Ecotin is a potent inhibitor of the contact system proteases factor XIIa and plasma kallikrein

摘要

>Ecotin, a serine protease inhibitor found in the periplasm of Escherichia coli, has been characterized as a potent reversible tight-binding inhibitor of the human contact activation proteases factor XIIa (FXIIa) and plasma kallikrein, having K _i values of 89 pM and 163 pM, respectively. Ecotin also inhibited human leukocyte elastase (HLE) with high affinity (K _i = 55 pM). The association rate constants k _on for FXIIa and kallikrein were 5.3 × 105 M−1·s−1 and 2.9 × 105 M−1·s−1, respectively. The dissociation rate constant k _off for kallikrein, measured in the presence of HLE to prevent reassociation, was 6.3 × 10−5 s−1; the k _off for ecotin with FXIIa was 4.7 × 10−5 s−1. Both FXIIa and kallikrein cleaved ecotin slowly at pH 5.0, identifying Met-84 as the P₁ residue. The potent anticoagulant effect by ecotin is explained by the coincident inhibition of FXIIa, kallikrein, and FXa and suggests that it may be useful in the study of inflammatory or thrombotic disorders such as sepsis or cardiopulmonary bypass.