Structure of Heparin

Heparin is a polydisperse mixture of GAGs with MWs ranging from 5 to 30 kDa, with an average MW of 13 kDa (Linhardt and Toida, 1997). It is composed of alternating b-D-glucosamine residues 1 ! 4-linked to either a-L-iduronic acid or b-D-glucuronic acid (Casu, 1985). The principal repeating unit in heparin is the trisulfated disaccharide ! 4)-a-L-iduronic acid-2-O-sulfate (1! 4)-a-D-glucosa-mine-2-N, 6-O-disulfate (1 ! (Fig. 1), which represents 75-90% of the heparin chain (Linhardt et al., 1992). The remaining 10-25% of disaccharide units differ in their degree and positions of sulfation (Linhardt et al., 1988). Besides, there are disaccharides consisting of unsulfated glucuronic acid and/or N-acetylglucosa-mine. With a SO4~: COO~ ratio of 2.0-2.5, heparin is the GAG with the highest charge density. By binding to domains containing positively charged amino acids, especially arginine and lysine, it interacts with many proteins, resulting in manifold biological activities. The most prominent example is a well-defined pentasaccharide sequence with a central a-D-glucosamine-2-N, 3-O, 6-O-trisulfate unit, which binds specifically to AT (Choay, 1989). About 30% (range 10-50%) of the heparin chains contain this pentasaccharide (Fig. 2). These molecules are called high-affinity heparin in contrast to the low-affinity heparin without this AT-binding site (Casu, 1990). AT is a natural serine protease inhibitor that controls blood coagulation by forming equimolar covalent complexes with certain coagulation enzymes. The anticoagulant action of heparin is mainly based on accelerating the slow rate of factor Xa and thrombin inhibition by AT (Bjork et al., 1989). Whereas the heparin pentasaccharide is sufficient for factor Xa inhibition, thrombin inhibition



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