A mechanism-based inactivation study of neutral endopeptidase 24.11.
The mechanism-based inactivation of human neutral endopeptidase 24.11 (NEP) was studied with N-[(R)-2-benzyl-5-cyano-4-oxopentanoyl]-L-phenylalanine (1) and its peptidic analogue, N(-)[N-(cyanoacetyl)-L-phenylalanyl]-L-phenylalanine (2). While both these active-site-directed molecules inactivate NEP, the related angiotensin-converting enzyme (ACE) is only inactivated by compound 2 [Ghosh et al. J. Med. Chem. 1992, 35, 4175-4179]. The selectivity in inactivation was addressed further by a comparative study of the interaction of compounds 1 and 2 with five other zinc proteases. The selective inactivation of NEP observed with the ketomethylene compound 1 suggests that the active site of NEP is less discriminating in its requirements for binding such substrate analogues as compared to ACE, a characteristic that may be exploited for designing specific mechanism-based inactivators for NEP. It is proposed that the inactivation is a result of NEP-catalyzed formation of ketenimine intermediates, which are subsequently trapped by an active-site nucleophile.
Levy
O E
OE
Salk Biotechnology/Industrial Associates, Inc., La Jolla, California 92138.
Taibi
P
P
Mobashery
S
S
Ghosh
S S
SS
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism; D007700:Kinetics; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D011480:Protease Inhibitors; D010649:Phenylalanine; D015260:Neprilysin