Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2
Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2
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DOI：
10.1074/jbc.m003505200
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发表时间：
2000-10-20
影响因子：
4.8
通讯作者：
Kudo, I
中科院分区：
文献类型：
--
作者：
Murakami, M;Naraba, H;Kudo, I
本文报道了膜结合谷胱甘肽（GSH）依赖性前列腺素（PG）E-2合酶（mPGES）的分子鉴定，mPGES是环氧化酶（考克斯）-2介导的PGE（2）生物合成途径的末端酶。巨噬细胞和成骨细胞中的mPGES活性在促炎刺激后显著增加。小鼠和大鼠mPGES的cDNA编码的功能蛋白，表现出与人类直系同源物（微粒体谷胱甘肽S-转移酶样1）的高度同源性。在各种组织和细胞中，促炎刺激可显著诱导mPGES表达，地塞米松可下调mPGES表达，同时伴有考克斯-2表达的变化和PGE（2）生成延迟。Arg（110）是微粒体谷胱甘肽S-转移酶家族中的一个保守残基，对催化功能至关重要。mPGES与考克斯-2的偶联作用明显优于与考克斯-1的偶联作用，特别是在花生四烯酸供应有限的情况下。胞浆磷脂酶A（2）的爆发性激活增加了花生四烯酸的供应，使mPGES与考克斯-1偶联。mPGES与两种考克斯同工酶共定位于核周膜。此外，稳定共转染考克斯-2和mPGES的细胞生长更快，高度聚集，并表现出异常形态。因此，考克斯-2和mPGES是延迟的PGE（2）生物合成的必要成分，这可能与炎症、发热、骨生成甚至癌症有关。
Here we report the molecular identification of membrane-bound glutathione (GSH)-dependent prostaglandin (PG) E-2 synthase (mPGES), a terminal enzyme of the cyclooxygenase (COX)-2-mediated PGE(2) biosynthetic pathway. The activity of mPGES was increased markedly in macrophages and osteoblasts following proinflammatory stimuli. cDNA for mouse and rat mPGESs encoded functional proteins that showed high homology with the human ortholog (microsomal glutathione S-transferase-like 1). mPGES expression was markedly induced by proinflammatory stimuli in various tissues and cells and was down-regulated by dexamethasone, accompanied by changes in COX-2 expression and delayed PGE(2) generation. Arg(110), a residue well conserved in the microsomal GSH S-transferase family, was essential for catalytic function, mPGES was functionally coupled with COX-2 in marked preference to COX-1, particularly when the supply of arachidonic acid was limited. Increased supply of arachidonic acid by explosive activation of cytosolic phospholipase A(2) allowed mPGES to be coupled with COX-1. mPGES colocalized with both COX isozymes in the perinuclear envelope. Moreover, cells stably cotransfected with COX-2 and mPGES grew faster, were highly aggregated, and exhibited aberrant morphology. Thus, COX-2 and mPGES are essential components for delayed PGE(2) biosynthesis, which may be linked to inflammation, fever, osteogenesis, and even cancer.