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(Received for publication, August 24, 1995) The therapeutic action of nonsteroidal anti-inflammatory drugs
(NSAIDs) is exerted through the inhibition of prostaglandin G/H
synthase (PGHS), which is expressed as two isoenzymes, termed PGHS-1
and PGHS-2. From the crystal structure of sheep PGHS-1, it has been
proposed that the carboxylic acid group of flurbiprofen is located in a
favorable position for interacting with the arginine 120 residue of
PGHS-1 (Picot, D., Loll, P. J., and Garavito, R. M.(1994) Nature 367, 243-249). Mutation of this Arg
Volume 270,
Number 49,
Issue of December 8, 1995 pp. 29372-29377
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
residue to
Glu was performed and expressed in COS-7 cells using a vaccinia virus
expression system. Comparison of microsomal enzyme preparations show
that the mutation results in a 20-fold reduction in the specific
activity of PGHS-1 and in a 100-fold increase in the apparent K
for arachidonic acid. Indomethacin,
flurbiprofen, and ketoprofen, inhibitors of PGHS activity containing a
free carboxylic acid group, do not exhibit any inhibitory effects
against the activity of PGHS-1(Arg
Glu).
Diclofenac and meclofenamic acid, other NSAIDs containing a free
carboxylic acid group, were 50-100-fold less potent inhibitors of
the activity of the mutant as compared with the wild type PGHS. In
contrast, the nonacid PGHS inhibitors,
5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonyl)thiophene (DuP697) and a
desbromo-sulfonamide analogue of DuP697 (L-746,483), were both more
potent inhibitors of PGHS-1(Arg
Glu) than of the
wild type PGHS-1. Inhibition of PGHS-1(Arg
Glu)
was time-dependent for diclofenac and time-independent for DuP697, as
observed for the wild type enzyme, indicating that the mutation does
not alter the basic mechanism of inhibition. Aspirin is an acid NSAID
that inhibits PGHS-1 through a unique covalent acetylation of the
enzyme and also showed a reduced rate of inactivation of the mutated
enzyme. These data provide biochemical evidence of the importance of
the Arg
residue in PGHS-1 for interaction with
arachidonic acid and NSAIDs containing a free carboxylic acid moiety.
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