculture. The market scale of pharmaceuticals

pesticides

food

and chemical industries relying on chiral amino acids is substantial and has been attracting increasing attention. The pursuit of efficient

environmentally friendly

and cost-effective synthesis of chiral amino acids has long been a goal for scientists. Commonly used preparation methods for chiral amino acids fall into four following categories: protein hydrolysis

fermentation

chemical synthesis

and enzyme-catalyzed synthesis. Among these

enzyme-catalyzed synthesis has demonstrated great potential due to its mild reaction conditions

high stereo-selectivity

simplicity of steps

and wide application range. In recent years

with the rapid development of bioinfo

rmatics

protein engineering

and computational biology

there has been an increasing number of high-performance enzyme preparations developed

leading to a steady increase in the diversity of enzymes and the gradual diversification of catalyzed reactions

further promoting the wide application of enzyme-catalyzed synthesis of chiral amino acids. The enzyme-catalyzed synthesis of chiral amino acids can be categorized into three groups: asymmetric synthesis

deracemization synthesis

and kinetic resolution. Kinetic resolution

due to its theoretical yield of only 50% and low atom economy

is not suitable for industrial applications. In contrast

asymmetric synthesis and deracemization synthesis with theoretical yield of 100% find wider industrial application. This article reviews the application of enzymatic asymmetric synthesis and deracemization synthesis in the synthesis of chiral amino acids. It includes the development and modification of key enzyme such as amino acid dehydrogenase

transaminase

ammonia lyase

aldolase

amino acid oxidase

and amino acid deaminase

as well as their application in the synthesis of high-value chiral amino acids such as phosphinothricin

tert

-leucine

and intermediate of sitagliptin. Additionally

it summarizes the main challenges faced in the field of enzymatic synthesis of chiral amino acids

such as the lack of key enzyme components

and low enantioselectivity

narrow substrate spectra

low catalytic activity

poor stability

limited reaction conditions of wild-type enzymes. Finally

it looks ahead to the application of cutting-edge technologies such as automated experimental devices

machine learning

and artificial intelligence in the field of enzyme modification

as well as the development of more efficient and environmentally friendly catalytic processes through reactor design and reaction process control. These endeavors collectively aim to facilitate the broader industrial application of enzymatic synthesis for chiral amino acids.

关键词

Keywords

references

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