title: A 2-sulfated, 3-linked alpha-L-galactan is an anticoagulant polysaccharide.
abstract: Marine alga is an abundant source of sulfated polysaccharides with potent anticoagulant activity. However, several attempts to identify the specific structural features in these compounds, which confer the biological activity, failed due to their complex, heterogeneous structure. We isolated and characterized several sulfated alpha-L-galactans and sulfated alpha-L-fucans from marine invertebrates. In contrast to the algal fucans and galactans, these invertebrate polysaccharides have a simple structure, composed of well-defined units of oligosaccharides. We employed two of these compounds to elucidate their structure-anticoagulant action relationship. Our results indicate that a 2-sulfated, 3-linked alpha-L-galactan, but not an alpha-L-fucan, is a potent thrombin inhibitor mediated by antithrombin or heparin cofactor II. The difference between the activities of these two polysaccharides is not very pronounced when factor Xa replaces thrombin. Thus, the anticoagulant activity of sulfated galactan and sulfated fucan is not merely a consequence of their charge density. The interaction of these polysaccharides with coagulation cofactors and their target proteases are specific. Identification of specific structural requirements in sulfated galactans and sulfated fucans necessary for interaction with coagulation cofactors is an essential step for a more rational approach to develop new anticoagulant and antithrombotic drugs.
authors.affiliation: Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Departamento de Bioquímica Médica, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Caixa Postal 68041, Rio de Janeiro RJ 21941-590, Brazil.
authors.forename: Mariana S
authors.initials: MS
authors.lastname: Pereira
authors.forename: Ana-Cristina E S
authors.initials: AC
authors.lastname: Vilela-Silva
authors.forename: Ana-Paula
authors.initials: AP
authors.lastname: Valente
authors.forename: Paulo A S
authors.initials: PA
authors.lastname: Mourão
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D000990:Antithrombin III / Q000494:pharmacology; D001780:Blood Coagulation Tests; D004347:Drug Interactions; D065427:Factor Xa Inhibitors; D005685:Galactans / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D015844:Heparin Cofactor II / Q000494:pharmacology; D006801:Humans; D011134:Polysaccharides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D012617:Sea Urchins / Q000737:chemistry; D013329:Structure-Activity Relationship; D013463:Sulfuric Acid Esters / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005685:Galactans; D011134:Polysaccharides; D013463:Sulfuric Acid Esters; D015844:Heparin Cofactor II; D000990:Antithrombin III; D013917:Thrombin