Abstract
Heparin and other iduronic acid-containing glycosaminoglycans (GAG) such as dermatan sulfate exert their anticoagulant properties primarily by accelerating the rate of inhibition of the natural protease inhibitors antithrombin III (AT, which inhibits both factor Xa and thrombin) and heparin cofactor II (HCII, which selectively inhibits thrombin). Although AT and HCII are structural homologs, only heparin binds to AT, and HCII has different binding sites for heparin and dermatan sulfate. Whereas the binding site of heparin for AT is a unique pentasaccharide sequence contained in only about one third of the chains of this GAG, HCIIbinding sequences of heparin and dermatan sulfate are less specific and contained in practically all the GAG chains. Protein binding and associated biological activities of heparin and dermatan sulfate are modulated by the “plasticity” of their iduronic acid residues due to the availability of up to three equienergetic conformation among which the protein selects the one favouring the most stable complex. Glycol-splitting of nonsulfated uronic acid residues, a device for generating flexible joints along the GAG chains, has different effects on different binding domains. Whereas it inactivates the binding site for AT causing a drop of the anticoagulant activity, it enhances the HCII-associated activity of both heparin and dermatan sulfate.
Keywords: heparin, heparan sulfate, structure, molecular conformation, molecular flexibility
Current Pharmaceutical Design
Title: Structural and Conformational Aspects of the Anticoagulant and Antithrombotic Activity of Heparin and Dermatan Sulfate
Volume: 10 Issue: 9
Author(s): Benito Casu, Marco Guerrini and Giangiacomo Torri
Affiliation:
Keywords: heparin, heparan sulfate, structure, molecular conformation, molecular flexibility
Abstract: Heparin and other iduronic acid-containing glycosaminoglycans (GAG) such as dermatan sulfate exert their anticoagulant properties primarily by accelerating the rate of inhibition of the natural protease inhibitors antithrombin III (AT, which inhibits both factor Xa and thrombin) and heparin cofactor II (HCII, which selectively inhibits thrombin). Although AT and HCII are structural homologs, only heparin binds to AT, and HCII has different binding sites for heparin and dermatan sulfate. Whereas the binding site of heparin for AT is a unique pentasaccharide sequence contained in only about one third of the chains of this GAG, HCIIbinding sequences of heparin and dermatan sulfate are less specific and contained in practically all the GAG chains. Protein binding and associated biological activities of heparin and dermatan sulfate are modulated by the “plasticity” of their iduronic acid residues due to the availability of up to three equienergetic conformation among which the protein selects the one favouring the most stable complex. Glycol-splitting of nonsulfated uronic acid residues, a device for generating flexible joints along the GAG chains, has different effects on different binding domains. Whereas it inactivates the binding site for AT causing a drop of the anticoagulant activity, it enhances the HCII-associated activity of both heparin and dermatan sulfate.
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Cite this article as:
Casu Benito, Guerrini Marco and Torri Giangiacomo, Structural and Conformational Aspects of the Anticoagulant and Antithrombotic Activity of Heparin and Dermatan Sulfate, Current Pharmaceutical Design 2004; 10 (9) . https://dx.doi.org/10.2174/1381612043452794
DOI https://dx.doi.org/10.2174/1381612043452794 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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