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PDBsum entry 4rut
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Oxidoreductase
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PDB id
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4rut
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References listed in PDB file
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Key reference
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Title
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13-Methylarachidonic acid is a positive allosteric modulator of endocannabinoid oxygenation by cyclooxygenase.
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Authors
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S.N.Kudalkar,
S.P.Nikas,
P.J.Kingsley,
S.Xu,
J.J.Galligan,
C.A.Rouzer,
S.Banerjee,
L.Ji,
M.R.Eno,
A.Makriyannis,
L.J.Marnett.
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Ref.
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J Biol Chem, 2015,
290,
7897-7909.
[DOI no: ]
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PubMed id
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Abstract
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Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid (AA) and the
endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonylethanolamide to
prostaglandins, prostaglandin glyceryl esters, and prostaglandin ethanolamides,
respectively. A structural homodimer, COX-2 acts as a conformational heterodimer
with a catalytic and an allosteric monomer. Prior studies have demonstrated
substrate-selective negative allosteric regulation of 2-AG oxygenation. Here we
describe AM-8138 (13(S)-methylarachidonic acid), a substrate-selective
allosteric potentiator that augments 2-AG oxygenation by up to 3.5-fold with no
effect on AA oxygenation. In the crystal structure of an AM-8138·COX-2 complex,
AM-8138 adopts a conformation similar to the unproductive conformation of AA in
the substrate binding site. Kinetic analysis suggests that binding of AM-8138 to
the allosteric monomer of COX-2 increases 2-AG oxygenation by increasing kcat
and preventing inhibitory binding of 2-AG. AM-8138 restored the activity of
COX-2 mutants that exhibited very poor 2-AG oxygenating activity and increased
the activity of COX-1 toward 2-AG. Competition of AM-8138 for the allosteric
site prevented the inhibition of COX-2-dependent 2-AG oxygenation by
substrate-selective inhibitors and blocked the inhibition of AA or 2-AG
oxygenation by nonselective time-dependent inhibitors. AM-8138 selectively
enhanced 2-AG oxygenation in intact RAW264.7 macrophage-like cells. Thus,
AM-8138 is an important new tool compound for the exploration of allosteric
modulation of COX enzymes and their role in endocannabinoid metabolism.
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