Cellular and Chemical Biology Department, Institut Curie, PSL Research University, U1143 INSERM, UMR3666 CNRS, 26 rue d'Ulm, CEDEX 05, 75248 Paris, France.
Molecules. 2021 May 31;26(11):3299. doi: 10.3390/molecules26113299.
Lipid membranes are common to all forms of life. While being stable barriers that delimitate the cell as the fundamental organismal unit, biological membranes are highly dynamic by allowing for lateral diffusion, transbilayer passage via selective channels, and in eukaryotic cells for endocytic uptake through the formation of membrane bound vesicular or tubular carriers. Two of the most abundant fundamental fabrics of membranes-lipids and complex sugars-are produced through elaborate chains of biosynthetic enzymes, which makes it difficult to study them by conventional reverse genetics. This review illustrates how organic synthesis provides access to uncharted areas of membrane glycobiology research and its application to biomedicine. For this Special Issue on Chemical Biology Research in France, focus will be placed on synthetic approaches (i) to study endocytic functions of glycosylated proteins and lipids according to the GlycoLipid-Lectin (GL-Lect) hypothesis, notably that of Shiga toxin; (ii) to mechanistically dissect its endocytosis and intracellular trafficking with small molecule; and (iii) to devise intracellular delivery strategies for immunotherapy and tumor targeting. It will be pointed out how the chemical biologist's view on lipids, sugars, and proteins synergizes with biophysics and modeling to "look" into the membrane for atomistic scale insights on molecular rearrangements that drive the biogenesis of endocytic carriers in processes of clathrin-independent endocytosis.
脂质膜存在于所有生命形式中。作为将细胞界定为基本生物单位的稳定屏障，生物膜具有高度动态性，允许侧向扩散、通过选择性通道跨膜转运，并且在真核细胞中通过形成膜结合的囊泡或管状载体进行胞吞作用。脂质和复杂糖是膜中最丰富的两种基本结构，它们是通过复杂的生物合成酶链产生的，这使得通过传统的反向遗传学来研究它们变得困难。这篇综述说明了有机合成如何为膜糖生物学研究的未知领域提供了途径，并展示了其在生物医学中的应用。本期关于法国化学生物学研究的特刊将重点介绍合成方法：(i) 根据糖脂-凝集素（GL-Lect）假说，研究糖基化蛋白和脂质的胞吞作用，特别是志贺毒素的胞吞作用；(ii) 用小分子在机制上剖析其胞吞作用和细胞内转运；(iii) 设计用于免疫治疗和肿瘤靶向的细胞内递药策略。本文将指出化学生物学家对脂质、糖和蛋白质的看法如何与生物物理学和建模协同作用，以便从原子尺度上“观察”膜内分子重排，从而推动网格蛋白独立胞吞作用过程中胞吞载体的生物发生。
