The Broad Substrate Specificity of Human Angiotensin I Converting Enzyme

Abstract

Angiotensin I converting enzyme (kininase II; ACE) has been described as a peptidyldipeptidase or dipeptidyl carboxypeptidase (EC 3.4.15.1) of the pulmonary endothelial cells, which liberates angiotensin II or inactivates kinins. However, ACE has a much wider distribution and substrate specifity; it is concentrated in human epithelial cells (e.g. brush border of the kidney, placenta, intestine and choroid plexus), neuroepithelial cells (subfornical organ, pallidonigral dendrites, median eminence) and male genital tract (testes, prostate, epididymides, seminal plasma). Its substrates include enkaphalins, the C-terminal extended proenkephalins and a protected chemotactic tripeptide. Recent, mostly in vitro studies with purified ACE, indicate that ACE also cleaves peptides by other than peptidyldipeptidase action. Homogeneous human ACE inactivated substance P in spite of its blocked C-terminus (Met11-NH2) primarily by releasing the C-terminal tripeptide. A blocked C-terminal tripeptide, Arg-Pro-Gly-NH2 was also released from the luteinizing hormone releasing hormone (LHRH). Although ACE shares many properties with carboxypeptidases, it surprisingly cleaves the N-terminal tripeptide greater than Glu1-His2-Trp3 from LHRH. Because human ACE hydrolyzes a variety of peptide hormones, actions of its inhibitors may go well beyond blocking the conversion of angiotensin I.