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首页> 外文期刊>Biochemistry >The catalytic outcomes of the constitutive and the mitogen inducible isoforms of prostaglandin H2 synthase are markedly affected by glutathione and glutathione peroxidase(s).
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The catalytic outcomes of the constitutive and the mitogen inducible isoforms of prostaglandin H2 synthase are markedly affected by glutathione and glutathione peroxidase(s).

机译：谷胱甘肽和谷胱甘肽过氧化物酶显着影响前列腺素H 2合酶的组成型和丝裂原诱导型亚型的催化结果。

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摘要

Reduced glutathione (GSH), at physiological concentrations, was found to markedly alter the profile of arachidonate metabolism by prostaglandin H2 synthase. In 1 mM GSH, the constitutive (COX-1) and the mitogen inducible (COX-2) isoforms metabolized arachidonate to 12-hydroxyheptadecatrienoic acid (12-HHT) (88% and 78% of total products, respectively). Prostanoid formation was consequently reduced to only 12% (COX-1) and 19% (COX-2) of the total metabolites. The GSH-dependent production of 12-HHT was regio- and enantioselective for the 12(S)-isomer. We propose that 12(S)-HHT is formed by a GSH-dependent enzymatic cleavage of the PGH2 8,9 and 11,12 carbon-carbon bonds based on the following: (a) nonsignificant GSH-dependent formation of 12(S)-HHT during chemical decomposition of synthetic PGH2, (b) the structural similarities between the asymmetric carbons at C(12) in 12-HHT and C(15) in PGH2, (c) the GSH concentration-dependent product/precursor relationship between 12-HHT and prostanoid production, and (d) aspirin inhibition of 12-HHT formation by both enzymes. Arachidonic acid oxidation by COX-1, and not by COX-2, was inhibited by the combined presence of GSH and liver cytosol. In contrast, metabolism by neither isoform was inhibited when the cytosol was obtained from selenium-depleted animals. This is consistent with a unique, selenium dependent, cytosolic GSH peroxidase that inhibits specifically prostanoid and 12(S)-HHT formation by COX-1. These results suggest an additional role for GSH and GSH peroxidase(s) in regulating prostanoid biosynthesis. Differences between the isoforms in their sensitivities to GSH peroxidase may reflect differences in their requirements for an "initiator hydroperoxide".
机译：人们发现，在生理浓度下还原型谷胱甘肽（GSH）会明显改变前列腺素H2合酶对花生四烯酸酯代谢的影响。在1 mM GSH中，组成型（COX-1）和有丝分裂原诱导型（COX-2）异构体将花生四烯酸酯代谢为12-羟基庚二烯三酸（12-HHT）（分别占总产品的88％和78％）。因此，前列腺素的形成减少到总代谢物的仅12％（COX-1）和19％（COX-2）。 GSH依赖的12 HHT的生产是12（S）异构体的区域和对映选择性。我们建议基于以下因素通过PGH2 8,9和11,12碳-碳键的GSH依赖性酶切形成12（S）-HHT：（a）12（S）的非显着GSH依赖性形成-HHT在合成PGH2的化学分解过程中，（b）12-HHT中C（12）和PGH2中C（15）的不对称碳之间的结构相似性，（c）12之间的GSH浓度依赖性产物/前体关系-HHT和前列腺素的产生，以及（d）阿司匹林通过这两种酶抑制12-HHT的形成。谷胱甘肽和肝细胞溶胶的共同存在抑制了花生四烯酸被COX-1而不是COX-2氧化。相反，当从贫硒动物中获得胞质溶胶时，两种亚型都不会抑制新陈代谢。这与独特的，硒依赖性的胞质GSH过氧化物酶一致，后者可特异性抑制COX-1生成的前列腺素和12（S）-HHT的形成。这些结果表明，GSH和GSH过氧化物酶在调节前列腺素的生物合成中具有额外的作用。同工型之间对GSH过氧化物酶敏感性的差异可能反映了它们对“引发剂氢过氧化物”的要求的差异。

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