Calcium enhances heparin catalysis of the antithrombin-factor Xa reaction by a template mechanism. Evidence that calcium alleviates Gla domain antagonism of heparin binding to factor Xa.

The Journal of Biological Chemistry
A R Rezaie

Abstract

It is believed that heparin accelerates factor Xa (FXa) inactivation by antithrombin (AT) by conformationally activating the inhibitor rather than by bridging AT and FXa in a ternary complex (template effect). This is derived from kinetic studies done in the absence of Ca2+ or in the presence of EDTA. To test the possibility that the anionic Gla domain of FXa, when not neutralized by Ca2+ ions, prevents heparin binding to FXa, the heparin and pentasaccharide dependence of FXa inactivation by AT in both the absence (100 microM EDTA) and presence of Ca2+ (2.5 mM) was studied using wild-type FXa and a FXa derivative that lacks the Gla domain (GDFXa). AT inactivated both FXa derivatives similarly in both the absence and presence of Ca2+ (k2 = 1.7-2.5 x 10(3) M-1 s-1). The active AT-binding pentasaccharide also accelerated the inactivation rates of both derivatives similarly in both the absence and presence of Ca2+ (k2 = 5.7-8.0 x 10(5) M-1 s-1). However, in the presence of an optimum concentration of heparin ( approximately 50 nM) the inactivation rate constant of FXa in the presence of Ca2+ (k2 = 4.4 x 10(7) M-1 s-1) was 13-fold higher than the rate constant in the absence of Ca2+ (k2 = 3.5 x 10(6) M-1 s-1). Heparin acceleration o...Continue Reading

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