Prothrombinase

The prothrombinase complex consists of the serine protein, Factor Xa, and the protein cofactor, Factor Va. The complex assembles on negatively charged phospholipid membranes in the presence of calcium ions. The prothrombinase complex catalyzes the conversion of prothrombin (Factor II), an inactive zymogen, to thrombin (Factor IIa), an active serine protease. The activation of thrombin is a critical reaction in the coagulation cascade, which functions to regulate hemostasis in the body. To produce thrombin, the prothrombinase complex cleaves two peptide bonds in prothrombin, one after Arg²⁷¹ and the other after Arg³²⁰. Although it has been shown that Factor Xa can activate prothrombin when unassociated with the prothrombinase complex, the rate of thrombin formation is severely decreased under such circumstances. The prothrombinase complex can catalyze the activation of prothrombin at a rate 3 x 10⁵-fold faster than can Factor Xa alone. Thus, the prothrombinase complex is required for the efficient production of activated thrombin and also for adequate hemostasis.

Both Factor X and Factor V circulate in the blood as inactive precursors prior to activation by the coagulation cascade. The inactive zymogen Factor X consists of two chains, a light chain (136 residues) and a heavy chain (306 residues). The light chain contains an N-terminal γ-carboxyglutamic acid domain (Gla domain) and two epidermal growth factor-like domains (EGF1 and EGF2). The heavy chain consists of an N-terminal activation peptide and a serine-protease domain. Factor X can be activated by both the factor VIIa-tissue factor complex of the extrinsic coagulation pathway and by the tenase complex of the intrinsic pathway. The intrinsic tenase complex is composed of both Factor IXa and Factor VIIIa. The activation peptide is released when Factor X is activated to Factor Xa, but the heavy and light chains remain covalently linked following activation.

Factor V circulates as a single-chain procofactor which contains six domains, A1-A2-B-A3-C1-C2. Thrombin activates Factor V by cleaving off the B domain. Other proteases also activate Factor Va, but this cleavage is primarily carried out by thrombin. Following cleavage, Factor Va contains a heavy chain, composed of the A1 and A2 domains and a light chain, consisting of the A3, C1, and C2 domains. The light and heavy chains of Factor Va are linked via a divalent metal ion, such as calcium.

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