Biosynthesis of heparin. Concerted action of late polymer-modification reactions.
The substrate specificity of O-sulfotransferases involved in the biosynthesis of heparin was studied by incubating exogenous polysaccharide acceptors with mouse mastocytoma microsomal fraction in the presence of phosphoadenylyl[35S]sulfate. Characterization of the labeled products showed that O-sulfation occurs preferentially in the vicinity of N-sulfate groups; that 2-O-sulfation of L-iduronic acid residues occurs preferentially or exclusively in the absence of a 6-O-sulfate group on adjacent D-glucosamine units; and that 6-O-sulfation of D-glucosamine residues occurs readily in the presence of 2-O-sulfate groups on adjacent L-iduronic acid units. Furthermore, structural analysis of microsomal heparin-precursor polysaccharides showed a distinct intermediate species that contained 2-O-sulfated L-iduronic acid units but essentially no 6-O-sulfate groups on the (N-sulfated) D-glucosamine residues. The results suggest that 2-O-sulfation of L-iduronic acid units is tightly coupled to the formation of these units (by 5-epimerization of D-glucuronic acid residues) and, furthermore, that both processes are completed before 6-O-sulfation of the polysaccharide molecule is initiated. D-Glucuronosyl 5-epimerization not accompanied by 2-O-sulfation occurs at a still earlier stage of polymer modification; the resulting L-iduronic acid units appear to remain nonsulfated throughout the subsequent modification reactions.[1]References
- Biosynthesis of heparin. Concerted action of late polymer-modification reactions. Jacobsson, I., Lindahl, U. J. Biol. Chem. (1980) [Pubmed]
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