Identification of novel arachidonic acid metabolites formed by prostaglandin H synthase

Hecker, Markus; Ullrich, Volker; Fischer, Christine; Meese, Claus O.

doi:10.1111/j.1432-1033.1987.tb13587.x

Cited by 63 publications

(36 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5D). The abundance and chiral purity of the 15-HETE are different from the results with other COX enzymes (22)(23)(24) and indicate that the P. homomalla COX enzyme has an active site that is set up to favor oxygenation in the 15R configuration. 5.…”

Section: Expression In Baculovirus Expressioncontrasting

confidence: 44%

The origin of 15 R -prostaglandins in the Caribbean coral Plexaura homomalla : Molecular cloning and expression of a novel cyclooxygenase

Valmsen

Järving

Boeglin

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The highest concentrations of prostaglandins in nature are found in the Caribbean gorgonian Plexaura homomalla. Depending on its geographical location, this coral contains prostaglandins with typical mammalian stereochemistry (15S-hydroxy) or the unusual 15R-prostaglandins. Their metabolic origin has remained the subject of mechanistic speculations for three decades. Here, we report the structure of a type of cyclooxygenase (COX) that catalyzes transformation of arachidonic acid into 15R-prostaglandins. Using a homology-based reverse transcriptase-PCR strategy, we cloned a cDNA corresponding to a COX protein from the R variety of P. homomalla. The deduced peptide sequence shows 80% identity with the 15S-specific coral COX from the Arctic soft coral Gersemia fruticosa and Ϸ50% identity to mammalian COX-1 and COX-2. The predicted tertiary structure shows high homology with mammalian COX isozymes having all of the characteristic structural units and the amino acid residues important in catalysis. Some structural differences are apparent around the peroxidase active site, in the membrane-binding domain, and in the pattern of glycosylation. When expressed in Sf9 cells, the P. homomalla enzyme forms a 15R-prostaglandin endoperoxide together with 11R-hydroxyeicosatetraenoic acid and 15R-hydroxyeicosatetraenoic acid as byproducts. The endoperoxide gives rise to 15R-prostaglandins and 12R-hydroxyheptadecatrienoic acid, identified by comparison to authentic standards. Evaluation of the structural differences of this 15R-COX isozyme should provide new insights into the substrate binding and stereospecificity of the dioxygenation reaction of arachidonic acid in the cyclooxygenase active site.

show abstract

Section: Expression In Baculovirus Expressioncontrasting

confidence: 44%

The origin of 15 R -prostaglandins in the Caribbean coral Plexaura homomalla : Molecular cloning and expression of a novel cyclooxygenase

Valmsen

Järving

Boeglin

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Moreover, selective inhibitors of the cyclo-oxygenase activity of PGHS-2 have been developed (Masferrer et al, consistent with the schema of formation of 8-epi-PGF2a via the corresponding endoperoxide by a biomimetic cyclization proposed by Corey et al (1984). Moreover, Hecker et al (1987) demonstrated that 8-epi-PGF2. is a product of the ram seminal vesicle PGHS.…”

Section: Introductionmentioning

confidence: 73%

Induction of prostaglandin endoperoxide synthase‐2 in human monocytes associated with cyclo‐oxygenase‐dependent F₂‐isoprostane formation

Patrignani

Santini

Panara

et al. 1996

British J Pharmacology

View full text Add to dashboard Cite

1 The isoprostane 8-epi-prostaglandin (PG)F2a is produced by free radical-catalyzed peroxidation of arachidonic acid. It may also be formed as a minor product of the cyclo-oxygenase activity of platelet PGH synthase (PGHS)-l. We investigated 8-epi-PGF2. production associated with induction of the human monocyte PGHS-2 and its pharmacological modulation. 2 Heparinized whole blood samples were drawn from healthy volunteers, 48 h following oral dosing with aspirin 300 mg to suppress platelet cyclo-oxygenase activity. One ml aliquots were incubated with lipopolysaccharide (LPS: 0.1-50 ug ml-') for 0-24 h at 37'C. PGE2 and 8-epi-PGF2a were measured in separated plasma by radioimmunoassay and enzyme immunoassay techniques. 3 Levels of both eicosanoids were undetectable (i.e. <60 pg ml-') at time 0. LPS induced the formation of PGE2 and 8-epi-PGF2, in a time-and concentration-dependent fashion, coincident with the induction of PGHS-2 detected by Western blot analysis of monocyte lysates. After 24 h at 10 mig ml-' LPS, immunoreactive PGE2 and 8-epi-PGF2, averaged 10,480+4,643 and 295+ 140 pg ml-' (mean + s.d., n = 6), respectively. 4 Dexamethasone-and 5-methanesulphonamido-6-(2,4-difluorothiophenyl)-l-indanone (L-745,337), a selective inhibitor of the cyclo-oxygenase activity of PGHS-2, reduced PGE2 and 8-epi-PGF2. production in response to LPS.5 Isolated monocytes produced PGE2 and 8-epi-PGF2, in response to LPS (10 Mg ml-') in a timedependent fashion. Monocyte PGE2 and 8-epi-PGF2a production was largely prevented by dexamethasone (2 gM) and cycloheximide (10 Mg ml-') in association with suppression of PGHS-2 but not of PGHS-1 expression. 6 We conclude that the induction of PGHS-2 in human monocytes is associated with cyclo-oxygenasedependent generation of the vasoconstrictor and platelet-agonist 8-epi-PGF2,.

show abstract

“…Thus, the contribution of lipoxygenases to the production of 9-HODE in mammalian tissues remains to be elucidated. In addition to cyclooxygenase activity converting arachidonic acid to prostaglandin G 2 , prostaglandin endoperoxide H synthases were found to exhibit some lipoxygenase activities producing certain amounts of 11-and 15-HETE from arachidonic acid (38,39). Many of the cytochrome P450 enzymes are also involved in the metabolism of linoleic and arachidonic acids to generate various hydroxy and epoxy fatty acids including HODE and HETE (23,24).…”

Section: Discussionmentioning

confidence: 99%

Identification of 9-Hydroxyoctadecadienoic Acid and Other Oxidized Free Fatty Acids as Ligands of the G Protein-coupled Receptor G2A

Obinata

Hattori

Nakane

et al. 2005

Journal of Biological Chemistry

157

136

View full text Add to dashboard Cite

G2A is a G protein-coupled receptor that is predominantly expressed in lymphoid tissues and macrophages. G2A can be induced by diverse stimuli to cause cell cycle arrest in the G 2 /M phase in pro-B and T cells. G2A is also expressed in macrophages within atherosclerotic lesions, suggesting G2A involvement in atherosclerosis. Recently, G2A was discovered to possess proton-sensing ability. In this paper, we report another function of G2A, that is, as a receptor for 9-hydroxyoctadecadienoic acid (9-HODE) and other oxidized free fatty acids. G2A, expressed in CHO-K1 or HEK293 cells, showed 9-HODE-induced intracellular calcium mobilization, inositol phosphate accumulation, inhibition of cAMP accumulation, [35 S]guanosine 5-3-O-(thio)triphosphate binding, and MAP kinase activation. Furthermore, G2A was activated by various oxidized derivatives of linoleic and arachidonic acids, but it was weakly activated by cholesteryl-9-HODE. Oxidized phosphatidylcholine (1-palmitoyl-2-linoleoyl) when hydrolyzed with phospholipase A 2 also evoked intracellular calcium mobilization in G2A-expressing cells. These results indicate that G2A is activated by oxidized free fatty acids produced by oxidation and subsequent hydrolysis of phosphatidylcholine or cholesteryl linoleate. Thus, G2A might have a biological role in diverse pathological conditions including atherosclerosis.

show abstract

Identification of novel arachidonic acid metabolites formed by prostaglandin H synthase

Cited by 63 publications

References 43 publications

The origin of 15 R -prostaglandins in the Caribbean coral Plexaura homomalla : Molecular cloning and expression of a novel cyclooxygenase

The origin of 15 R -prostaglandins in the Caribbean coral Plexaura homomalla : Molecular cloning and expression of a novel cyclooxygenase

Induction of prostaglandin endoperoxide synthase‐2 in human monocytes associated with cyclo‐oxygenase‐dependent F₂‐isoprostane formation

Identification of 9-Hydroxyoctadecadienoic Acid and Other Oxidized Free Fatty Acids as Ligands of the G Protein-coupled Receptor G2A

Contact Info

Product

Resources

About

Identification of novel arachidonic acid metabolites formed by prostaglandin H synthase

Cited by 63 publications

References 43 publications

The origin of 15 R -prostaglandins in the Caribbean coral Plexaura homomalla : Molecular cloning and expression of a novel cyclooxygenase

The origin of 15 R -prostaglandins in the Caribbean coral Plexaura homomalla : Molecular cloning and expression of a novel cyclooxygenase

Induction of prostaglandin endoperoxide synthase‐2 in human monocytes associated with cyclo‐oxygenase‐dependent F2‐isoprostane formation

Identification of 9-Hydroxyoctadecadienoic Acid and Other Oxidized Free Fatty Acids as Ligands of the G Protein-coupled Receptor G2A

Contact Info

Product

Resources

About

Induction of prostaglandin endoperoxide synthase‐2 in human monocytes associated with cyclo‐oxygenase‐dependent F₂‐isoprostane formation