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.

Enzymatic degradation of glycosaminoglycans.

Polysaccharide lyases (or eliminases) are a class of enzymes (EC 4.2.2.-) that act to cleave certain activated glycosidic linkages present in acidic polysaccharides. These enzymes act through an eliminase mechanism, rather than through hydrolysis, resulting in unsaturated oligosaccharide products. Acidic polysaccharides are ubiquitous and so are the lyases that degrade them. This review article examines lyases that act on acidic polysaccharides of plant, animal, and microbial origin. These lyases are predominantly of microbial origin and come from a wide variety of both pathogenic and nonpathogenic bacteria and fungi. The lyases discussed include alginate lyase (EC 4.2.2.3), pectin lyase (EC 4.2.2.10), pectate lyase (EC 4.2.2.2), oligogalacturonide lyase (EC 4.2.2.6), exopolygalacturonate lyase (EC 4.2.2.9), chondroitin lyases (EC 4.2.2.4 and EC 4.2.2.5), hyaluronate lyase (EC 4.2.2.1), heparin lyase (EC 4.2.2.7), heparan lyase (EC 4.2.2.8), and other unclassified lyases. This review examines the sources, regulation, purification, and properties of these polysaccharide lyases.

Polysaccharide lyases

Streptococcus pneumoniae hyaluronate lyase (spnHL) is a pathogenic bacterial spreading factor and cleaves hyaluronan, an important constituent of the extracellular matrix of connective tissues, through an enzymatic β-elimination process, different from the hyaluronan degradation by hydrolases in animals. The mechanism of hyaluronan binding and degradation was proposed based on the 1.56 A resolution crystal structure, substrate modeling and mutagenesis studies on spnHL. Five mutants, R243V, N349A, H399A, Y408F and N580G, were constructed and their activities confirmed our mechanism hypothesis. The important roles of Tyr408, Asn349 and His399 in enzyme catalysis were proposed, explained and confirmed by mutant studies. The remaining weak enzymatic activity of the H399A mutant, the role of the free carboxylate group on the glucuronate residue, the enzymatic behavior on chondroitin and chondroitin sulfate, and the small activity increase in the N580G mutant were explained based on this mechanism. A possible function of the C-terminal β-sheet domain is to modulate enzyme activity through binding to calcium ions.

/pdf/structural-basis-of-hyaluronan-degradation-by-streptococcus-34eienp2t3.pdf

Structural basis of hyaluronan degradation by Streptococcus pneumoniae hyaluronate lyase.

https://pure.mpg.de/pubman/item/item_599541_5/component/file_1479195/599541.pdf

Mechanism of hyaluronan degradation by Streptococcus pneumoniae hyaluronate lyase. Structures of complexes with the substrate.

Crystal structure of chondroitin AC lyase, a representative of a family of glycosaminoglycan degrading enzymes.

Hyaluronate lyase from streptococci group A was purified by chromatography on DEAE-Sephadex A-50 and on Biogel P-150, thereby enriching it about 1,000-fold and separating it into two enzyme fractions with the same amino acid composition. The photooxidation of hyaluronate lyase in the presence of methylene blue results in rapid inactivation of the enzyme. The histidine content of the enzyme is decreased considerably, but also the content of methionine, tyrosine, and lysine is lowered. The enzyme is inhibited, but incompletely so, by N-tosyl-L-phenyl-alanine-chloromethyl ketone (TPCK) and N-α-p-tosyl-L-lysine chloromethyl ketone (TLCK). Hyaluronic acid methyl ester, prepared from hyaluronic acid and diazomethane, is not split by hyaluronate lyase (EC 4.2.2.1). Hyaluronic acid methyl ester is not a competitive inhibitor of hyaluronate lyase. For the mechanism of the enzymatic elimination reaction a proton transfer between histidine of the enzyme and the carboxylate group of hyaluronate is proposed.

Studies on the mechanism of hyaluronate lyase action.

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Studies on the mechanism of hyaluronate lyase action.