Regulation of Prostaglandin E2 Biosynthesis by Inducible Membrane-associated Prostaglandin E2 Synthase That Acts in Concert with Cyclooxygenase-2*
By M. Murakami, H. Naraba, T. Tanioka, Natsuki Semmyo, Yoshihito Nakatani, Fumiaki Kojima, Tomomi Ikeda, M. Fueki, A. Ueno, S. Oh‐ishi and 1 more. Journal of Biological Chemistry, 2000
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Here we report the molecular identification of membrane-bound glutathione (GSH)-dependent prostaglandin (PG) E2 synthase (mPGES), a terminal enzyme of the cyclooxygenase (COX)-2-mediated PGE2 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 glutathioneS-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 PGE2 generation. Arg110, a residue well conserved in the microsomal GSHS-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 A2 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 PGE2 biosynthesis, which may be linked to inflammation, fever, osteogenesis, and even cancer.
Subfields: Genetics, Pharmacology
View Paper: https://www.semanticscholar.org/paper/de15928aa6fdf827bb3b0de22d9a2120862b27c9
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In Pharmacology
Citations in the corpus
- Mechanism of Action of Paracetamol (2005, background): “At low concentrations of arachidonic acid, PGE2 is synthesized mainly by COX-2 and a membrane-associated PGE synthase.(23,25) On the other hand, high concentrations of arachidonic acid are converted to larger amounts of PGE2 by COX-1 and cytosolic PGE synthase.”
- Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma (2005, background): “mPGES-1 preferentially metabolizes PGH2 derived from COX-2, while mPGES-2 has similar affinity for PGH2 derived from COX-1 and COX-2 and is up-regulated in several carcinomas (23).”
- Why there are two cyclooxygenase isozymes. (2001, background): “There also appears to be an mPGE synthase that is coordinately induced with PGHS-2 and seems to function preferentially with PGHS-2, rather than PGHS-1 (24, 36).”
- Vascular Endothelial Growth Factor and Angiogenesis (2004, background): “Prostaglandin E2 (PGE2) production has been shown to be selectively linked to COX-2 activity through the inducible PGE2 synthase pathway in both inflammatory and aberrant cell growth processes (Murakami et al., 2000).”