An unexpected link between angiotensinogen and thrombin

Angiotensinogen is well known as source protein for a group of potent vasoactive hormones, however, a discrete biochemical activity of the angiotensinogen body is not known. Here we investigated angiotensinogen from the lamprey Lampetra fluviatilis (L. fluviatilis), an early-diverged vertebrate. The recombinantly produced protein showed progressive inhibitory activity towards human alpha-thrombin with a second-order rate constant of 2.6 x 10(4) M-1 min(-1). Heparin enhanced the reaction rate > 800-fold with a bell-shaped dose-response curve and a stoichiometry of inhibition (SI) of 1.3, revealing lamprey angiotensinogen as an effective a-thrombin inhibitor. Genomic, biochemical, and protein sequence data indicate that angiotensinogen and heparin cofactor II (HCII) originated from a common ancestral thrombin antagonist, thus providing insight into an early stage of thrombin control. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.