title: Effect of oversulphated chondroitin and dermatan sulphate upon thrombin and factor Xa inactivation by antithrombin III or heparin cofactor II.
abstract: The kinetics of inhibition of human thrombin and Factor Xa by antithrombin III or heparin cofactor II were examined under pseudo-first-order conditions as a function of the concentration of naturally occurring oversulphated chondroitin and dermatan sulphates. The sulphated glycosaminoglycans (GAGs) studied were chondroitin sulphate D (CSD) (GlcA-2-SO4-GalNAc-6-SO4), chondroitin sulphate K (CSK) (GlcA-3-SO4-GalNAc-4-SO4), chondroitin sulphate H (CSH) (IdA-GalNAc-4,6-diSO4) and polysulphated dermatan sulphate (DPS) (IdA-2-SO4 or -3-SO4-GalNAc-4,6-diSO4). The data for the antithrombin III inhibition of thrombin showed a low degree of maximal potentiation of this interaction (congruent to 10-fold), which would appear to be characteristic of GAGs devoid of the high-affinity antithrombin III binding site. In contrast there was a greater potentiation of the inhibition of thrombin by heparin cofactor II with DPS showing an activity comparable to heparin in this interaction at a concentration two orders of magnitude lower than dermatan sulphate. DPS potentiated antithrombin III-Factor Xa interaction by 1200-fold, similar to that shown by high-affinity heparin of 6 kDa. The antithrombin III-Factor Xa interaction was potentiated by all other GAGs studied to a degree similar to that of heparin pentasaccharide with high affinity for antithrombin III. The findings suggest more stringent structural requirements for GAG stimulation of antithrombin-thrombin interaction than for antithrombin-Factor Xa or heparin cofactor-thrombin interaction, which may also be of significance in physiological control of haemostasis.
mesh_terms: D000990:Antithrombin III / Q000494:pharmacology*; D001665:Binding Sites; D002807:Chondroitin / Q000031:analogs & derivatives*; D002809:Chondroitin Sulfates / Q000494:pharmacology*; D003871:Dermatan Sulfate / Q000494:pharmacology*; D004357:Drug Synergism; D015951:Factor Xa; D006023:Glycoproteins / Q000494:pharmacology*; D015844:Heparin Cofactor II; D006801:Humans; D007700:Kinetics; D011134:Polysaccharides / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors
chemical_list: D006023:Glycoproteins; D011134:Polysaccharides; D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; D003871:Dermatan Sulfate; D015844:Heparin Cofactor II; D000990:Antithrombin III; D002807:Chondroitin; D002809:Chondroitin Sulfates; D015951:Factor Xa