Selective cleavage and anticoagulant activity of a sulfated fucan: Stereospecific removal of a 2-sulfate ester from the polysaccharide by mild acid hydrolysis, preparation of oligosaccharides, and heparin cofactor II-dependent anticoagulant activity

Vitor H. Pomin, Mariana S. Pereira, Ana Paula Valente, Douglas M. Tollefsen, Mauro S.G. Pavão, Paulo A.S. Mourão

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Abstract

A linear sulfated fucan with a regular repeating sequence of [3)-α-L-Fucp-(2SO4)-(1→3)-α-L-Fucp-(4SO 4)-(1→3)-α-L-Fucp-(2,4SO4)-(1→3)-α- L-Fucp-(2SO4)-(1→]n is an anticoagulant polysaccharide mainly due to thrombin inhibition mediated by heparin cofactor II. No specific enzymatic or chemical method is available for the preparation of tailored oligosaccharides from sulfated fucans. We employ an apparently nonspecific approach to cleave this polysaccharide based on mild hydrolysis with acid. Surprisingly, the linear sulfated fucan was cleaved by mild acid hydrolysis on an ordered sequence. Initially a 2-sulfate ester of the first fucose unit is selectively removed. Thereafter the glycosidic linkage between the nonsulfated fucose residue and the subsequent 4-sulfated residue is preferentially cleaved by acid hydrolysis, forming oligosaccharides with well-defined size. The low-molecular-weight derivatives obtained from the sulfated fucan were employed to determine the requirement for interaction of this polysaccharide with heparin cofactor II and to achieve complete thrombin inhibition. The linear sulfated fucan requires significantly longer chains than mammalian glycosaminoglycans to achieve anticoagulant activity. A slight decrease in the molecular size of the sulfated fucan dramatically reduces its effect on thrombin inactivation mediated by heparin cofactor II. Sulfated fucan with ∼ 45 tetrasaccharide repeating units binds to heparin cofactor II but is unable to link efficiently the plasma inhibitor and thrombin. This last effect requires chains with ∼ 100 or more tetrasaccharide repeating units. We speculate that the template mechanism may predominate over the allosteric effect in the case of the linear sulfated fucan inactivation of thrombin in the presence of heparin cofactor II.

Original languageEnglish
Pages (from-to)369-381
Number of pages13
JournalGlycobiology
Volume15
Issue number4
DOIs
StatePublished - Jan 1 2005

Keywords

  • Anticoagulant activity
  • Heparin cofactor II
  • Selective cleavage of sulfated polysaccharide
  • Stereospecific desulfation
  • Sulfated fucans

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