Distributed throughout the cell surface and the extracellular matrix are long, unbranched polysaccharides known as heparan sulfate glycosaminoglycans (GAGs). Through their covalent linkages to core proteins, GAGs form proteoglycan glycoconjugates, which modulate many biological and pathological processes by binding protein growth factors, such as the Fibroblast Growth Factor-2. The sulfation of GAGs at various positions along its disaccharide repeating unit (e.g.N-, 2O-, or 6O-SO3) encodes a highly complex system that dictates growth factor binding. To elucidate this complex architectural code, a systematic study of sulfation pattern-specific GAGs that adequately mimic their long, unbranched structures, is required. However, chemical and chemoenzymatic efforts have only afforded abbreviated GAG oligosaccharides that lack the length innate in native GAGs. To this end, we have synthesized various azide-modified β-D-xylose-aglycone conjugates that hijack the GAG biosynthesis machinery to produce sulfation pattern-specific heparan sulfate GAGs. These molecules act as substrates of theβ4GalT7 enzyme, which catalyzes the second step of GAG biosynthesis. Integration of these molecules with sulfation-mutant cell lines allows the generation of recombinant heparan sulfate GAGs that recapitulate native GAG structures. We also evaluate the effect of the aglycone on the composition of recombinant heparan sulfate. In future studies, our recombinant library will be used to explore the influence of GAG fine structure on key cellular processes.

Azido-modified xylosides generate recombinant sulfation pattern-specific heparan sulfate glycosaminoglycans

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.