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The Suicide Substrate Reaction Between Plasminogen Activator Inhibitor 1 and Thrombin Is Regulated by the Cofactors Vitronectin and Heparin
Marja van Meijer,
Annelies Smilde,
Guido Tans,
Michael E. Nesheim,
Hans Pannekoek, and
Anton J.G. Horrevoets
From the Departments of Biochemistry of the Academic Medical Center, University of Amsterdam, Amsterdam; University of Limburg, Maastricht, the Netherlands; and Queen's University, Kingston, Canada.
The interaction of thrombin with plasminogen activator inhibitor 1 (PAI-1) is shown to result in the simultaneous formation of both cleaved PAI-1 and a sodium dodecyl sulfate-stable thrombin-PAI-1 complex. The kinetics of this reaction can be described by a "suicide substrate" mechanism that includes a branched reaction pathway, which terminates in either the stable inhibitor-enzyme complex or the cleaved inhibitor plus free enzyme. Because of the branched pathway, approximately three moles of PAI-1 are needed to completely inhibit one mole of thrombin. Heparin and vitronectin enhance the rate of inhibition from 9.8 × 102 L mol-1 s-1 to 6.2 × 104 L mol-1 s-1 and 2.1 × 105 L mol-1 s-1, respectively, under optimal conditions. In addition to enhancing the rate of inhibition, both cofactors increase the apparent stoichiometry of the PAI-1-thrombin interaction, with cofactor concentration dependencies similar to the inhibition reaction. Thus, at 37°C approximately six cleavage reactions occur per inhibition reaction. Therefore, thrombin will efficiently inactivate PAI-1 in the presence of either vitronectin or heparin, unless a sufficient excess of the inhibitor is present. These results show that physiological cofactors are able to switch a protease-serpin inhibition reaction to a substrate reaction, depending on the local concentrations of each of the components.
Blood, Vol. 90 No. 5 (September 1), 1997:
pp. 1874-1882
© 1997 by The American Society of Hematology.
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