id: PW:0001243 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0001243 title: prostanoid biosynthetic pathway description: Phospholipid derived arachidonic acid can be metabolized via three routes to give rise to a wide range of metabolites collectively referred to as eicosanoids. Of these, the members of the prostanoid subclass are derived from the prostaglandin H2 (PGH2) precursor generated in the cyclooxygenase mediated pathway of arachidonic acid metabolism (lipooxygenases and cytochrome P450 monooxygenases mediate the other two routes to produce leukotriene and other metabolites). The prostanoids bind to andactivate the prostanoid receptors, G-protein coupled (GPCRs) to elicit a vast range of responses including sensitization to pain, inflammation and fever, immune and cardiovascular functions. The Ptgs1 and Ptgs2 cyclooxygenases, better known as Cox1 and Cox2 are bifunctional enzymes that in addition to the first cyclooxygenase activity, carry out a second, peroxidase activity. In the first reaction arachidonic acid is oxidized to prostaglandin G2 (PGG2) - a reaction dependent on a tyrosine radical on the enzyme, the generation of which involves the peroxidase activity. PGG2 is converted to prostaglandin H2 (PGH2) in the second, peroxidase mediated reaction. PGH2 is the substrate for various, cell specific prostaglandin synthases to produce the final prostaglandins, prostacyclin and thromboxane, collectively known as prostanoids. The formation of prostaglandin D2 (PGD2) is catalyzed by either the hematopoietic prostaglandin D synthase ( Hpgds ) or the brain specific lipocalin-type synthase ( Htgds ). Pgd2 activates two receptor types to modulate immune and inflammatory responses; its involvement in nociception is poorly defined. Prostaglandin E2 (PGE2) is one of the most abundant prostanoids and its formation from PGH2 is catalyzed by microsomal or cytosolic prostaglandin E synthases (Ptges) [ click to see the structure of a microsomal synthase ]. There are four PGE2 receptors and alternative splicing of type 1 and 3 receptors further diversifies the range of responses PGE2 can elicit. Prostaglandin I2 ( PGI2 ), also known as prostacyclin, is the primary prostaglandin of the endothelial cell and its synthesis is catalyzed by prostaglandin I2 synthase (Ptgis) - a member of the cytochrome P450 superfamily also known as Cyp8a1. PGI2 binds one receptor type to elicit potent vasodilation and anti-thrombic effects that oppose the function of thromboxane. Thromboxane A2 (TXA2) is involved in smooth muscle contraction and proliferation and also in platelet function. Its synthesis is catalyzed by the thromboxane A synthase 1 (Tbxas1), also a member of the cytochrome P450 superfamily, known as Cyp5a1. TXA2 engages one or two receptors. TXA2 and PGI2 are the major prostanoids of the cardiovascular system where they mediate opposite functions. Finally, the formation of prostaglandin F2alpha (PGF2alpha) metabolites, critical for mammalian reproduction, can be catalyzed by members of AKR (aldo-keto reductase) and thioredoxin-like superfamilies that require NAPH or NADPH and thioredoxin, respectively. In addition to the PGH2 derived route, the PGF2alphas can also be derived from PGE2 and PGD2. The PGH2 based route is believed to be the result of Fam213b oxidoreductase activity as well as of Akr1a1 and Akr1b1 activities whereas the formation of PGF2alpha from PGD2 and PGE2 requires the activities of Akr1c3 and Cbr1, respectively [ click to see a structure of Akr1c3 ]. The Cox enzymes are targets of various non-steroidal anti-inflammatory (NSAID) and specific Cox-2 inhibitor drugs that inhibit the first reaction. On the other hand, paracetamol, a widely used analgesic and antipyretic drug, inhibits the second reaction. The prostanoid receptors are also targets for drug development. The expression of Cox and several prostaglandin synthases is deregulated in cancer. The inducible Cox-2 enzyme, responsible for most of prostanoid synthesis during inflammation, is up-regulated in several cancer types as well as other diseases. diagram_image: https://rgd.mcw.edu/pathway/PW0001243/prostanoid%20biosynthetic%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0001243/prostanoid%20biosynthetic%20pathway/prostanoid%20biosynthetic%20pathway.gpp diagram_pathway_links: - id: PW:0000461 label: cyclooxygenase mediated pathway of arachidonic acid metabolism - id: PW:0001527 label: thromboxane A2 signaling pathway - id: PW:0001529 label: prostaglandin E2 signaling pathway - id: PW:0001530 label: prostaglandin D2 signaling pathway - id: PW:0001531 label: prostaglandin I2 signaling pathway - id: PW:0001535 label: prostaglandin F2alpha signaling pathway diagram_gene_links: - id: RGD:68346 label: Akr1a1 - id: RGD:2092 label: Akr1b1 - id: RGD:708428 label: Akr1c3 - id: RGD:2286 label: Cbr1 - id: RGD:1308251 label: Fam213b - id: RGD:69251 label: Hpgds - id: RGD:3433 label: Ptgds - id: RGD:62076 label: Ptges - id: RGD:1310836 label: Ptges2 - id: RGD:3438 label: Ptgis - id: RGD:3439 label: Ptgs1 - id: RGD:620349 label: Ptgs2 - id: RGD:3826 label: Tbxas1 diagram_chemicals: - id: CHEBI:15843 label: arachidonic acid - id: CHEBI:15555 label: PGD2 - id: CHEBI:15551 label: PGE2 - id: CHEBI:15553 label: PGF2alpha - id: CHEBI:27647 label: PGG2 - id: CHEBI:15554 label: PGH2 - id: CHEBI:15552 label: PGI2 - id: CHEBI:15627 label: TXA2 diagram_edges: - source: PGD2 relation: positively_affects target: PGF2alpha - source: PGD2 relation: positively_affects target: immunomodulation - source: PGD2 relation: positively_affects target: inflammatory response - source: PGE2 relation: positively_affects target: PGF2alpha - source: PGE2 relation: positively_affects target: cardiovascular functions - source: PGE2 relation: positively_affects target: immunomodulation - source: PGE2 relation: positively_affects target: inflammatory response - source: PGE2 relation: positively_affects target: perception of pain - source: PGF2alpha relation: positively_affects target: reproduction - source: PGG2 relation: positively_affects target: PGH2 - source: PGH2 relation: positively_affects target: PGD2 - source: PGH2 relation: positively_affects target: PGE2 - source: PGH2 relation: positively_affects target: PGF2alpha - source: PGH2 relation: positively_affects target: PGI2 - source: PGH2 relation: positively_affects target: TXA2 - source: PGI2 relation: positively_affects target: cardiovascular functions - source: TXA2 relation: positively_affects target: cardiovascular functions - source: arachidonic acid relation: positively_affects target: PGG2 diagram_labels: - cardiovascular functions - immunomodulation - inflammatory response - perception of pain - Ptges3 - reproduction references: - id: RGD:8552701 citation: 'Hirata T and Narumiya S, Adv Immunol. 2012;116:143-74. doi: 10.1016/B978-0-12-394300-2.00005-3.' - id: RGD:8552712 citation: 'Majed BH and Khalil RA, Pharmacol Rev. 2012 Jul;64(3):540-82. doi: 10.1124/pr.111.004770. 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