Glycosaminoglycan (GAG) biosynthesis and GAG-binding proteins

Abstract

Two major types of glycosaminoglycan (GAG) polysaccharides, heparan sulfate and chondroitin sulfate, are polymerized and modified by enzymes that are encoded by more than 40 genes in animal cells. Because of the expression repertoire of the GAG assembly and modification enzymes, each heparan sulfate and chondroitin sulfate chain has a sulfation pattern, chain length, and fine structure that is potentially unique to each animal cell. GAGs interact with hundreds of proteins. Such interactions protect growth factors, chemokines, and cytokines against proteolysis. GAGs catalyze protease (such as thrombin) inhibition by serpins. GAGs regulate multiple signaling pathways including, but not limited to, fibroblast growth factor (FGF)/FGFR, hepatocyte growth factor (HGF)/c-Met, glial cell line-derived neurotrophic factor (GDNF)/c-Ret/GFRalpha1, vascular endothelial growth factor (VEGF)/VEGFR, platelet derived growth factor (PDGF)/PDGFR, BAFF/TACI, Indian hedgehog, Wnt, and BMP signaling pathways,where genetic studies have revealed an absolute requirement for GAGs in these pathways. Most importantly, protein/GAG aggregates induce thrombin generation and immune system upregulation by activating the contact system. Abnormal protein/GAG aggregates are associated with a variety of devastating human diseases including, but not limited to, Alzheimer's, diabetes, prion or transmissible spongiform encephalopathies, Lupus, heparin-induced thrombocytopenia/thrombosis, and different kinds of cancers. Therefore, GAGs are essential components of modern molecular biology and human physiology. Understanding GAG structure and function at molecular level with regard to development and health represents a unique opportunity in combating different kinds of human diseases.