Recent advances in enzymatic synthesis of dipeptides

LOU Longwei; WANG Shuhong; CHEN Dongyu; ZHANG Yi; SU Haixia; YANG Liu; CLI Zonglin; LI Zhimin

doi:10.12211/2096-8280.2026-060

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Recent advances in enzymatic synthesis of dipeptides

更新时间：2026-08-18

- Recent advances in enzymatic synthesis of dipeptides
- 二肽的酶催化合成研究进展
- Synthetic Biology Journal Pages: 1-26(2026)
- 作者机构：
  
  1.华东理工大学，生物工程学院，生物反应器工程全国重点实验室，上海 200237
  2.中国石化催化剂有限公司，工程技术研究院，北京 101111
- 作者简介：
- 基金信息：
- DOI：10.12211/2096-8280.2026-060
  CLC： Q816
- Received：02 July 2026，
  
  Revised：2026-08-14，
  
  Online First：18 August 2026，
- 稿件说明：
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娄龙威，王淑弘，陈冬宇，张毅，苏海霞，杨柳，李宗霖，李志敏. 二肽的酶催化合成研究进展［J］. 合成生物学， 2026， 7. DOI： 10.12211/2096-8280.2026-060

LOU Longwei， WANG Shuhong， CHEN Dongyu， ZHANG Yi， SU Haixia， YANG Liu， CLI Zonglin， LI Zhimin. Recent advances in enzymatic synthesis of dipeptides［J］. Synthetic Biology Journal， 2026， 7. DOI： 10.12211/2096-8280.2026-060
娄龙威，王淑弘，陈冬宇，张毅，苏海霞，杨柳，李宗霖，李志敏. 二肽的酶催化合成研究进展［J］. 合成生物学， 2026， 7. DOI： 10.12211/2096-8280.2026-060 DOI：

LOU Longwei， WANG Shuhong， CHEN Dongyu， ZHANG Yi， SU Haixia， YANG Liu， CLI Zonglin， LI Zhimin. Recent advances in enzymatic synthesis of dipeptides［J］. Synthetic Biology Journal， 2026， 7. DOI： 10.12211/2096-8280.2026-060 DOI：

摘要

功能性二肽凭借优异的溶解性、结构稳定性与生物吸收利用率，在功能食品、生物医药、精细化工等领域具备极高的应用价值与广阔产业化前景。传统二肽制备依赖化学合成，存在工艺繁琐、环境污染严重、产物可控性差等缺陷，而酶催化绿色合成技术凭借反应条件温和、立体选择性高、副产物少等优势，已成为当下二肽高效生物制造的主流发展方向。本文系统梳理了二肽合成技术的发展历程，聚焦四大核心酶催化体系，包括非核糖体肽合成酶（NRPS）、ATP依赖型

-氨基酸连接酶（Lal）、蛋白酶/肽酶及

-氨基酸酯酰转移酶（AET），详细阐释了各类酶系差异化的肽键形成催化机制、研究进展与应用场景，总结了不同酶系的底物谱特征、催化优势与固有缺陷，归纳了结构域重构、定点突变、半理性设计、宿主代谢改造及固定化催化等主流酶工程与工艺优化策略，梳理了各类体系合成功能性二肽的典型研究案例。同时，深度剖析了当前酶法合成存在的核心瓶颈，包括工具酶固有催化缺陷、底物特异性限制、新型酶资源匮乏等问题。本文旨在为功能性二肽的绿色高效、规模化、定制化生物制造提供系统的理论参考与技术思路，推动酶催化二肽合成技术的持续发展。

Abstract

Functional dipeptides are small molecular bioactive compounds with superior solubility

structural stability and bioavailability

which endow them with broad application prospects in functional food

biomedicine

cosmetics and nutritional health industries. Compared with free amino acids and long-chain polypeptides

dipeptides can be efficiently absorbed and utilized by organisms with low metabolic loss

and exhibit diverse physiological functions such as antioxidant

anti-fatigue

antihypertensive and immunomodulatory activities. With the rapid development of precision nutrition and biomedical industries

the market demand for high-value functional dipeptides continues to expand

driving the rapid innovation of green and efficient dipeptide manufacturing technologies. Traditional dipeptide produc

tion method was chemical synthesis

which restricted by inherent technical defects. Chemical synthesis suffers from cumbersome protection-deprotection procedures

massive organic solvent consumption and severe environmental pollution

while microbial fermentation is also limited by complex intracellular metabolic networks

resulting in insufficient product diversity and unstable yield. Enzymatic catalysis has emerged as a prominent alternative for dipeptide biosynthesis due to its mild reaction conditions

excellent stereoselectivity

minimal by-products formation and high atom economy. This review systematically summarizes the century-long development history of dipeptide synthetic technologies and comprehensively elaborates four core enzymatic catalytic systems

namely non-ribosomal peptide synthetases (NRPSs)

ATP-dependent

-amino acid ligases (Lals)

proteases/peptidases

and α-amino acid ester acyltransferases (AETs). The distinct peptide bond formation mechanisms

substrate recognition patterns

catalytic characteristics and application scopes of different enzyme families are analyzed in detail. We further conclude recent research advances in novel enzyme mining

structural modification

directed evolution

metabolic engineering optimization and immobilization strategies

and summarize typical cases of natural and unnatural functional dipeptides synthesized by different enzymatic platforms. Meanwhile

the current technical bottlenecks restricting the industrialization of enzymatic dipeptide synthesis are thoroughly discussed

including inherent substrate specificity limitations

unavoidable hydrolysis side reactions

insufficient energy utilization efficiency

poor heterologous expression performance

and immature supporting industrial processes. In the end

future development trends are prospected based on the integration of structural biology

artificial intelligence-assisted enzyme design and synthetic biology

covering precise enzyme directional transformation

multi-enzyme cascade sys

tem construction

industrial continuous process optimization

and innovative functional dipeptide exploitation. This review aims to provide systematic theoretical guidance and technical references for the further development and large-scale industrial application of green enzymatic dipeptide manufacturing technology.

关键词

Keywords

references

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Related Institution

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State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences

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Tianjin Key Laboratory of Biosensing and Molecular Recognition， Research Center for Analytical Sciences， Frontiers Science Center for New Organic Matter， Haihe Laboratory of Sustainable Chemical Transformations， College of Chemistry， Nankai University

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