Selective inhibition of the C-domain of angiotensin I converting enzyme by bradykinin potentiating peptides.
Somatic angiotensin I converting enzyme (ACE) contains two functional active sites. Up to now, most of the studies aimed at characterizing the selectivity of inhibitors toward the two ACE active sites relied on the use of ACE mutants containing a single functional active site. By developing new fluorogenic synthetic substrates of ACE, we demonstrated that inhibitor selectivity can be assessed directly by using somatic ACE. This useful screening approach led us to discover that some bradykinin potentiating peptides turned out to be selective inhibitors of the C-domain of ACE. The peptide pGlu-Gly-Leu-Pro-Pro-Arg-Pro-Lys-Ile-Pro-Pro, with K(i)(app) values of 30 nM and 8 microM, respectively, for the C- and N-domain of ACE, is to our knowledge the most highly selective C-domain inhibitor of ACE so far reported. Inhibitors able to block selectively either the N- or C-domain of ACE will represent unique tools to probe the function of each domain in the regulation of blood pressure or other physiopathological events involving ACE activity.
Cotton
Joël
J
CEA, Département d'Ingénierie et d'Etudes des Protéines, CE-Saclay, 91191 Gif/Yvette Cedex, France.
Hayashi
Mirian A F
MA
Cuniasse
Philippe
P
Vazeux
Gilles
G
Ianzer
Danielle
D
De Camargo
Antonio C M
AC
Dive
Vincent
V
D000595:Amino Acid Sequence; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000819:agonists*; D016466:CHO Cells; D020134:Catalytic Domain / Q000235:genetics; D006224:Cricetinae; D005456:Fluorescent Dyes; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D017706:Lisinopril / Q000494:pharmacology; D008954:Models, Biological; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010721:Phosphinic Acids / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
D000806:Angiotensin-Converting Enzyme Inhibitors; D005456:Fluorescent Dyes; D009842:Oligopeptides; D010721:Phosphinic Acids; C118733:RXP 407; D011994:Recombinant Proteins; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A; D001920:Bradykinin