Prothrombinase - Activity

Activity

The fully assembled prothrombinase complex catalyzes the conversion of the zymogen prothrombin to the serine protease thrombin. Specifically, Factor Xa cleaves prothrombin in two locations, following Arg271 and Arg320 in human prothrombin. Because there are two cleavage events, prothrombin activation can proceed by two pathways. In one pathway, prothrombin is first cleaved at Arg271. This cleavage produces Fragment 1•2, comprising the first 271 residues, and the intermediate prethrombin 2, which is made up of residues 272-579. Fragment 1•2 is released as an activation peptide, and prethrombin 2 is cleaved at Arg320, yielding active thrombin. The two chains formed after the cleavage at Arg320, termed the A and B chains, are linked by a disulfide bond in active thrombin. In the alternate pathway for thrombin activation, prothrombin is first cleaved at Arg320, producing a catalytically active intermediate called meizothrombin. Meizothrombin contains fragment 1•2 A chain linked to the B chain by a disulfide bond. Subsequent cleavage of meizothrombin by Factor Xa at Arg271 gives Fragment 1•2 and active thrombin, consisting of the A and B chains linked by a disulfide bond. When thrombin is generated by Factor Xa alone, the first pathway predominates and prothrombin is first cleaved after Arg271, producing prethrombin 2, which is subsequently cleaved after Arg320. If Factor Xa acts as a component of the prothrombinase complex, however, the second pathway is favored, and prothrombin is first cleaved after Arg320, producing meizothrombin, which is cleaved after Arg271 to produce active thrombin. Thus, the formation of the prothrombinase complex alters the sequence of prothrombin bond cleavage.