Ernst S, Langer R, Cooney C L, Sasisekharan R
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge 02139, USA.
Crit Rev Biochem Mol Biol. 1995;30(5):387-444. doi: 10.3109/10409239509083490.
Glycosaminoglycans (GAGs) play an intricate role in the extracellular matrix (ECM), not only as soluble components and polyelectrolytes, but also by specific interactions with growth factors and other transient components of the ECM. Modifications of GAG chains, such as isomerization, sulfation, and acetylation, generate the chemical specificity of GAGs. GAGs can be depolymerized enzymatically either by eliminative cleavage with lyases (EC 4.2.2.-) or by hydrolytic cleavage with hydrolases (EC 3.2.1.-). Often, these enzymes are specific for residues in the polysaccharide chain with certain modifications. As such, the enzymes can serve as tools for studying the physiological effect of residue modifications and as models at the molecular level of protein-GAG recognition. This review examines the structure of the substrates, the properties of enzymatic degradation, and the enzyme substrate-interactions at a molecular level. The primary structure of several GAGs is organized macroscopically by segregation into alternating blocks of specific sulfation patterns and microscopically by formation of oligosaccharide sequences with specific binding functions. Among GAGs, considerable dermatan sulfate, heparin and heparan sulfate show conformational flexibility in solution. They elicit sequence-specific interactions with enzymes that degrade them, as well as with other proteins, however, the effect of conformational flexibility on protein-GAG interactions is not clear. Recent findings have established empirical rules of substrate specificity and elucidated molecular mechanisms of enzyme-substrate interactions for enzymes that degrade GAGs. Here we propose that local formation of polysaccharide secondary structure is determined by the immediate sequence environment within the GAG polymer, and that this secondary structure, in turn, governs the binding and catalytic interactions between proteins and GAGs.
糖胺聚糖（GAGs）在细胞外基质（ECM）中发挥着复杂的作用，不仅作为可溶性成分和聚电解质，还通过与生长因子和ECM的其他瞬时成分的特异性相互作用发挥作用。GAG链的修饰，如异构化、硫酸化和乙酰化，产生了GAGs的化学特异性。GAGs可以通过裂解酶（EC 4.2.2.-）的消除性切割或水解酶（EC 3.2.1.-）的水解性切割进行酶促解聚。通常，这些酶对具有特定修饰的多糖链中的残基具有特异性。因此，这些酶可作为研究残基修饰的生理效应的工具，以及作为蛋白质 - GAG识别分子水平的模型。本综述在分子水平上研究了底物的结构、酶促降解的性质以及酶 - 底物相互作用。几种GAGs的一级结构在宏观上通过分离成特定硫酸化模式的交替块来组织，在微观上通过形成具有特定结合功能的寡糖序列来组织。在GAGs中，相当数量的硫酸皮肤素、肝素和硫酸乙酰肝素在溶液中表现出构象灵活性。它们引发与降解它们的酶以及其他蛋白质的序列特异性相互作用，然而，构象灵活性对蛋白质 - GAG相互作用的影响尚不清楚。最近的研究结果已经建立了底物特异性的经验规则，并阐明了降解GAGs的酶的酶 - 底物相互作用的分子机制。在这里，我们提出多糖二级结构的局部形成由GAG聚合物内的直接序列环境决定，并且这种二级结构反过来又控制蛋白质和GAG之间的结合和催化相互作用。
