Inhibition of angiotensin-converting enzyme by angiotensin I analogue peptide inhibitors. A kinetic study.
Angiotensin I analogues with a phosphonic acid group replacing the C-terminal carboxyl group were shown to be competitive inhibitors of angiotensin-converting enzyme. This new class of inhibitors was used to study the binding requirements of the angiotensin I-like ligands to the enzyme's active site. These studies indicate that angiotensin-converting enzyme recognizes at least five amino acid residues at the C-terminus of the peptide. The effect of pH on the binding of the most potent inhibitor peptide was compared to Captopril. The two inhibitors showed similar Ki-pH profiles despite their structural differences. Chloride enhanced the binding of the peptide inhibitor at both pH 9.0 and pH 6.5. At pH 9.0 the inhibitor peptide and the anion bind randomly to the enzyme, while at pH 6.5 the mechanism is ordered. In the latter case, the anion binds first to the enzyme.
D000803:Angiotensin I / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D007202:Indicators and Reagents; D007700:Kinetics; D008168:Lung / Q000201:enzymology*; D007703:Peptidyl-Dipeptidase A / Q000302:isolation & purification; D011817:Rabbits; D013329:Structure-Activity Relationship
D000806:Angiotensin-Converting Enzyme Inhibitors; D007202:Indicators and Reagents; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A