Polymorphic human prostaglandin H synthase-2 proteins and their interactions with cyclooxygenase substrates and inhibitors.
Polymorphic human prostaglandin H synthase-2 proteins and their interactions with cyclooxygenase substrates and inhibitors.
复制标题
多态性人前列腺素 H 合酶 2 蛋白及其与环氧合酶底物和抑制剂的相互作用。
DOI：
10.1038/tpj.2010.49
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Kulmacz,RJ
中科院分区：
文献类型：
--
作者：
Liu,W;Poole,EM;Ulrich,CM;Kulmacz,RJ
The cyclooxygenase (COX) activity of prostaglandin H synthase-2 (PGHS-2) is implicated in colorectal cancer and is targeted by nonsteroidal anti-inflammatory drugs (NSAIDs) and dietary n− 3 fatty acids. We used purified, recombinant proteins to evaluate the functional impacts of the R228H, E488G, V511A and G587R PGHS-2 polymorphisms on COX activity, fatty acid selectivity and NSAID actions. Compared to wild-type PGHS-2, COX activity with arachidonate was∼ 20% lower in 488G and∼ 20% higher in 511A. All variants showed time-dependent inhibition by the COX-2-specific inhibitor (coxib) nimesulide, but 488G and 511A had 30–60% higher residual COX activity; 511A also showed up to 70% higher residual activity with other time-dependent inhibitors. In addition, 488G and 511A differed significantly from wild type in V max values with the two fatty acids: 488G showed∼ 20% less and 511A showed∼ 20% more discrimination against eicosapentaenoic acid. The V max value for eicosapentaenoate was not affected in 228H or 587R, nor were the K m values or the COX activation efficiency (with arachidonate) significantly altered in any variant. Thus, the E488G and V511A PGHS-2 polymorphisms may predict who will most likely benefit from interventions with some NSAIDs or n− 3 fatty acids.
