Prostanoid biosynthesis — cyclooxygenase conversion of arachidonate to PGH2 and its isomerisation or reduction to PGE2, PGD2, PGI2, TXA2 and PGF2alpha; PTGS1/PTGS2/PTGES/PTGES2/PTGES3/HPGDS/PTGDS/PTGIS/TBXAS1/AKR1C3/AKR1B1/PRXL2B/CBR1

Prostanoids (the prostaglandins, prostacyclin and the thromboxanes) are oxygenated derivatives of arachidonate that act locally through G-protein-coupled prostanoid receptors in inflammation, pain and fever, vascular tone, platelet function, immunity and reproduction. Their synthesis is a two-stage reaction chain. In the first, committed stage, prostaglandin G/H synthase (cyclooxygenase, COX), a bifunctional haem enzyme on the lumenal face of the endoplasmic reticulum and nuclear envelope, adds two molecules of O2 to free arachidonate to form the hydroperoxy endoperoxide prostaglandin G2 (PGG2) at its cyclooxygenase site, and reduces PGG2 to the hydroxy endoperoxide prostaglandin H2 (PGH2) at its peroxidase site. Two isoforms carry out this stage: COX-1 (PTGS1), expressed constitutively in most tissues and in platelets, and COX-2 (PTGS2), induced by cytokines, growth factors and lipopolysaccharide and responsible for most prostanoid production in inflammation. Both are the targets of non-steroidal anti-inflammatory drugs. In the second stage, PGH2 is converted by cell-type-specific terminal enzymes into the individual prostanoids. Prostaglandin E2 (PGE2) is formed by isomerisation by the glutathione-dependent, inducible microsomal PGE synthase-1 (PTGES), by microsomal PGE synthase-2 (PTGES2) and by the cytosolic PGE synthase p23 (PTGES3). PGD2 is formed by the glutathione-dependent haematopoietic PGD synthase (HPGDS) of mast cells and other immune cells, and by the secreted lipocalin-type PGD synthase (PTGDS) of the brain, male genital tract and heart. Prostacyclin (PGI2) and thromboxane A2 (TXA2) are formed by two atypical cytochrome P450 isomerases of the endoplasmic reticulum, prostacyclin synthase (PTGIS, CYP8A1) in endothelium and thromboxane synthase (TBXAS1, CYP5A1) in platelets, which need no external electron donor or O2. PGF2alpha is formed by reduction rather than isomerisation: aldo-keto reductases AKR1C3 and AKR1B1 reduce PGH2 with NADPH, the thioredoxin-like prostamide/PGF synthase PRXL2B reduces PGH2 with reduced thioredoxin, and carbonyl reductase CBR1 reduces PGE2 at C-9. AKR1C3 also reduces PGD2 at C-11, giving the stereoisomer 11-epi-PGF2alpha (9alpha,11beta-PGF2). Which prostanoids a cell makes depends on its complement of terminal enzymes and on their coupling to COX-1 or COX-2.

Derived from the RGD Pathway Ontology diagram PW:0001243 through the RGD_PATHWAY_ONTOLOGY project's diagram->module route; GO mapping GO:0046457 prostanoid biosynthetic process (closeMatch). The RGD diagram supplied the boundary (arachidonate in, five prostanoid classes out), the PGG2 -> PGH2 -> terminal product topology, the secondary PGE2 -> PGF2alpha and PGD2 -> PGF2alpha edges, and the gene list. It is modelled as a reaction chain: one COX part with COX-1 and COX-2 as variants, then one terminal-synthase part whose variant set branches from PGH2 by prostanoid product, with nested enzyme variants where more than one enzyme makes the same product. Boundary decisions. (1) Arachidonate release from membrane phospholipids by cytosolic phospholipase A2 (PLA2G4A, RHEA:40427 for 1-hexadecanoyl-2-arachidonoyl-PC) is substrate supply and is left outside: it is not in the PW:0001243 gene list, belongs to the parent RGD pathway PW:0000461 together with its regulators (ANXA1, MKNK1, VIM), and supplies arachidonate to the lipoxygenase and cytochrome P450 branches as well. (2) The five prostanoid signalling subpathways (receptors PTGER1-4, PTGDR/PTGDR2, PTGIR, PTGFR, TBXA2R) are downstream and out of scope. (3) Prostanoid inactivation (HPGD 15-hydroxyprostaglandin dehydrogenase, transport by SLCO2A1 and export by ABCC4) is out of scope; CBR1's PGE2 9-ketoreductase step is kept because RGD draws it as a PGF2alpha-forming route, but CBR1 also oxidises the 15-hydroxyl of PGE1, PGE2 and PGF2alpha (GO:0047021, EXP) and is better known as a catabolic enzyme, so its PGF2alpha output is a minor route. (4) AKR1A1 is drawn by RGD on the PGH2 -> PGF2alpha route, but neither its reviewed UniProt entry (P14550; no prostaglandin reaction) nor its QuickGO annotations (checked 2026-10-26; no prostaglandin-related term) record any prostaglandin reductase activity, and no supporting primary paper was found, so it is not included as a participant; this is recorded as a knowledge gap. (5) PTGDS is secreted and acts in the extracellular region (cerebrospinal fluid, seminal plasma) as well as being a lipophilic-ligand carrier; only its PGD synthase activity is modelled. Molecular functions were taken from each protein's experimental GO annotations in QuickGO (checked 2026-10-26) and cross-checked against the experimentally evidenced Rhea reactions in the reviewed UniProt entries: PTGS1 and PTGS2 GO:0004666 (IDA; PTGS2 also EXP), whose Rhea xref RHEA:23728 is the overall reaction and which GO does not split into separate cyclooxygenase (RHEA:42596) and peroxidase (RHEA:42600) activities; PTGES GO:0050220 (EXP, IDA); PTGES2 GO:0050220 (EXP, IDA); PTGES3 GO:0050220 (EXP, IDA; and the completed PTGES3 gene review accepts it as core); HPGDS GO:0004667 (EXP, IDA); PTGDS GO:0004667 (EXP, IDA); PTGIS GO:0008116 (EXP, IDA); TBXAS1 GO:0004796 (EXP, IDA, IMP); AKR1C3 GO:0036130 (EXP) and GO:0036131 (EXP); AKR1B1 GO:0036130 (IDA); CBR1 GO:0050221 (EXP). GO:0047017 prostaglandin F synthase activity was not used. Its definition and Rhea xref (RHEA:10140) describe PGD2 reduction, not PGH2 reduction. AKR1C3 does carry it (EXP), but this module models AKR1C3's PGD2 route by the more specific 11-ketoreductase term GO:0036131 (RHEA:45316, the reaction that gives 11-epi-PGF2alpha). PRXL2B carries GO:0047017 by IBA/ISS. That conflicts with the primary report on the orthologous mouse and swine enzyme (PMID:18006499), which found PGD2 is not a substrate, and is a candidate for upstream review. PRXL2B's actual reaction, thioredoxin-dependent PGH2 reduction (EC 1.11.1.20, RHEA:28214), has no GO molecular-function term (the NADPH-defined GO:0036130 on PRXL2B is IEA only), so the PRXL2B annoton carries a preferred_term and Rhea evidence but no GO id; human PRXL2B activity is by similarity in UniProt (ECO:0000250 from mouse Q9DB60). PTGES3 is also the HSP90 co-chaperone p23. Its PGE synthase activity is shown in vitro and in cells (PMID:10922363), but how much it contributes to PGE2 in vivo relative to mPGES-1 is less well established than for PTGES, and this is recorded in the annoton. No human GO-CAM covers any of these genes (gocams/index.tsv checked 2026-10-26), and no existing module models eicosanoid synthesis; modules/ferroptosis.yaml and modules/c_elegans_lysosomal_lipid_signaling.yaml mention arachidonate only in other contexts. Gene reviews exist only for PTGES3. All cited publications are abstract-only in the publications cache except PMID:10377395 and PMID:17344335.