Heparan sulfate (HS) and heparin are negatively charged polysaccharides consisting repeating disaccharide unit of α-D-(1,4)-glucosamine and β-D-(1,4)-glucuronic or α-L-(1,4)-iduronic acid with different sulfations. Several biological important proteins are mediated by heparan sulfates, including FGFs, FGFRs, chemokines, selectins, antithrombin and several proteases in coagulation cascade. Diversity of sulfation patterns and plasticity of iduronic acid (IdoA) are known associated with the protein binding; however, the understanding of relationship between sulfations and saccharide conformations is deficient. This study is to systematically investigate the relation between the various sulfations and the saccharide conformations among heparan sulfate. Chemoenzymatic approach was used to synthesize total of 8 IdoA-containing hexasaccharides with different sulfation patterns. To calculate the realistic equilibrium population of IdoA conformations, we deconvolute the NMR measured parameters into simulated parameters for each conformation with corresponding populations. Both spin-spin coupling constant (3JH-H) and intensity of nuclear overhauser effects (NOE) are used to monitor the conformational change and corresponding population in this study. Our results suggest that given 2-O-sulfation or not could shift the conformation equilibrium of IdoA toward opposite preference. The biosynthetic downstream 6-O- and 3-O-sulfations provide different environment lead 2-O-sulfated IdoA2S toward 2So conformation; oppositely, drive IdoA majorly populate at 1C4 conformation (Figure). Comparing to relatively rigid glucuronic acid, IdoA-containing oligosaccharide could show different conformational preference in response to different sulfation patterns. The understanding of the sulfation-conformation relationship will assist the design of next generation heparin-based therapeutics.

Sulfation pattern dictates the conformation of heparan sulfate

251st National Meeting (2016)

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