| Autor: |
van Meijer, Marja, Smilde, Annelies, Tans, Guido, Nesheim, Michael E., Pannekoek, Hans, Horrevoets, Anton J.G. |
| Zdroj: |
Blood; September 1997, Vol. 90 Issue: 5 p1874-1882, 9p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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