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标题：Interactions of 2-O-arachidonylglycerol ether and ibuprofen with the allosteric and catalytic subunits of human COX-2
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作者：Liang Dong ; Hechang Zou ; Chong Yuan 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2016
卷号：57
期号：6
页码：1043-1050
DOI：10.1194/jlr.M067512
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：Prostaglandin (PG) endoperoxide H synthase (PGHS)-2, also known as cyclooxygenase (COX)-2, can convert arachidonic acid (AA) to PGH₂ in the committed step of PG synthesis. PGHS-2 functions as a conformational heterodimer composed of an allosteric (E_allo) and a catalytic (E_cat) monomer. Here we investigated the interplay between human (hu)PGHS-2 and an alternative COX substrate, the endocannabinoid, 2-arachidonoylglycerol (2-AG), as well as a stable analog, 2- O -arachidonylglycerol ether (2-AG ether). We also compared the inhibition of huPGHS-2-mediated oxygenation of AA, 2-AG, and 2-AG ether by the well-known COX inhibitor, ibuprofen. When tested with huPGHS-2, 2-AG and 2-AG ether exhibit very similar kinetic parameters, responses to stimulation by FAs that are not COX substrates, and modes of inhibition by ibuprofen. The 2-AG ether binds E_cat more tightly than E_allo and, thus, can be used as a stable E_cat-specific substrate to examine certain E_allo-dependent responses. Ibuprofen binding to E_allo of huPGHS-2 completely blocks 2-AG or 2-AG ether oxygenation; however, inhibition by ibuprofen of huPGHS-2-mediated oxygenation of AA engages a combination of both allosteric and competitive mechanisms.
关键词：cyclooxygenase-2 ; prostaglandin, half-sites ; 2-arachindonoylglycerol ; arachidonic acid ; palmitic acid ; ibuprofen