ENZYMATIC DEGRADATION OF GLYCOSAMINOGLYCANS

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 isomeriza tion, sulfation, and acetylation, generate the chemical specificity of GAGs. GAGs can be depolymerized enzymatically either by eliminative c leavage with lyases (EC 4.2.2.-) or by hydrolytic cleavage with hydrol ases (EC 3.2.1.-). Often, these enzymes are specific for residues in t he polysaccharide chain with certain modifications. As such, the enzym es can serve as tools for studying the physiological effect of residue modifications and as models at the molecular level of protein-GAG rec ognition. This review examines the structure of the substrates, the pr operties of enzymatic degradation, and the enzyme substrate-interactio ns at a molecular level. The primary structure of several GAGs is orga nized macroscopically by segregation into alternating blocks of specif ic sulfation patterns and microscopically by formation of oligosacchar ide sequences with specific binding functions. Among GAGs, considerabl e dermatan sulfate, heparin and heparan sulfate show conformational fl exibility in solution. They elicit sequence-specific interactions with enzymes that degrade them, as well as with other proteins, however, t he effect of conformational flexibility on protein-GAG interactions is not clear. Recent findings have established empirical rules of substr ate specificity and elucidated molecular mechanisms of enzyme-substrat e interactions for enzymes that degrade GAGs. Here we propose that loc al formation of polysaccharide secondary structure is determined by th e immediate sequence environment within the GAG polymer, and that this secondary structure, in turn, governs the binding and catalytic inter actions between proteins and GAGs.