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Department of Biochemistry and Molecular Biology, Merck Frosst
Centre for Therapeutic Research, Kirkland, Québec, Canada
(J.A.M., G.P.O., C.B., J.-P.F., D.R.), and
Department of Molecular
Sciences, Pfizer Central Research, Sandwich, Kent CT13 9NJ, England
(P.J.V.)
Aspirin (ASA) acetylates Ser516 of prostaglandin G/H synthase-2
(PGHS-2) resulting in a modified enzyme that converts arachidonic acid
to 15(R)-hydroxy-eicosatetraenoic acid
[15(R)-HETE]. ASA has pharmacological benefits that
may not all be limited to inhibition of prostaglandin synthesis, and
this study was initiated to further investigate the properties of
ASA-acetylated PGHS-2 and of the mutation of Ser516 to methionine,
which mimics ASA acetylation. Both the S516M mutant and ASA-acetylated
form of PGHS-2 (ASA-PGHS-2) synthesize 15(R)-HETE and
have apparent Km values for arachidonic acid within 10-fold of the apparent
Km value for untreated PGHS-2.
The time courses of turnover-dependent inactivation were similar for
reactions catalyzed by PGHS-2 and ASA-PGHS-2, whereas the PGHS-2(S516M)
showed a decrease in both the initial rate of 15-HETE production and
rate of enzyme inactivation. The production of 15-HETE by modified
PGHS-2 was sensitive to inhibition by most nonsteroidal
anti-inflammatory drugs (NSAIDs), including selective PGHS-2
inhibitors. As observed for the cyclooxygenase activity of PGHS-2, the
inhibition of 15-HETE production by indomethacin was time-dependent for
both ASA-PGHS-2 and PGHS-2(S516M). However, two potent, structurally
related NSAIDs, diclofenac and meclofenamic acid, do not inhibit either
ASA-PGHS-2 or the PGHS-2(S516M) mutant. These results demonstrate that
the sensitivity to inhibition by NSAIDs of the 15-HETE production by
ASA-treated PGHS-2 is different than that of prostaglandin production
by PGHS-2 and that Ser516 plays an important role in the interaction
with fenamate inhibitors. The results also indicate that the conversion
of arachidonic acid to 15-HETE by ASA-PGHS-2 is an efficient process
providing a unique mechanism among NSAIDs that will not lead to
arachidonic acid accumulation or shunting to other biosynthetic
pathways.
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