Microbial heparin/heparan sulphate lyases: potential and applications

Abstract

Heparin/heparan sulphate glycosaminoglycans (HSGAGs) are composed of linear chains of 20-100 disaccharide units of N-acetylated D: -glucosamine α (1-4) linked to glucuronic acid. HSGAGs are widely distributed on the cell surface and extracellular cell matrix of virtually every mammalian cell type and play critical role in regulating numerous functions of blood vessel wall, blood coagulation, inflammation response and cell differentiation. These glycosaminoglycans present in this extracellular environment very significantly influence the blood coagulation system and cardiovascular functions. Recent studies have investigated the mechanism by which cancer causes thrombosis and emphasizes the importance of the coagulation system in angiogenesis and tumour metastasis. Heparan sulphate/heparin lyases or heparinases are a class of enzymes that are capable of specifically cleaving the (1-4) glycosidic linkages in heparin and heparan sulphate to generate biologically active oligosaccharides with substantially significant and distinct clinical, pharmaceutical and prophylactic/therapeutic applications. Bioavailability and pharmacokinetic behaviour and characteristics of these oligosaccharides vary significantly depending on the origin/nature of the substrate (heparin or heparan sulphate-like glycosaminoglycans), the source of enzyme and method of preparation. Various microorganisms are reported/patented to produce these enzymes with different properties. Heparinases are commercially used for the depolymerization of unfractionated heparin to produce low molecular weight heparins (LMWHs), an effective anticoagulant. Individual LMWHs are chemically different and unique and thus cannot be interchanged therapeutically. Heparinases and LMWHs are reported to control angiogenesis and metastasis also. This review catalogues the degradation of HSGAGs by microbial heparin/heparan sulphate lyases and their potential either specific to the enzymes or with the dual role for generation of oligosaccharides for a new generation of compounds, as shown by various laboratory or clinical studies.

Deliberate Attenuation of Chikungunya Virus by Adaptation to Heparan Sulfate-Dependent Infectivity: A Model for Rational Arboviral Vaccine Design

“…We examined the infectivity of each virus for MC3T3-E1 cells digested with microbial heparinases, (Hep) I, II and III, which digest cell-surface HS chains (recently reviewed in [49]). Hep II acts with little specificity, cleaving both HS chains and heparin regardless of sulfation.…”

Applications of capillary electrophoresis electrospray ionization mass spectrometry in glycosaminoglycan analysis

“…Prior to CE ESI MS, the long heparin/HS chains are usually submitted to depolymerization using bacterial heparinases, that is, heparin and HS lyases. Following the specific cleavage mechanism of lyases, bacterial heparinases cleave the glycosidic linkages between the amino sugars and the uronic acids in heparin and HS with the formation of a C4‐C5 double bond in the uronic acid.…”

Oscillospira and related bacteria – From metagenomic species to metabolic features

“…Glucuronate is a common host‐derived sugar in the human body, and a key component of heparin/heparan sulphate glycosaminoglycans that are found on the cell surface and in the extracellular matrix of most human tissues (Tripathi et al ., ), and common to all vertebrates (Poulain and Yost, ). Glucuronate therefore represents a good substrate for gut symbionts, and its utilization by some Oscillospira strains could explain why the relative abundance of such strains increased in the cecum following prolonged fasting in a bird, a fish and a mouse (Kohl et al ., ).…”