ID   PGH1_RABIT              Reviewed;         606 AA.
AC   O97554;
DT   13-SEP-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1999, sequence version 1.
DT   27-MAR-2024, entry version 127.
DE   RecName: Full=Prostaglandin G/H synthase 1;
DE            EC=1.14.99.1 {ECO:0000250|UniProtKB:P23219};
DE   AltName: Full=Cyclooxygenase-1;
DE            Short=COX-1;
DE   AltName: Full=Prostaglandin H2 synthase 1;
DE            Short=PGH synthase 1;
DE            Short=PGHS-1;
DE            Short=PHS 1;
DE   AltName: Full=Prostaglandin-endoperoxide synthase 1;
DE   Flags: Precursor;
GN   Name=PTGS1; Synonyms=COX1;
OS   Oryctolagus cuniculus (Rabbit).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX   NCBI_TaxID=9986;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   STRAIN=New Zealand white;
RA   Guan Y., Zhang Y., Breyer R.M., Davis L., Redha R., Chang S., Breyer M.D.;
RT   "Intrarenal localization of cyclooxygenase-1 and -2 and their differential
RT   expression in acute hydronephrotic kidney.";
RL   Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases.
CC   -!- FUNCTION: Dual cyclooxygenase and peroxidase that plays an important
CC       role in the biosynthesis pathway of prostanoids, a class of C20
CC       oxylipins mainly derived from arachidonate ((5Z,8Z,11Z,14Z)-
CC       eicosatetraenoate, AA, C20:4(n-6)), with a particular role in the
CC       inflammatory response. The cyclooxygenase activity oxygenates AA to the
CC       hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase
CC       activity reduces PGG2 to the hydroxy endoperoxide prostaglandin H2
CC       (PGH2), the precursor of all 2-series prostaglandins and thromboxanes.
CC       This complex transformation is initiated by abstraction of hydrogen at
CC       carbon 13 (with S-stereochemistry), followed by insertion of molecular
CC       O2 to form the endoperoxide bridge between carbon 9 and 11 that defines
CC       prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase
CC       activity) yields a hydroperoxy group in PGG2 that is then reduced to
CC       PGH2 by two electrons. Involved in the constitutive production of
CC       prostanoids in particular in the stomach and platelets. In gastric
CC       epithelial cells, it is a key step in the generation of prostaglandins,
CC       such as prostaglandin E2 (PGE2), which plays an important role in
CC       cytoprotection. In platelets, it is involved in the generation of
CC       thromboxane A2 (TXA2), which promotes platelet activation and
CC       aggregation, vasoconstriction and proliferation of vascular smooth
CC       muscle cells. Can also use linoleate (LA, (9Z,12Z)-octadecadienoate,
CC       C18:2(n-6)) as substrate and produce hydroxyoctadecadienoates (HODEs)
CC       in a regio- and stereospecific manner, being (9R)-HODE ((9R)-hydroxy-
CC       (10E,12Z)-octadecadienoate) and (13S)-HODE ((13S)-hydroxy-(9Z,11E)-
CC       octadecadienoate) its major products. {ECO:0000250|UniProtKB:P05979}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(5Z,8Z,11Z,14Z)-eicosatetraenoate + AH2 + 2 O2 = A + H2O +
CC         prostaglandin H2; Xref=Rhea:RHEA:23728, ChEBI:CHEBI:13193,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15379, ChEBI:CHEBI:17499,
CC         ChEBI:CHEBI:32395, ChEBI:CHEBI:57405; EC=1.14.99.1;
CC         Evidence={ECO:0000250|UniProtKB:P23219};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:23729;
CC         Evidence={ECO:0000250|UniProtKB:P23219};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(5Z,8Z,11Z,14Z)-eicosatetraenoate + 2 O2 = prostaglandin G2;
CC         Xref=Rhea:RHEA:42596, ChEBI:CHEBI:15379, ChEBI:CHEBI:32395,
CC         ChEBI:CHEBI:82629; Evidence={ECO:0000250|UniProtKB:P23219};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42597;
CC         Evidence={ECO:0000250|UniProtKB:P23219};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=AH2 + prostaglandin G2 = A + H2O + prostaglandin H2;
CC         Xref=Rhea:RHEA:42600, ChEBI:CHEBI:13193, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:17499, ChEBI:CHEBI:57405, ChEBI:CHEBI:82629;
CC         Evidence={ECO:0000250|UniProtKB:P23219};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42601;
CC         Evidence={ECO:0000250|UniProtKB:P23219};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(9Z,12Z)-octadecadienoate + AH2 + O2 = (9R)-hydroxy-(10E,12Z)-
CC         octadecadienoate + A + H2O; Xref=Rhea:RHEA:75447, ChEBI:CHEBI:13193,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15379, ChEBI:CHEBI:17499,
CC         ChEBI:CHEBI:30245, ChEBI:CHEBI:77895;
CC         Evidence={ECO:0000250|UniProtKB:P05979};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75448;
CC         Evidence={ECO:0000250|UniProtKB:P05979};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(9Z,12Z)-octadecadienoate + AH2 + O2 = (9S)-hydroxy-(10E,12Z)-
CC         octadecadienoate + A + H2O; Xref=Rhea:RHEA:75459, ChEBI:CHEBI:13193,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15379, ChEBI:CHEBI:17499,
CC         ChEBI:CHEBI:30245, ChEBI:CHEBI:77852;
CC         Evidence={ECO:0000250|UniProtKB:P05979};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75460;
CC         Evidence={ECO:0000250|UniProtKB:P05979};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(9Z,12Z)-octadecadienoate + AH2 + O2 = (13S)-hydroxy-(9Z,11E)-
CC         octadecadienoate + A + H2O; Xref=Rhea:RHEA:75451, ChEBI:CHEBI:13193,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15379, ChEBI:CHEBI:17499,
CC         ChEBI:CHEBI:30245, ChEBI:CHEBI:90850;
CC         Evidence={ECO:0000250|UniProtKB:P05979};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75452;
CC         Evidence={ECO:0000250|UniProtKB:P05979};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(9Z,12Z)-octadecadienoate + AH2 + O2 = (13R)-hydroxy-(9Z,11E)-
CC         octadecadienoate + A + H2O; Xref=Rhea:RHEA:75455, ChEBI:CHEBI:13193,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15379, ChEBI:CHEBI:17499,
CC         ChEBI:CHEBI:30245, ChEBI:CHEBI:136655;
CC         Evidence={ECO:0000250|UniProtKB:P05979};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75456;
CC         Evidence={ECO:0000250|UniProtKB:P05979};
CC   -!- COFACTOR:
CC       Name=heme b; Xref=ChEBI:CHEBI:60344; Evidence={ECO:0000250};
CC       Note=Binds 1 heme b (iron(II)-protoporphyrin IX) group per subunit.
CC       {ECO:0000250};
CC   -!- ACTIVITY REGULATION: The cyclooxygenase activity is inhibited by
CC       nonsteroidal anti-inflammatory drugs (NSAIDs) including ibuprofen,
CC       flurbiprofen, ketoprofen, naproxen, flurbiprofen, anirolac, fenclofenac
CC       and diclofenac. {ECO:0000250|UniProtKB:P23219}.
CC   -!- PATHWAY: Lipid metabolism; prostaglandin biosynthesis.
CC       {ECO:0000250|UniProtKB:P23219}.
CC   -!- SUBUNIT: Homodimer. {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Microsome membrane {ECO:0000250}; Peripheral
CC       membrane protein {ECO:0000250}. Endoplasmic reticulum membrane
CC       {ECO:0000250}; Peripheral membrane protein {ECO:0000250}.
CC   -!- MISCELLANEOUS: The conversion of arachidonate to prostaglandin H2 is a
CC       2 step reaction: a cyclooxygenase (COX) reaction which converts
CC       arachidonate to prostaglandin G2 (PGG2) and a peroxidase reaction in
CC       which PGG2 is reduced to prostaglandin H2 (PGH2). The cyclooxygenase
CC       reaction occurs in a hydrophobic channel in the core of the enzyme. The
CC       peroxidase reaction occurs at a heme-containing active site located
CC       near the protein surface. The nonsteroidal anti-inflammatory drugs
CC       (NSAIDs) binding site corresponds to the cyclooxygenase active site.
CC   -!- MISCELLANEOUS: Conversion of arachidonate to prostaglandin H2 is
CC       mediated by 2 different isozymes: the constitutive PTGS1 and the
CC       inducible PTGS2. PTGS1 is expressed constitutively and generally
CC       produces prostanoids acutely in response to hormonal stimuli to fine-
CC       tune physiological processes requiring instantaneous, continuous
CC       regulation (e.g. hemostasis). PTGS2 is inducible and typically produces
CC       prostanoids that mediate responses to physiological stresses such as
CC       infection and inflammation.
CC   -!- MISCELLANEOUS: PTGS1 and PTGS2 are the targets of nonsteroidal anti-
CC       inflammatory drugs (NSAIDs) including aspirin and ibuprofen. Aspirin is
CC       able to produce an irreversible inactivation of the enzyme through a
CC       serine acetylation. Inhibition of the PGHSs with NSAIDs acutely reduces
CC       inflammation, pain, and fever, and long-term use of these drugs reduces
CC       fatal thrombotic events, as well as the development of colon cancer and
CC       Alzheimer's disease. PTGS2 is the principal isozyme responsible for
CC       production of inflammatory prostaglandins. New generation PTGSs
CC       inhibitors strive to be selective for PTGS2, to avoid side effects such
CC       as gastrointestinal complications and ulceration.
CC   -!- SIMILARITY: Belongs to the prostaglandin G/H synthase family.
CC       {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; AF026008; AAD01796.1; -; mRNA.
DR   RefSeq; NP_001076150.1; NM_001082681.1.
DR   AlphaFoldDB; O97554; -.
DR   SMR; O97554; -.
DR   STRING; 9986.ENSOCUP00000031756; -.
DR   BindingDB; O97554; -.
DR   ChEMBL; CHEMBL3334; -.
DR   DrugCentral; O97554; -.
DR   PeroxiBase; 4131; OcuPGHS01.
DR   GlyCosmos; O97554; 4 sites, No reported glycans.
DR   PaxDb; 9986-ENSOCUP00000002186; -.
DR   GeneID; 100009407; -.
DR   KEGG; ocu:100009407; -.
DR   CTD; 5742; -.
DR   eggNOG; KOG2408; Eukaryota.
DR   InParanoid; O97554; -.
DR   OrthoDB; 1086441at2759; -.
DR   UniPathway; UPA00662; -.
DR   PRO; PR:O97554; -.
DR   Proteomes; UP000001811; Unplaced.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0051213; F:dioxygenase activity; IEA:UniProtKB-KW.
DR   GO; GO:0020037; F:heme binding; IEA:InterPro.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0004601; F:peroxidase activity; IEA:UniProtKB-KW.
DR   GO; GO:0004666; F:prostaglandin-endoperoxide synthase activity; IEA:UniProtKB-EC.
DR   GO; GO:0001516; P:prostaglandin biosynthetic process; IEA:UniProtKB-UniPathway.
DR   GO; GO:0006979; P:response to oxidative stress; IEA:InterPro.
DR   CDD; cd00054; EGF_CA; 1.
DR   CDD; cd09816; prostaglandin_endoperoxide_synthase; 1.
DR   Gene3D; 1.10.640.10; Haem peroxidase domain superfamily, animal type; 1.
DR   Gene3D; 2.10.25.10; Laminin; 1.
DR   InterPro; IPR000742; EGF-like_dom.
DR   InterPro; IPR019791; Haem_peroxidase_animal.
DR   InterPro; IPR010255; Haem_peroxidase_sf.
DR   InterPro; IPR037120; Haem_peroxidase_sf_animal.
DR   PANTHER; PTHR11903; PROSTAGLANDIN G/H SYNTHASE; 1.
DR   PANTHER; PTHR11903:SF6; PROSTAGLANDIN G_H SYNTHASE 1; 1.
DR   Pfam; PF03098; An_peroxidase; 1.
DR   PRINTS; PR00457; ANPEROXIDASE.
DR   SUPFAM; SSF57196; EGF/Laminin; 1.
DR   SUPFAM; SSF48113; Heme-dependent peroxidases; 1.
DR   PROSITE; PS50026; EGF_3; 1.
DR   PROSITE; PS50292; PEROXIDASE_3; 1.
PE   2: Evidence at transcript level;
KW   Dioxygenase; Disulfide bond; EGF-like domain; Endoplasmic reticulum;
KW   Fatty acid biosynthesis; Fatty acid metabolism; Glycoprotein; Heme; Iron;
KW   Lipid biosynthesis; Lipid metabolism; Membrane; Metal-binding; Microsome;
KW   Oxidoreductase; Peroxidase; Prostaglandin biosynthesis;
KW   Prostaglandin metabolism; Reference proteome; Signal.
FT   SIGNAL          1..30
FT                   /evidence="ECO:0000255"
FT   CHAIN           31..606
FT                   /note="Prostaglandin G/H synthase 1"
FT                   /id="PRO_0000041818"
FT   DOMAIN          38..76
FT                   /note="EGF-like"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT   ACT_SITE        213
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00298"
FT   ACT_SITE        391
FT                   /note="For cyclooxygenase activity"
FT                   /evidence="ECO:0000250"
FT   BINDING         394
FT                   /ligand="heme b"
FT                   /ligand_id="ChEBI:CHEBI:60344"
FT                   /ligand_part="Fe"
FT                   /ligand_part_id="ChEBI:CHEBI:18248"
FT                   /note="axial binding residue"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00298"
FT   SITE            536
FT                   /note="Aspirin-acetylated serine"
FT                   /evidence="ECO:0000250"
FT   CARBOHYD        74
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        110
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        150
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        416
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        42..53
FT                   /evidence="ECO:0000250"
FT   DISULFID        43..165
FT                   /evidence="ECO:0000250"
FT   DISULFID        47..63
FT                   /evidence="ECO:0000250"
FT   DISULFID        65..75
FT                   /evidence="ECO:0000250"
FT   DISULFID        575..581
FT                   /evidence="ECO:0000250"
SQ   SEQUENCE   606 AA;  69076 MW;  DB751FD1E2F1CD77 CRC64;
     MSRSSPSLRL PVLLLLLLLL LLPPPPPVLP ADPGAPAPVN PCCYFPCQHQ GVCVRVALDR
     YQCDCTRTGY SGPNCTVPDL WTWLRSSLRP SPTFVHYLLT HVRWFWEFVN ATFIRDTLMR
     LVLTVRSNLI PSPPTYNLDY DYISWEAFSN VSYYTRVLPS VPKDCPTPMG TKGKKQLPDA
     QVLAHRFLLR RTFIPDPQGT NLMFAFFAQH FTHQFFKTSG KMGPGFTKAL GHGVDLGHIY
     GDSLERQYHL RLFKDGKLKY QVLDGEVYPP SVEEAPVLMH YPRGVPPRSQ MAVGQEVFGL
     LPGLMLYATL WLREHNRVCD LLKAEHPTWD DEQLFQTTRL ILIGETIKIV IEEYVQQLSG
     YFLQLKFDPE MLFSVQFQYR NRIAMEFNHL YHWHPLMPDS FQVGSQEYSY EQFLFNTSML
     VDYGVEALVD AFSRQSAGRI GGGRNIDHHV LHVAVEVIKE SREMRLQPFN EYRKRFGLKP
     YASFQELTGE TEMAAELEEL YGDIDALEFY PGLLLEKCQP NSIFGESMIE IGAPFSLKGL
     LGNPICSPEY WKPSTFGGEV GSNLIKTATL KKLVCLNTKT CPYVSFRVPR SSGDDGPAAE
     RRSTEL
//