HEPARAN SULFATE PROTEOGLYCANS: Biosynthesis, Structures and Functions
In the post-genomics era, it is now accepted that complex glycoconjugates such as proteoglycan regulate numerous patho-physiological processes in all living species. They carry enormous structural information in terms of sulfation, epimerization, domain organization, chain length, number of chains and type of chains along with their core proteins. Production of proteoglycans with such high complexity occurs in template-independent fashion seamlessly, yet our understanding of their biosynthesis, structures and functions is somewhat incomplete and imperfect. We are developing a wide variety of chemical biology tools to define the biosynthetic pathways of heparan sulfate and related glycosaminoglycans (GAG) such as chondroitin sulfate and dermatan sulfate. We synthesize heparin and heparan sulfate structures with a dozen recombinant enzymes to define the structural basis for the interactions of growth factors and Heparan sulfates and the subsequent biological actions. We recently found that a library of click-xylosides produce distinct GAG chains in cellular systems and proposed a GAGOSOME model for the dynamic regulation of combinatorial GAG biosynthesis. These molecular tools are currently used in the lab to define the snap shots of biosynthetic events and signaling events that are associated with development and diseases with a final goal to advance the study of heparanomics.