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The Conversion of Prothrombin to Thrombin

III. THE FACTOR X_a-CATALYZED ACTIVATION OF PROTHROMBIN

From the ¹ From the Department of Biological Chemistry, Division of Biology and Biomedical Sciences, Washington University, St. Louis, Missouri 63110

Prothrombin activation either by activated Factor X alone or by activated Factor X, Factor V, Phospholipid, and calcium ions results in the formation of the protease thrombin and, when thrombin proteolysis is prevented with diisopropyl fluorophosphate (iPr₂P-F), a single activation fragment (Fragment 1.2) (Esmon, C. T., Owen, W. G., and Jackson, C. M. (1974) J. Biol. Chem. 249, 606–611). Of the two pathways which were proposed to account for these and other intermediate activation products, it is established by this report that the principal, if not exclusive, route of prothrombin conversion to thrombin by Factor X_a alone is

[see PDF for equation]

If thrombin action is permitted to occur, Fragment 1·2 is cleaved into two products, Fragment 1 and Fragment 2 as shown by Esmon et al. That this particular pathway is not in some unknown way dependent upon the presence of iPr₂P-F was demonstrated by measuring the formation of Intermediate 2 and Fragment 1·2 directly in the absence of iPr₂P-F. These experiments were carried out by activating tritium-labeled prothrombin and determining the product distributions in sodium dodecyl sulfate electrophoresis gels under conditions in which thrombin action could be independently assessed.

The necessary requirement for Intermediate 2 being on the direct pathway from prothrombin to thrombin, i.e. that the rate of Intermediate 2 activation be greater than or equal to that of prothrombin activation, was shown to be met. An attempt to demonstrate the existence of the alternative pathway which can account for Fragment 1·2, although not Intermediate 2, was also made but no evidence for its existence or contribution to the Factor X_a-catalyzed activation process was found.

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