Novel activity of endothelin-converting enzyme: hydrolysis of bradykinin

Abstract

Endothelin-converting enzyme (ECE) is the key enzyme in the production of the potent vasoconstrictor endothelin from its inactive precursor big endothelin. To date, no other physiological peptide substrate has been identified for ECE. Here, by using Chinese hamster ovary (CHO) cells transfected with rat ECE-1 cDNA, we have established that ECE can hydrolyse the vasodilator bradykinin. The hydrolysis of bradykinin by ECE is exclusively at the Pro7–Phe8 bond, producing bradykinin-(1–7) and bradykinin-(8–9). Hydrolysis is completely inhibited by 100 μM phosphoramidon and 200 μM EDTA, but only slightly by the specific neprilysin inhibitor thiorphan (100 μM). The ability of ECE to act as a peptidyl dipeptidase rather than an endopeptidase in hydrolysing bradykinin suggests a much broader specificity for the enzyme than previously recognized, which may lead to the design of new and specific inhibitors of ECE and to the identification of other potential physiological substrates.