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Journal of Biochemistry Advance Access published online on December 13, 2006
Journal of Biochemistry, doi:10.1093/jb/mvm001
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© 2006 The Japanese Biochemical Society

Analysis of Inhibition Rate Enhancement by Covalent Linkage of Antithrombin to Heparin as a Potential Predictor of Reaction Mechanism

Sanjay Patel1, Leslie R. Berry1,2 and Anthony K. C Chan1,2,3

1 Henderson Research Centre, 711 Concession Street, Hamilton, Canada L8V 1C3.
2 McMaster University, Department of Pediatrics, Hamilton, Canada L8S 4L8.
3 Hospital for Sick Children, University of Toronto, Toronto, Canada M5G 1X8

Correspondence to: Dr. Anthony K. C. Chan, Henderson Research Centre, 711 Concession Street, Hamilton, Ontario, Canada L8V 1C3, Telephone: (905) 527-2299 extension 43559, FAX: (905) 575-2646, E-mail: achan{at}thrombosis.hhscr.org

Received August 18, 2006; Accepted November 7, 2006


  Abstract

Antithrombin (AT) inhibition of coagulation enzymes is catalyzed by unfractionated heparin (UFH) and other heparinoids. Reaction proceeds either via conformational activation of the inhibitor or template-mediated binding of both inhibitor and protease. We investigated if the relative inhibition rates of AT + UFH and covalent AT-heparin conjugate (ATH) with coagulation factors might be indicative of the mechanism involved. Rates were determined by discontinuous assay and mechanisms were probed by a variety of binding studies with UFH or ATH heparin chains. Rates were increased more than 2-fold with ATH over AT + UFH in reactions with thrombin, factor (F) VIIa + tissue factor + Ca2+ + lipid, FIXa and FXIa, but not with FXa or FXIIa. In comparison, UFH or ATH heparin binding (evidence of a template mechanism) was only observed with thrombin, tissue factor, FIXa and FXIa. Thus, inhibition rate enhancement by conjugation of AT with heparin were predictive of inhibitorcenzyme template bridging by heparin. Rationales behind this novel concept are discussed.

Key Words: antithrombin, heparin, mechanism, anticoagulant, coagulation factor


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