Inhibition by converting enzyme inhibitors of pig kidney aminopeptidase P.
Several inhibitors of angiotensin converting enzyme were also found to inhibit aminopeptidase P, whereas inhibitors of other mammalian aminopeptidases were ineffective. Aminopeptidase P purified from pig kidney cortex was found to contain one atom of zinc per polypeptide chain, confirming its metalloenzyme nature. The concentrations of converting enzyme inhibitors required to cause 50% inhibition (I50) of aminopeptidase P were in the low micromolar range. The most potent converting enzyme inhibitors toward aminopeptidase P were the carboxylalkyl compounds, cilazaprilat, enalaprilat, and ramiprilat (I50 values of 3-12 microM). The sulfhydryl compounds captopril (I50 110 microM) and YS980 (I50 20 microM) were slightly less potent at inhibiting aminopeptidase P. In contrast, the carboxylalkyl compounds benazeprilat, lisinopril, and pentoprilat; the sulfhydryl compound rentiapril; and the phosphoryl compounds ceranopril and fosinoprilat had no inhibitory effect against aminopeptidase P. This compares with I50 values in the 1-6 nM range for these inhibitors with angiotensin converting enzyme. Inhibition of aminopeptidase P may account for some of the effects or side effects noted with the clinical use of converting enzyme inhibitors. These results may provide the basis for the design of more selective inhibitors of angiotensin converting enzyme or mixed inhibitors of aminopeptidase P and angiotensin converting enzyme, or both.
Hooper
N M
NM
Department of Biochemistry and Molecular Biology, University of Leeds, UK.
Hryszko
J
J
Oppong
S Y
SY
Turner
A J
AJ
D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D002216:Captopril / Q000494:pharmacology*; D015773:Enalaprilat / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D013552:Swine / Q000502:physiology*; D015032:Zinc / Q000032:analysis
D000806:Angiotensin-Converting Enzyme Inhibitors; D002216:Captopril; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase; D008666:Metalloendopeptidases; D015773:Enalaprilat; D015032:Zinc