Jd. Park et al., A new inhibitor design strategy for carboxypeptidase A as exemplified by N-(2-chloroethyl)-N-methylphenylalanine, BIO MED CH, 9(2), 2001, pp. 237-243
N-(2-Chloroethyl)-N-methylphenylalanine was designed and synthesized in an
optically active form as a novel class of mechanism-based inactivator for c
arboxypeptidase A (CPA). It was anticipated that the chloroethylamino moiet
y of the CPA bound inhibitor undergoes an intramolecular S(N)2 reaction to
generate a chemically reactive species (an aziridinium ion) which is expect
edly subjected to a nucleophilic attack by the carboxylate of Glu-270, lead
ing to covalent modification of the carboxylate. The irreversible nature of
the inhibition of CPA by the inhibitor was supported by the kinetic data:
the enzyme lost its enzymic activity in a time-dependent manner in the pres
ence of the inhibitor and the inactivated CPA failed to regain the activity
upon dialysis. Interestingly, the (R)-isomer that belongs to the D-series
was more potent than its enantiomer. (C) 2001 Elsevier Science Ltd. All rig
hts reserved.