The first mechanism-based inactivators for angiotensin-converting enzyme.
The first example of mechanism-based inactivation of angiotensin-converting enzyme (ACE) is described for N-[N-(cyanoacetyl)-L-phenylalanyl]-L-phenylalanine (compound 1). It is proposed that an ACE-mediated deprotonation of 1 unmasks a ketenimine intermediate, which traps an active-site nucleophile, and hence irreversibly modifies the enzyme. In competition with the inactivation reaction, ACE also hydrolyzes 1 with a partition ratio of 8300 (i.e., kcat/kinact). Since the corresponding keto analogue, N-[(R)-2-benzyl-5-cyano-4-oxopentanyl]-L-phenylalanine (compound 4), does not inactivate the enzyme, it is suggested that the NH in compound 1 is critical for the proper active-site anchoring of the inhibitor for the inactivation process to take place.
Ghosh
S S
SS
Baxter Diagnostics Inc., San Diego, California 92191-0492.
Said-Nejad
O
O
Roestamadji
J
J
Mobashery
S
S
D000595:Amino Acid Sequence; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology; D007700:Kinetics; D008969:Molecular Sequence Data; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D004151:Dipeptides; D010649:Phenylalanine; D007703:Peptidyl-Dipeptidase A