id: MODULE:prostanoid_biosynthesis title: 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 description: >- 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. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0001243 title: prostanoid biosynthetic pathway statement: >- The module boundary and its core gene products follow the RGD interactive diagram for this Pathway Ontology term. The diagram draws arachidonic acid positively affecting PGG2, PGG2 positively affecting PGH2, PGH2 positively affecting PGD2, PGE2, PGF2alpha, PGI2 and TXA2, and PGD2 and PGE2 each positively affecting PGF2alpha, with the gene products Ptgs1, Ptgs2, Ptges, Ptges2, Ptges3, Hpgds, Ptgds, Ptgis, Tbxas1, Akr1c3, Akr1b1, Akr1a1, Fam213b (PRXL2B) and Cbr1. The prostanoid outputs link to the PGE2, PGD2, PGI2, PGF2alpha and TXA2 signalling pathways (PW:0001529, PW:0001530, PW:0001531, PW:0001535, PW:0001527) and the input links to the cyclooxygenase pathway of arachidonic acid metabolism (PW:0000461). Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0001243.yaml). - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0001243.yaml title: RGD PW:0001243 record text (project snapshot) statement: >- The RGD record text assigns the three PGF2alpha routes to specific enzymes, including Akr1a1 on the PGH2 route; that Akr1a1 assignment is the one RGD claim not carried into this module (see notes). supporting_text: 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 - source_id: GO:0046457 title: prostanoid biosynthetic process statement: >- The module is grounded in GO prostanoid biosynthetic process, the closeMatch GO mapping recorded for PW:0001243 in the project's module seeds. - source_id: GO:0019371 title: cyclooxygenase pathway statement: >- The committed COX step is the GO cyclooxygenase pathway, defined as prostaglandin formation from arachidonic acid with prostaglandin-endoperoxide synthase catalysing the committed step to PGG2 and PGH2. - source_id: PMID:10377395 title: 'Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target.' statement: >- States the two-stage architecture: PGH2 made by COX-1 or COX-2 is the common precursor of the individual prostanoids. supporting_text: Downstream of the cyclooxygenases, the product PGH 2 can be further metabolized into the various physiologically important eicosanoids notes: >- 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. knowledge_gaps: - gap_statement: >- Whether aldehyde reductase AKR1A1 reduces PGH2 to PGF2alpha, as the RGD record states, and whether it contributes to PGF2alpha formation in any human tissue, is undetermined. boundary: >- AKR1A1 is an established NADPH-dependent aldehyde reductase, and the related AKR1B1 and AKR1C3 have measured PGH2 reductase activity (PMID:19010934). The reviewed human AKR1A1 UniProt entry records no prostaglandin reaction, and AKR1A1 has no prostaglandin-related GO annotation. gap_kind: - BIOLOGY status: OPEN significance: >- Decides whether AKR1A1 belongs among the PGF2alpha synthases of this module or the RGD assignment should be withdrawn. resolution: >- Assay purified human AKR1A1 with PGH2 and NADPH alongside AKR1B1 and AKR1C3 controls, and measure PGF2alpha output in AKR1A1-depleted cells that express it. provenance: - reference_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0001243.yaml supporting_text: The PGH2 based route is believed to be the result of Fam213b oxidoreductase activity as well as of Akr1a1 and Akr1b1 activities module: id: prostanoid_biosynthesis label: Prostanoid biosynthesis module_type: METABOLIC_PATHWAY description: >- Arachidonate is converted by COX-1 or COX-2 to PGH2, which cell-specific terminal isomerases and reductases convert to PGE2, PGD2, PGI2, TXA2 or PGF2alpha. concepts: - preferred_term: prostanoid biosynthetic process term: id: GO:0046457 label: prostanoid biosynthetic process description: >- Formation of prostaglandins, prostacyclin and thromboxanes from arachidonate through the PGH2 endoperoxide. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens description: >- Members are grounded on the human proteins; the RGD diagram is drawn for rat and the pathway is conserved across mammals. cellular_components: - preferred_term: endoplasmic reticulum membrane term: id: GO:0005789 label: endoplasmic reticulum membrane description: >- COX-1, COX-2, prostacyclin synthase and thromboxane synthase are endoplasmic reticulum membrane enzymes. - preferred_term: cytosol term: id: GO:0005829 label: cytosol description: >- Asserted alongside the endoplasmic reticulum membrane because the soluble terminal enzymes (cPGES/p23, HPGDS, AKR1C3, AKR1B1, PRXL2B, CBR1) act in the cytosol on PGH2 released from the membrane-bound COX. parts: - order: 1 role: cyclooxygenase conversion of arachidonate to PGH2 node: id: pgh2_formation label: Cyclooxygenase and peroxidase conversion of arachidonate to PGH2 module_type: REACTION description: >- The committed step. The cyclooxygenase site adds two O2 to arachidonate to form PGG2, and the peroxidase site of the same enzyme reduces the 15-hydroperoxide of PGG2 to give PGH2. COX-1 and COX-2 catalyse the same chemistry and differ in regulation: COX-1 is constitutive and COX-2 is induced. concepts: - preferred_term: cyclooxygenase pathway term: id: GO:0019371 label: cyclooxygenase pathway variant_sets: - id: cox_isoform label: Cyclooxygenase isoform axis: enzyme isoform (constitutive vs inducible) selection: ONE_OR_MORE variants: - id: cox1_variant label: COX-1 (PTGS1) module_type: REACTION annotons: - id: ptgs1_cox label: COX-1 (PTGS1) prostaglandin-endoperoxide synthase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTGS1 (COX-1) term: id: UniProtKB:P23219 label: Prostaglandin G/H synthase 1 function: preferred_term: prostaglandin-endoperoxide synthase activity term: id: GO:0004666 label: prostaglandin-endoperoxide synthase activity substrates: - preferred_term: arachidonate term: id: CHEBI:32395 label: arachidonate - preferred_term: O2 term: id: CHEBI:15379 label: dioxygen - preferred_term: reductant (AH2) term: id: CHEBI:17499 label: hydrogen donor products: - preferred_term: prostaglandin H2 term: id: CHEBI:57405 label: prostaglandin H2(1-) - preferred_term: oxidised reductant (A) term: id: CHEBI:13193 label: hydrogen acceptor - preferred_term: water term: id: CHEBI:15377 label: water evidence: - source_id: RHEA:23728 statement: >- (5Z,8Z,11Z,14Z)-eicosatetraenoate + AH2 + 2 O2 = prostaglandin H2 + A + H2O; the overall reaction and the Rhea xref of GO:0004666. - source_id: RHEA:42596 statement: >- Cyclooxygenase half-reaction: arachidonate + 2 O2 = prostaglandin G2 (CHEBI:82629). - source_id: RHEA:42600 statement: >- Peroxidase half-reaction: prostaglandin G2 + AH2 = prostaglandin H2 + A + H2O. processes: - preferred_term: cyclooxygenase pathway term: id: GO:0019371 label: cyclooxygenase pathway locations: - preferred_term: endoplasmic reticulum membrane term: id: GO:0005789 label: endoplasmic reticulum membrane role_description: >- Constitutive cyclooxygenase of most tissues and the only COX of platelets, where it supplies PGH2 to thromboxane synthase; preferentially coupled to cPGES/p23 for immediate PGE2 synthesis. evidence: - source_id: PMID:7947975 statement: >- Purified recombinant human PGHS-1 and PGHS-2 both have cyclooxygenase and peroxidase activity with arachidonate as substrate. supporting_text: The recombinant human PGHS-1 and PGHS-2 possessed both cyclooxygenase and peroxidase activities. - source_id: PMID:1380156 statement: >- COX-1 and COX-2 are encoded by separate, differentially regulated genes; this is the IDA source for both isoforms' GO:0004666 annotation. supporting_text: Together, these data demonstrate that the Cox enzyme is encoded by at least two genes that are expressed and differentially regulated in a variety of cell types. - id: cox2_variant label: COX-2 (PTGS2) module_type: REACTION annotons: - id: ptgs2_cox label: COX-2 (PTGS2) prostaglandin-endoperoxide synthase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTGS2 (COX-2) term: id: UniProtKB:P35354 label: Prostaglandin G/H synthase 2 function: preferred_term: prostaglandin-endoperoxide synthase activity term: id: GO:0004666 label: prostaglandin-endoperoxide synthase activity substrates: - preferred_term: arachidonate term: id: CHEBI:32395 label: arachidonate - preferred_term: O2 term: id: CHEBI:15379 label: dioxygen - preferred_term: reductant (AH2) term: id: CHEBI:17499 label: hydrogen donor products: - preferred_term: prostaglandin H2 term: id: CHEBI:57405 label: prostaglandin H2(1-) - preferred_term: oxidised reductant (A) term: id: CHEBI:13193 label: hydrogen acceptor - preferred_term: water term: id: CHEBI:15377 label: water evidence: - source_id: RHEA:23728 statement: >- (5Z,8Z,11Z,14Z)-eicosatetraenoate + AH2 + 2 O2 = prostaglandin H2 + A + H2O. - source_id: RHEA:42596 statement: >- Cyclooxygenase half-reaction: arachidonate + 2 O2 = prostaglandin G2 (CHEBI:82629). - source_id: RHEA:42600 statement: >- Peroxidase half-reaction: prostaglandin G2 + AH2 = prostaglandin H2 + A + H2O. processes: - preferred_term: cyclooxygenase pathway term: id: GO:0019371 label: cyclooxygenase pathway locations: - preferred_term: endoplasmic reticulum membrane term: id: GO:0005789 label: endoplasmic reticulum membrane role_description: >- Inducible cyclooxygenase that supplies most PGH2 in inflammation, coupled preferentially to mPGES-1 for delayed PGE2 synthesis. It also oxygenates other substrates (2-arachidonoylglycerol, eicosapentaenoate), which are outside this module. evidence: - source_id: PMID:1380156 statement: >- Expressed human COX-2 has cyclooxygenase activity and its mRNA is induced by inflammatory stimuli. supporting_text: Expression of the hCox-2 open reading frame in Cos-7 monkey kidney cells results in the elaboration of cyclooxygenase activity. - source_id: PMID:1380156 statement: COX-2 is the inducible isoform. supporting_text: Cox-2 mRNA was preferentially induced by phorbol 12-myristate 13-acetate and lipopolysaccharide in human endothelial cells and monocytes. - source_id: PMID:7947975 statement: >- Purified recombinant human PGHS-2 has both cyclooxygenase and peroxidase activity. supporting_text: Both had high affinities for arachidonate as substrate and underwent self-inactivation during catalysis. - order: 2 role: terminal conversion of PGH2 to individual prostanoids node: id: terminal_prostanoid_synthesis label: Terminal prostanoid synthases acting on PGH2 module_type: METABOLIC_PATHWAY description: >- PGH2 is the common substrate of five terminal routes. Isomerases form PGE2, PGD2, PGI2 and TXA2; reductases form PGF2alpha, either from PGH2 directly or from PGE2 and PGD2. A cell's prostanoid profile is set by which of these enzymes it expresses. variant_sets: - id: prostanoid_product label: Terminal prostanoid product axis: prostanoid product (cell-type-specific terminal enzyme) selection: ONE_OR_MORE variants: - id: pge2_synthesis label: PGE2 synthesis (PGE synthases) module_type: REACTION description: >- Isomerisation of the 9,11-endoperoxide of PGH2 to the 9-keto, 11-hydroxy structure of PGE2 (RHEA:12893). variant_sets: - id: pges_enzyme label: PGE synthase axis: enzyme (inducible microsomal, constitutive microsomal, cytosolic) selection: ONE_OR_MORE variants: - id: mpges1_variant label: mPGES-1 (PTGES) module_type: REACTION annotons: - id: ptges_pge_synthase label: mPGES-1 (PTGES) prostaglandin-E synthase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTGES (mPGES-1) term: id: UniProtKB:O14684 label: Prostaglandin E synthase function: preferred_term: prostaglandin-E synthase activity term: id: GO:0050220 label: prostaglandin-E synthase activity substrates: - preferred_term: prostaglandin H2 term: id: CHEBI:57405 label: prostaglandin H2(1-) products: - preferred_term: prostaglandin E2 term: id: CHEBI:606564 label: prostaglandin E2(1-) cofactors: - preferred_term: glutathione term: id: CHEBI:57925 label: glutathionate(1-) evidence: - source_id: RHEA:12893 statement: prostaglandin H2 = prostaglandin E2; the Rhea xref of GO:0050220. processes: - preferred_term: prostaglandin biosynthetic process term: id: GO:0001516 label: prostaglandin biosynthetic process locations: - preferred_term: endoplasmic reticulum membrane term: id: GO:0005789 label: endoplasmic reticulum membrane role_description: >- MAPEG-family membrane enzyme that requires glutathione as a cofactor (not consumed). Induced with COX-2 by inflammatory cytokines, and the main source of inflammatory PGE2. QuickGO places it in membrane (EXP) and endoplasmic reticulum (IDA); UniProt adds the perinuclear region, colocalised with COX-1 and COX-2. evidence: - source_id: PMID:10377395 statement: >- Recombinant human mPGES-1 is a membrane-bound glutathione-dependent PGE synthase whose expression is induced by IL-1beta. supporting_text: In summary, we have identified a human membrane bound PGE synthase. - source_id: PMID:10377395 statement: The activity requires glutathione. supporting_text: The enzyme activity is glutathione-dependent, and the protein expression is induced by the proinflammatory cytokine IL-1 - id: mpges2_variant label: mPGES-2 (PTGES2) module_type: REACTION annotons: - id: ptges2_pge_synthase label: mPGES-2 (PTGES2) prostaglandin-E synthase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTGES2 (mPGES-2) term: id: UniProtKB:Q9H7Z7 label: Prostaglandin E synthase 2 function: preferred_term: prostaglandin-E synthase activity term: id: GO:0050220 label: prostaglandin-E synthase activity substrates: - preferred_term: prostaglandin H2 term: id: CHEBI:57405 label: prostaglandin H2(1-) products: - preferred_term: prostaglandin E2 term: id: CHEBI:606564 label: prostaglandin E2(1-) evidence: - source_id: RHEA:12893 statement: prostaglandin H2 = prostaglandin E2. processes: - preferred_term: prostaglandin biosynthetic process term: id: GO:0001516 label: prostaglandin biosynthetic process locations: - preferred_term: Golgi membrane term: id: GO:0000139 label: Golgi membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Constitutive, thioredoxin-motif (Cys110) PGE synthase made as a Golgi-membrane protein and cleaved to a soluble cytosolic form (both locations IDA). Its haem-bound form instead fragments PGH2 to 12-HHT and malondialdehyde (RHEA:48644), a reaction outside this module. evidence: - source_id: PMID:12804604 statement: >- Cys110 in the redoxin motif is essential for the PGE synthase activity of mPGES-2. supporting_text: The mutation from 110Cys to Ser or the double mutation from 110Cys and 113Cys to Ser caused loss of PGE synthase activity - id: cpges_variant label: cPGES/p23 (PTGES3) module_type: REACTION annotons: - id: ptges3_pge_synthase label: cPGES/p23 (PTGES3) prostaglandin-E synthase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTGES3 (cPGES/p23) term: id: UniProtKB:Q15185 label: Prostaglandin E synthase 3 function: preferred_term: prostaglandin-E synthase activity term: id: GO:0050220 label: prostaglandin-E synthase activity substrates: - preferred_term: prostaglandin H2 term: id: CHEBI:57405 label: prostaglandin H2(1-) products: - preferred_term: prostaglandin E2 term: id: CHEBI:606564 label: prostaglandin E2(1-) cofactors: - preferred_term: glutathione term: id: CHEBI:57925 label: glutathionate(1-) evidence: - source_id: RHEA:12893 statement: prostaglandin H2 = prostaglandin E2. - source_id: file:human/PTGES3/PTGES3-ai-review.yaml statement: >- The completed PTGES3 gene review accepts prostaglandin-E synthase activity as a core molecular function alongside its HSP90 co-chaperone role. processes: - preferred_term: prostaglandin biosynthetic process term: id: GO:0001516 label: prostaglandin biosynthetic process locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Glutathione-dependent cytosolic PGE synthase, identical to the HSP90 co-chaperone p23 and coupled preferentially to COX-1 for immediate PGE2 release. How much it contributes to PGE2 in vivo, compared with mPGES-1, is less certain than its in vitro activity. evidence: - source_id: PMID:10922363 statement: >- Recombinant p23 reproduces cytosolic GSH-dependent PGES activity. supporting_text: Recombinant p23 expressed in Escherichia coli and 293 cells exhibited all the features of PGES activity detected in rat brain cytosol - source_id: PMID:10922363 statement: cPGES/p23 couples preferentially to COX-1. supporting_text: cPGES/p23 was functionally linked with COX-1 in marked preference to COX-2 to produce PGE(2) from exogenous and endogenous arachidonic acid - id: pgd2_synthesis label: PGD2 synthesis (PGD synthases) module_type: REACTION description: >- Isomerisation of PGH2 to PGD2, with the 9-hydroxy, 11-keto structure (RHEA:10600). variant_sets: - id: pgds_enzyme label: PGD synthase axis: enzyme (haematopoietic sigma-class GST vs lipocalin type) selection: ONE_OR_MORE variants: - id: hpgds_variant label: Haematopoietic PGD synthase (HPGDS) module_type: REACTION annotons: - id: hpgds_pgd_synthase label: HPGDS prostaglandin-D synthase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: HPGDS term: id: UniProtKB:O60760 label: Hematopoietic prostaglandin D synthase function: preferred_term: prostaglandin-D synthase activity term: id: GO:0004667 label: prostaglandin-D synthase activity substrates: - preferred_term: prostaglandin H2 term: id: CHEBI:57405 label: prostaglandin H2(1-) products: - preferred_term: prostaglandin D2 term: id: CHEBI:57406 label: prostaglandin D2(1-) cofactors: - preferred_term: glutathione term: id: CHEBI:57925 label: glutathionate(1-) evidence: - source_id: RHEA:10600 statement: prostaglandin H2 = prostaglandin D2; the Rhea xref of GO:0004667. processes: - preferred_term: prostaglandin metabolic process term: id: GO:0006693 label: prostaglandin metabolic process locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Glutathione-requiring sigma-class GST of mast cells, megakaryocytes and other immune cells; the source of PGD2 in allergic inflammation. evidence: - source_id: PMID:9353279 statement: >- Human megakaryoblastic-cell PGD synthase is cytosolic, glutathione-dependent and of the haematopoietic type. supporting_text: The PGD synthase activity was localized in the cytosol of CMK cells, and absolutely required glutathione. - id: ptgds_variant label: Lipocalin-type PGD synthase (PTGDS) module_type: REACTION annotons: - id: ptgds_pgd_synthase label: L-PGDS (PTGDS) prostaglandin-D synthase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTGDS (L-PGDS) term: id: UniProtKB:P41222 label: Prostaglandin-H2 D-isomerase function: preferred_term: prostaglandin-D synthase activity term: id: GO:0004667 label: prostaglandin-D synthase activity substrates: - preferred_term: prostaglandin H2 term: id: CHEBI:57405 label: prostaglandin H2(1-) products: - preferred_term: prostaglandin D2 term: id: CHEBI:57406 label: prostaglandin D2(1-) evidence: - source_id: RHEA:10600 statement: prostaglandin H2 = prostaglandin D2. processes: - preferred_term: prostaglandin biosynthetic process term: id: GO:0001516 label: prostaglandin biosynthetic process locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Secreted lipocalin with a catalytic Cys65 that isomerises PGH2 without glutathione; the PGD2 source of the central nervous system (sleep regulation) and male genital tract. evidence: - source_id: PMID:20667974 statement: Human L-PGDS is a lipocalin-type enzyme of arachidonate metabolism. supporting_text: Human prostaglandin D synthase (L-PGDS) is a lipocalin-type enzyme involved in the metabolism of arachidonic acid - source_id: PMID:20667974 statement: Cys65 is the catalytic nucleophile. supporting_text: Met64 seems to function as a kinetic clamp, pushing the thiol group of Cys65 close to the site of nucleophilic attack during catalysis. - id: pgi2_synthesis label: Prostacyclin (PGI2) synthesis (PTGIS) module_type: REACTION annotons: - id: ptgis_pgi_synthase label: Prostacyclin synthase (PTGIS) prostaglandin-I synthase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTGIS (CYP8A1) term: id: UniProtKB:Q16647 label: Prostacyclin synthase function: preferred_term: prostaglandin-I synthase activity term: id: GO:0008116 label: prostaglandin-I synthase activity substrates: - preferred_term: prostaglandin H2 term: id: CHEBI:57405 label: prostaglandin H2(1-) products: - preferred_term: prostaglandin I2 (prostacyclin) term: id: CHEBI:57403 label: prostaglandin I2(1-) cofactors: - preferred_term: heme (cytochrome P450 thiolate haem) evidence: - source_id: RHEA:23580 statement: prostaglandin H2 = prostaglandin I2; the Rhea xref of GO:0008116. processes: - preferred_term: prostaglandin biosynthetic process term: id: GO:0001516 label: prostaglandin biosynthetic process locations: - preferred_term: endoplasmic reticulum membrane term: id: GO:0005789 label: endoplasmic reticulum membrane role_description: >- Atypical cytochrome P450 isomerase of endothelium and vascular smooth muscle; its product prostacyclin is vasodilatory and anti-aggregatory and opposes thromboxane A2. evidence: - source_id: PMID:15115769 statement: Purified recombinant human PGIS acts on PGH2 with defined kinetics. supporting_text: The K(m) and V(max) values of the purified human PGIS for PGH(2) were 30 microM and 15 micromol/min/mg of protein at 24 degrees C, respectively. - source_id: PMID:15115769 statement: Activity depends on the thiolate-ligated haem. supporting_text: A Cys441His mutant of the enzyme possessed no heme-binding ability or enzyme activity. - id: txa2_synthesis label: Thromboxane A2 synthesis (TBXAS1) module_type: REACTION annotons: - id: tbxas1_txa_synthase label: Thromboxane synthase (TBXAS1) thromboxane-A synthase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TBXAS1 (CYP5A1) term: id: UniProtKB:P24557 label: Thromboxane-A synthase function: preferred_term: thromboxane-A synthase activity term: id: GO:0004796 label: thromboxane-A synthase activity substrates: - preferred_term: prostaglandin H2 term: id: CHEBI:57405 label: prostaglandin H2(1-) products: - preferred_term: thromboxane A2 term: id: CHEBI:57445 label: thromboxane A2(1-) cofactors: - preferred_term: heme (cytochrome P450 thiolate haem) evidence: - source_id: RHEA:17137 statement: prostaglandin H2 = thromboxane A2; the Rhea xref of GO:0004796. - source_id: RHEA:48644 statement: >- Parallel fragmentation of PGH2 to 12(S)-HHTrE (CHEBI:90694) and malonaldehyde (CHEBI:566274), formed in a 1:1:1 ratio with TXA2; recorded but not modelled as a separate step. processes: - preferred_term: prostaglandin biosynthetic process term: id: GO:0001516 label: prostaglandin biosynthetic process locations: - preferred_term: endoplasmic reticulum membrane term: id: GO:0005789 label: endoplasmic reticulum membrane role_description: >- Atypical cytochrome P450 isomerase of platelets and macrophages that needs no external electron donor or O2; TXA2 drives platelet aggregation and vasoconstriction. evidence: - source_id: PMID:8436233 statement: Recombinant human thromboxane synthase converts PGH2 to TXA2 and HHT. supporting_text: The recombinant TX synthase catalyzed the conversion of prostaglandin (PG) H2 to TXA2 and 12-hydroxy-heptadecatrienoic acid (HHT). - source_id: PMID:11297515 statement: >- Thromboxane synthase isomerises or fragments PGH2 without an external electron donor, reductase or O2. supporting_text: Without any need for an external electron donor, or for a reductase or molecular oxygen, it uses prostaglandin H2 (PGH2) to catalyze either an isomerization reaction to form thromboxane A2 (TXA2) or a fragmentation reaction - id: pgf2alpha_synthesis label: PGF2alpha synthesis (prostaglandin reductases) module_type: METABOLIC_PATHWAY description: >- PGF2alpha-type products are formed by reduction. PGH2 can be reduced directly at the endoperoxide, PGE2 at its 9-keto group, or PGD2 at its 11-keto group, the last giving the 11beta stereoisomer. variant_sets: - id: pgf_route label: PGF2alpha-forming reductase and substrate route axis: enzyme and substrate (PGH2, PGE2 or PGD2) selection: ONE_OR_MORE variants: - id: akr1c3_pgh2_reduction label: AKR1C3 reduction of PGH2 to PGF2alpha module_type: REACTION annotons: - id: akr1c3_pgh2_reductase label: AKR1C3 prostaglandin H2 endoperoxidase reductase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AKR1C3 (lung-type PGF synthase) term: id: UniProtKB:P42330 label: Aldo-keto reductase family 1 member C3 function: preferred_term: prostaglandin H2 endoperoxidase reductase activity term: id: GO:0036130 label: prostaglandin H2 endoperoxidase reductase activity substrates: - preferred_term: prostaglandin H2 term: id: CHEBI:57405 label: prostaglandin H2(1-) - preferred_term: NADPH term: id: CHEBI:57783 label: NADPH(4-) - preferred_term: H+ term: id: CHEBI:15378 label: hydron products: - preferred_term: prostaglandin F2alpha term: id: CHEBI:57404 label: prostaglandin F2alpha(1-) - preferred_term: NADP+ term: id: CHEBI:58349 label: NADP(3-) evidence: - source_id: RHEA:45312 statement: >- prostaglandin F2alpha + NADP(+) = prostaglandin H2 + NADPH + H(+), physiologically right-to-left; the Rhea xref of GO:0036130. processes: - preferred_term: prostaglandin metabolic process term: id: GO:0006693 label: prostaglandin metabolic process locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Multifunctional AKR (also a 17beta-hydroxysteroid dehydrogenase); its PGH2 reductase activity is low compared with AKR1B1 and with its own PGD2 11-ketoreductase activity. evidence: - source_id: PMID:15047184 statement: AKR1C3 reduces both PGH2 and PGD2. supporting_text: which also catalyzes the reduction of PGH(2) and PGD(2) to PGF(2alpha) and 9alpha,11beta-PGF(2), respectively - id: akr1b1_pgh2_reduction label: AKR1B1 reduction of PGH2 to PGF2alpha module_type: REACTION annotons: - id: akr1b1_pgh2_reductase label: AKR1B1 prostaglandin H2 endoperoxidase reductase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AKR1B1 (aldose reductase) term: id: UniProtKB:P15121 label: Aldo-keto reductase family 1 member B1 function: preferred_term: prostaglandin H2 endoperoxidase reductase activity term: id: GO:0036130 label: prostaglandin H2 endoperoxidase reductase activity substrates: - preferred_term: prostaglandin H2 term: id: CHEBI:57405 label: prostaglandin H2(1-) - preferred_term: NADPH term: id: CHEBI:57783 label: NADPH(4-) - preferred_term: H+ term: id: CHEBI:15378 label: hydron products: - preferred_term: prostaglandin F2alpha term: id: CHEBI:57404 label: prostaglandin F2alpha(1-) - preferred_term: NADP+ term: id: CHEBI:58349 label: NADP(3-) evidence: - source_id: RHEA:45312 statement: >- prostaglandin F2alpha + NADP(+) = prostaglandin H2 + NADPH + H(+). locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Aldose reductase with higher affinity and turnover for PGH2 than AKR1C3. Its GO process annotation for prostaglandin metabolism is IEA only, so no process is asserted here. evidence: - source_id: PMID:19010934 statement: >- Human AKR1B1 reduces PGH2 to PGF2alpha with NADPH, more efficiently than AKR1C3. supporting_text: catalyse the reduction of prostaglandin (PG) H(2), a common intermediate of various prostanoids, to form PGF(2alpha) in the presence of NADPH - id: prxl2b_pgh2_reduction label: PRXL2B (FAM213B) thioredoxin-dependent reduction of PGH2 to PGF2alpha module_type: REACTION annotons: - id: prxl2b_pgh2_reductase label: PRXL2B prostamide/prostaglandin F synthase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PRXL2B (FAM213B, prostamide/PGF synthase) term: id: UniProtKB:Q8TBF2 label: Prostamide/prostaglandin F synthase function: preferred_term: thioredoxin-dependent prostamide/prostaglandin F synthase activity (EC 1.11.1.20; no GO term) substrates: - preferred_term: prostaglandin H2 term: id: CHEBI:57405 label: prostaglandin H2(1-) - preferred_term: reduced thioredoxin ([thioredoxin]-dithiol) term: id: CHEBI:29950 label: L-cysteine residue products: - preferred_term: prostaglandin F2alpha term: id: CHEBI:57404 label: prostaglandin F2alpha(1-) - preferred_term: oxidised thioredoxin ([thioredoxin]-disulfide) term: id: CHEBI:50058 label: L-cystine residue evidence: - source_id: RHEA:28214 statement: >- prostaglandin H2 + [thioredoxin]-dithiol = prostaglandin F2alpha + [thioredoxin]-disulfide (EC 1.11.1.20); no GO molecular-function term carries this Rhea xref. locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Thioredoxin-like-superfamily enzyme with active-site Cys44, expressed mainly in brain and spinal cord, that also reduces prostamide H2 (the ethanolamide). Human activity is inferred from the mouse and swine enzymes. evidence: - source_id: PMID:18006499 statement: >- The purified and recombinant enzyme reduces PGH2 to PGF2alpha as well as prostamide H2. supporting_text: The enzyme expressed in Escherichia coli as well as the native enzyme catalyzed not only the reduction of prostamide H(2) to prostamide F(2alpha) but also that of PGH(2) to PGF(2alpha). - source_id: PMID:18006499 statement: >- PGE2 and PGD2 are not substrates, which argues against the PGD2-defined GO:0047017 that PRXL2B receives by IBA/ISS. supporting_text: Neither PGE(2) nor PGD(2) served as a substrate for this synthase. - source_id: PMID:18006499 statement: Reduced thioredoxin is the preferred reductant. supporting_text: reduced thioredoxin preferentially served as a reducing equivalent donor for this enzyme - id: cbr1_pge2_reduction label: CBR1 9-ketoreduction of PGE2 to PGF2alpha module_type: REACTION annotons: - id: cbr1_pge2_9_reductase label: CBR1 prostaglandin E2 9-reductase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CBR1 (carbonyl reductase 1) term: id: UniProtKB:P16152 label: Carbonyl reductase [NADPH] 1 function: preferred_term: prostaglandin E2 9-reductase activity term: id: GO:0050221 label: prostaglandin E2 9-reductase activity substrates: - preferred_term: prostaglandin E2 term: id: CHEBI:606564 label: prostaglandin E2(1-) - preferred_term: NADPH term: id: CHEBI:57783 label: NADPH(4-) - preferred_term: H+ term: id: CHEBI:15378 label: hydron products: - preferred_term: prostaglandin F2alpha term: id: CHEBI:57404 label: prostaglandin F2alpha(1-) - preferred_term: NADP+ term: id: CHEBI:58349 label: NADP(3-) evidence: - source_id: RHEA:24508 statement: >- prostaglandin F2alpha + NADP(+) = prostaglandin E2 + NADPH + H(+) (EC 1.1.1.189), physiologically right-to-left; the Rhea xref of GO:0050221. locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Broad-specificity short-chain dehydrogenase/reductase. Its conversion of PGE2 to PGF2alpha also lowers PGE2 levels, and CBR1 additionally 15-oxidises prostaglandins, so this is a minor, partly catabolic route. evidence: - source_id: PMID:17344335 statement: CBR1 reduces PGE2 to PGF2alpha with NADPH. supporting_text: For example, CBR1 converts the potent fever mediator prostaglandin E 2 (PGE 2 ) into the less active metabolite PGF 2 α - id: akr1c3_pgd2_reduction label: AKR1C3 11-ketoreduction of PGD2 to 11-epi-PGF2alpha module_type: REACTION annotons: - id: akr1c3_pgd2_11_ketoreductase label: AKR1C3 prostaglandin D2 11-ketoreductase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AKR1C3 (lung-type PGF synthase) term: id: UniProtKB:P42330 label: Aldo-keto reductase family 1 member C3 function: preferred_term: prostaglandin D2 11-ketoreductase activity term: id: GO:0036131 label: prostaglandin D2 11-ketoreductase activity substrates: - preferred_term: prostaglandin D2 term: id: CHEBI:57406 label: prostaglandin D2(1-) - preferred_term: NADPH term: id: CHEBI:57783 label: NADPH(4-) - preferred_term: H+ term: id: CHEBI:15378 label: hydron products: - preferred_term: 11-epi-prostaglandin F2alpha (9alpha,11beta-PGF2) term: id: CHEBI:85173 label: 11-epi-prostaglandin F2alpha(1-) - preferred_term: NADP+ term: id: CHEBI:58349 label: NADP(3-) evidence: - source_id: RHEA:45316 statement: >- prostaglandin D2 + NADPH + H(+) = 11beta-prostaglandin F2 + NADP(+); the Rhea xref of GO:0036131. processes: - preferred_term: prostaglandin metabolic process term: id: GO:0006693 label: prostaglandin metabolic process locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- AKR1C3's most efficient prostaglandin reaction. Its product is the 11beta epimer of PGF2alpha, which RGD draws as PGF2alpha. evidence: - source_id: PMID:10622721 statement: >- Human lung PGF synthase (AKR1C3) reduces PGD2 and PGH2, with highest efficiency for PGD2. supporting_text: The human PGFS catalyzed the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ), and the oxidation of 9alpha,11beta-PGF2 to PGD2. - source_id: PMID:15047184 statement: The PGD2 product is 9alpha,11beta-PGF2. supporting_text: which also catalyzes the reduction of PGH(2) and PGD(2) to PGF(2alpha) and 9alpha,11beta-PGF(2), respectively connections: - source: pge2_synthesis target: cbr1_pge2_reduction connection_type: PROVIDES_INPUT_FOR description: PGE2 made by the PGE synthases is the substrate of CBR1 9-ketoreduction. chaining_status: VERIFIED chaining_note: PGE2 (CHEBI:606564) is the product of RHEA:12893 and the substrate of RHEA:24508. - source: pgd2_synthesis target: akr1c3_pgd2_reduction connection_type: PROVIDES_INPUT_FOR description: PGD2 made by the PGD synthases is the substrate of AKR1C3 11-ketoreduction. chaining_status: VERIFIED chaining_note: PGD2 (CHEBI:57406) is the product of RHEA:10600 and the substrate of RHEA:45316. connections: - source: pgh2_formation target: terminal_prostanoid_synthesis connection_type: PROVIDES_INPUT_FOR description: >- PGH2 made by COX-1 or COX-2 is the shared substrate of every terminal synthase and of the PGH2-reducing PGF synthases. chaining_status: VERIFIED chaining_note: >- PGH2 (CHEBI:57405) is the product of RHEA:23728 and the substrate of RHEA:12893, RHEA:10600, RHEA:23580, RHEA:17137, RHEA:45312 and RHEA:28214.