title: Roles of the two active sites of somatic angiotensin-converting enzyme in the cleavage of angiotensin I and bradykinin: insights from selective inhibitors.
abstract: Somatic angiotensin-converting enzyme (ACE) contains two homologous domains, each bearing a functional active site. The in vivo contribution of each active site to the release of angiotensin II (Ang II) and the inactivation of bradykinin (BK) is still unknown. To gain insights into the functional roles of these two active sites, the in vitro and in vivo effects of compounds able to selectively inhibit only one active site of ACE were determined, using radiolabeled Ang I or BK, as physiological substrates of ACE. In vitro studies indicated that a full inhibition of the Ang I and BK cleavage requires a blockade of the two ACE active sites. In contrast, in vivo experiments in mice demonstrated that the selective inhibition of either the N-domain or the C-domain of ACE by these inhibitors prevents the conversion of Ang I to Ang II, while BK protection requires the inhibition of the two ACE active sites. Thus, in vivo, the cleavage of Ang I and BK by ACE appears to obey to different mechanisms. Remarkably, in vivo the conversion of Ang I seems to involve the two active sites of ACE, free of inhibitor. Based on these findings, it might be suggested that the gene duplication of ACE in vertebrates may represent a means for regulating the cleavage of Ang I differently from that of BK.
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Zografou, Athens, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Georgiadis
authors.forename: Fabrice
authors.initials: F
authors.lastname: Beau
authors.forename: Bertrand
authors.initials: B
authors.lastname: Czarny
authors.forename: Joël
authors.initials: J
authors.lastname: Cotton
authors.forename: Athanasios
authors.initials: A
authors.lastname: Yiotakis
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
mesh_terms: D000803:Angiotensin I / Q000378:metabolism*; D000804:Angiotensin II / Q000096:biosynthesis; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001920:Bradykinin / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010721:Phosphinic Acids / Q000494:pharmacology*; D013379:Substrate Specificity / Q000502:physiology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides; D010721:Phosphinic Acids; C118733:RXP 407; C476531:RXPA380; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C058504:goralatide; D001920:Bradykinin