Regulation of Prostaglandin E2 Biosynthesis by Inducible Membrane-associated Prostaglandin E2 Synthase That Acts in Concert with Cyclooxygenase-2
Open accessAbstract
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.
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- Authors
- Murakami, M., Naraba, H., Tanioka, T., Semmyo, N., Nakatani, Y., Kojima, F., Ikeda, T., Fueki, M., Ueno, A., Oh-ishi, S., & Kudo, I.
- Affiliations
- SHOWA Medical University (JP)
- Kitasato University (JP)
- Corresponding author
- Kudo, Ichiro
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-10
- Volume
- 275
- Issue
- 42
- Pages
- 32783-32792
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2167029659
- Cited by
- 964
- References
- 2
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 16 · 2023: 16 · 2022: 16 · 2021: 17 · 2020: 20 · 2019: 22 · 2018: 27 · 2017: 24 · 2016: 20 · 2015: 34 · 2014: 39 · 2013: 38 · 2012: 48
- FWCI
- 29.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- cyclooxygenase-2, prostaglandin E2 synthesis, glutathione-dependent enzymes, arachidonic acid, cytosolic phospholipase A2, cyclooxygenase-1, macrophages, osteoblasts, inflammation, dexamethasone, enzyme colocalization, cell proliferation
- MeSH terms
- Prostaglandin-E Synthases, Amino Acid Sequence, Animals, Cell Membrane, Glutathione Transferase, Humans, Isoenzymes, Kinetics, Macrophages, Membrane Proteins, Microsomes, Molecular Sequence Data, Osteoblasts, Prostaglandin-Endoperoxide Synthases, Rabbits, Recombinant Proteins, Dinoprostone, Mutagenesis, Site-Directed, Sequence Alignment, Rats, Sprague-Dawley, Sequence Homology, Amino Acid, Intramolecular Oxidoreductases, Mice, Rats, Cyclooxygenase 2
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