Endopeptidase 3.4.24.11 converts N-1-(R,S)carboxy-3-phenylpropyl-Ala-Ala-Phe-p-carboxyanilide into a potent inhibitor of angiotensin-converting enzyme.
It was reported recently that N-1-(R,S)carboxy-3-phenylpropyl-Ala-Ala-Phe-p-carboxyanilide (CPP-A-A-F-pAB), an inhibitor of endopeptidase 3.4.24.15 (E-24.15), also inhibits angiotensin-converting enzyme (ACE) from rabbit lung. We have found that this compound is without effect on ACE purified from pig kidney, at a concentration some 1000-fold greater than the Ki reported for inhibition of the enzyme from lung. However, preincubation of CPP-A-A-F-pAB with neutral endopeptidase 3.4.24.11 (E-24.11) does result in potent inhibitory effects on ACE. We have shown this to be due to formation of a fragment, CPP-A-A, the structure of which is closely related to ACE inhibitors such as enalaprilat. CPP-A-A was found to be a potent inhibitor of pig ACE. Under the conditions used it had an IC50 value of 1.6 x 10(-8) M, compared with the value obtained for captopril of 7.5 x 10(-10) M. These results have important implications for studies of E-24.15 when using CPP-A-A-F-pAB in vivo or in crude tissue extracts where E-24.11 might also be present.
Division of Biochemistry, School of Biology and Biochemistry, Queen's University of Belfast, U.K.
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CH
Williams
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Yamamoto
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Walsh
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Allsop
D000595:Amino Acid Sequence; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D007668:Kidney / Q000201:enzymology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D015260:Neprilysin / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism*; D011817:Rabbits; D013552:Swine
D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides; C064939:N-(1-carboxy-3-phenylpropyl)-alanyl-alanyl-phenylalanine-4-aminobenzoate; D008666:Metalloendopeptidases; D015260:Neprilysin; C022510:thimet oligopeptidase