The transition of prothrombin to thrombin
Article first published online: 30 JUN 2013
© 2013 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Special Issue: State of the Art 2013
Volume 11, Issue Supplement s1, pages 265–276, June 2013
How to Cite
The transition of prothrombin to thrombin. J Thromb Haemost 2013; 11(Suppl. 1): 265–76..
- Issue published online: 30 JUN 2013
- Article first published online: 30 JUN 2013
- National Institutes of Health
- enzyme regulation;
- proteinase allostery;
- serine proteinase;
- substrate specificity;
The proteolytic conversion of prothrombin to thrombin catalyzed by prothrombinase is one of the more extensively studied reactions of blood coagulation. Sophisticated biophysical and biochemical insights into the players of this reaction were developed in the early days of the field. Yet, many basic enzymological questions remained unanswered. I summarize new developments that uncover mechanisms by which high substrate specificity is achieved, and the impact of these strategies on enzymic function. Two principles emerge that deviate from conventional wisdom that has otherwise dominated thinking in the field. (i) Enzymic specificity is dominated by the contribution of exosite binding interactions between substrate and enzyme rather than by specific recognition of sequences flanking the scissile bond. Coupled with the regulation of substrate conformation as a result of the zymogen to proteinase transition, novel mechanistic insights result for numerous aspects of enzyme function. (ii) The transition of zymogen to proteinase following cleavage is not absolute and instead, thrombin can reversibly interconvert between zymogen-like and proteinase-like forms depending on the complement of ligands bound to it. This establishes new paradigms for considering proteinase allostery and how enzyme function may be modulated by ligand binding. These insights into the action of prothrombinase on prothrombin have wide-ranging implications for the understanding of function in blood coagulation.