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Glycobiology Advance Access originally published online on December 8, 2004
Glycobiology 2005 15(4):369-381; doi:10.1093/glycob/cwi021
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Glycobiology vol. 15 no. 4 © Oxford University Press 2004; all rights reserved.

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. Pomin2,3, Mariana S. Pereira2,4, Ana-Paula Valente3,5, Douglas M. Tollefsen6, Mauro S. G. Pavão2,3 and Paulo A. S. Mourão1,2,3

2 Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Caixa Postal 68041, Rio de Janeiro, RJ, 21941-590, Brazil; 3 Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Caixa Postal 68041, Rio de Janeiro, RJ, 21941-590, Brazil; 4 Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Caixa Postal 68041, Rio de Janeiro, RJ, 21941-590, Brazil; 5 Centro Nacional de Ressonância Nuclear Magnética de Macromoléculas, Universidade Federal do Rio de Janeiro, Caixa Postal 68041, Rio de Janeiro, RJ, 21941-590, Brazil; and 6 Division of Hematology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110

1 To whom correspondence should be addressed; e-mail: pmourao{at}hucff.ufrj.br

Received on September 16, 2004; revised on November 30, 2004; accepted on December 2, 2004

A linear sulfated fucan with a regular repeating sequence of [3)-{alpha}-L-Fucp-(2SO4)-(1->3)-{alpha}-L-Fucp-(4SO4)-(1->3)-{alpha}-L-Fucp-(2,4SO4)-(1->3)-{alpha}-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.

Key words: anticoagulant activity / heparin cofactor II / selective cleavage of sulfated polysaccharide / stereospecific desulfation / sulfated fucans


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