鞘糖脂的化学酶促合成研究进展

马源; 陈嘉乐; 郝天辉; 李铁海

doi:10.12211/2096-8280.2026-023

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鞘糖脂的化学酶促合成研究进展

特约评述 | 更新时间：2026-09-04

- 鞘糖脂的化学酶促合成研究进展
- Recent advances in chemoenzymatic synthesis of glycosphingolipids
- 合成生物学 2026年7卷第4期页码：905-929
- 作者机构：
  
  1.中国科学院上海药物研究所，生命过程小分子调控全国重点实验室，上海 201203
  2.中国科学院大学，北京 100049
- 作者简介：
  
  马源（2000—），男，博士研究生。研究方向为糖脂的化学酶促合成及功能。E-mail：mayuan@simm.ac.cn
  李铁海（1982—），男，研究员，博士生导师。研究方向为糖化学生物学，具体集中在发展高效的化学合成法和化学酶促合成法，制备具有生理活性的复杂糖链与糖缀合物，用于药物先导化合物的筛选和靶标发现。E-mail：tiehaili@simm.ac.cn
- 基金信息：
  
  国家自然科学基金(92578103;22377134)
- DOI：10.12211/2096-8280.2026-023
  中图分类号： Q816
- 收稿：2026-04-13，
  
  修回：2026-05-18，
  
  纸质出版：2026-08-31
- 稿件说明：
移动端阅览
马源，陈嘉乐，郝天辉，李铁海. 鞘糖脂的化学酶促合成研究进展［J］. 合成生物学， 2026， 7（4）： 905-929

MA Yuan， CHEN Jiale， HAO Tianhui， LI Tiehai. Recent advances in chemoenzymatic synthesis of glycosphingolipids［J］. Synthetic Biology Journal， 2026， 7（4）： 905-929
马源，陈嘉乐，郝天辉，李铁海. 鞘糖脂的化学酶促合成研究进展［J］. 合成生物学， 2026， 7（4）： 905-929 DOI： 10.12211/2096-8280.2026-023.

MA Yuan， CHEN Jiale， HAO Tianhui， LI Tiehai. Recent advances in chemoenzymatic synthesis of glycosphingolipids［J］. Synthetic Biology Journal， 2026， 7（4）： 905-929 DOI： 10.12211/2096-8280.2026-023.

摘要

糖脂是生物膜表面的关键分子，在细胞识别、信号转导、免疫调控及病理过程中发挥重要作用。然而，天然糖脂的结构异质性高、分离纯化困难，限制了其功能研究与临床应用。化学合成与酶促合成是获取结构明确糖脂的主要途径，但各自存在技术瓶颈。化学酶促组装策略融合化学合成的灵活性与酶反应的立体/区域专一性，成为复杂糖脂精准制备的重要方向。本文首先梳理鞘糖脂的结构特征与生物学功能，对比分析传统化学合成与酶促合成的局限；进而重点阐述化学酶促合成的关键技术，包括模块化组装、一锅多酶（OPME）策略及功能化修饰鞘糖脂的精准合成等研究进展。未来结合人工智能辅助酶工程、自动化合成及合成生物学等前沿技术，有望实现复杂鞘糖脂的高效精准制备，推动其生物医药应用。

Abstract

Glycosphingolipids (GSLs) are important glycoconjugates located on the cell membrane surface that possess both structural and functional properties

playing critical roles in cellular recognition

signal transduction

immune regulation

and the development and progression of diseases. Among them

complex glycolipids such as gangliosides exhibit remarkable structural heterogeneity and biological complexity owing to their diverse glycan and lipid architectures. However

naturally derived glycolipids generally suffer from low abundance

high structural heterogeneity

and difficulties in their isolation and purification

which severely restrict their functional studies and clinical applications. Although chemical synthesis offers high structural tunability

it is still challenged by the stereoselective construction of glycosidic linkages and tedious protection/deprotection manipulations. In contrast

enzymatic synthesis relies on key enzyme systems such as glycosyltransferases and glycosynthases and is often limited by substrate scope

enzyme stability

and poor tolerance toward hydrophobic lipid acceptors. Consequently

chemoenzymatic assembly strategies

which integrate the flexibility of chemical synthesis with the high regio- and stereoselectivity of enzymatic catalysis

have emerged as an important approach for the precise construction of complex glycosphingolipids. This review systematically summarizes recent advances in the chemoenzymatic synthesis of glycosphingolipids. First

the structural characteristics

classifications

and biological functions of glycosphingolipids are introduced

followed by a comparative discussion of the advantages and limitations of chemical or enzymatic synthetic strategies. Subsequently

key technologies in chemoenzymatic assembly are highlighted

including modular assembly strategies

one-pot multienzyme (OPME) systems

glycosynthase-mediated glycan-lipid coupling approaches

and the precise synthesis of functionalized glycolipids. In addition

critical challenges in current systems

including the solubility mismatch of amphiphilic substrates

insufficient enzyme tolerance toward hydrophobic lipid substrates

limited compatibility of multienzyme systems

and difficulties in large-scale preparation

are discussed. Future developments are expected to integrate emerging technologies such as artificial intelligence-assisted enzyme engineering

structure prediction and machine learning-guided directed evolution

automated synthesis platforms

microfluidic continuous-flow systems

and synthetic biology-based microbial cell factories. Through the development of chemoenzymatic cascade systems with improved efficiency

generality

and scalability

together with high-throughput screening and function-oriented molecular design

the efficient

precise

and scalable synthesis of complex glycosphingolipids is anticipated to become achievable

thereby further promoting their translational applications in cancer immunotherapy

diagnosis and treatment of neurodegenerative diseases

drug delivery

and precision medicine.

关键词

Keywords

references

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