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Prostaglandin G/H synthase 2 (EC 1.14.99.1) (Cyclooxygenase-2) (COX-2) (PHS II) (Prostaglandin H2 synthase 2) (PGH synthase 2) (PGHS-2) (Prostaglandin-endoperoxide synthase 2)

 PGH2_SHEEP              Reviewed;         603 AA.
P79208;
15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
01-MAY-1997, sequence version 1.
16-JAN-2019, entry version 138.
RecName: Full=Prostaglandin G/H synthase 2;
EC=1.14.99.1 {ECO:0000269|PubMed:10438452};
AltName: Full=Cyclooxygenase-2;
Short=COX-2;
AltName: Full=PHS II;
AltName: Full=Prostaglandin H2 synthase 2;
Short=PGH synthase 2;
Short=PGHS-2;
AltName: Full=Prostaglandin-endoperoxide synthase 2;
Flags: Precursor;
Name=PTGS2; Synonyms=COX2;
Ovis aries (Sheep).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Laurasiatheria; Cetartiodactyla; Ruminantia;
Pecora; Bovidae; Caprinae; Ovis.
NCBI_TaxID=9940;
[1]
NUCLEOTIDE SEQUENCE [MRNA].
PubMed=8878543; DOI=10.1006/bbrc.1996.1536;
Zhang V., O'Sullivan M., Hussain H., Roswit W.T., Holtzman M.J.;
"Molecular cloning, functional expression, and selective regulation of
ovine prostaglandin H synthase-2.";
Biochem. Biophys. Res. Commun. 227:499-506(1996).
[2]
PROTEIN SEQUENCE OF 17-52; 99-115; 183-196; 247-257; 286-306; 444-454;
473-485 AND 508-532.
TISSUE=Placenta;
PubMed=7503555; DOI=10.1006/abbi.1995.9934;
Johnson J.L., Wimsatt J., Buckel S.D., Dyer R.D., Maddipati K.R.;
"Purification and characterization of prostaglandin H synthase-2 from
sheep placental cotyledons.";
Arch. Biochem. Biophys. 324:26-34(1995).
[3]
FUNCTION, CATALYTIC ACTIVITY, AND INHIBITION BY NSAIDS.
PubMed=10438452; DOI=10.1074/jbc.274.33.22903;
Marnett L.J., Rowlinson S.W., Goodwin D.C., Kalgutkar A.S.,
Lanzo C.A.;
"Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of
catalysis and inhibition.";
J. Biol. Chem. 274:22903-22906(1999).
-!- FUNCTION: Converts arachidonate to prostaglandin H2 (PGH2), a
committed step in prostanoid synthesis (PubMed:10438452).
Constitutively expressed in some tissues in physiological
conditions, such as the endothelium, kidney and brain, and in
pathological conditions, such as in cancer. PTGS2 is responsible
for production of inflammatory prostaglandins. Up-regulation of
PTGS2 is also associated with increased cell adhesion, phenotypic
changes, resistance to apoptosis and tumor angiogenesis. In cancer
cells, PTGS2 is a key step in the production of prostaglandin E2
(PGE2), which plays important roles in modulating motility,
proliferation and resistance to apoptosis (By similarity).
{ECO:0000250|UniProtKB:Q05769, ECO:0000269|PubMed:10438452}.
-!- CATALYTIC ACTIVITY:
Reaction=(5Z,8Z,11Z,14Z)-eicosatetraenoate + AH2 + 2 O2 = A + H2O
+ prostaglandin H2; Xref=Rhea:RHEA:23728, ChEBI:CHEBI:13193,
ChEBI:CHEBI:15377, ChEBI:CHEBI:15379, ChEBI:CHEBI:17499,
ChEBI:CHEBI:32395, ChEBI:CHEBI:57405; EC=1.14.99.1;
Evidence={ECO:0000269|PubMed:10438452};
-!- COFACTOR:
Name=heme b; Xref=ChEBI:CHEBI:60344;
Evidence={ECO:0000250|UniProtKB:Q05769};
Note=Binds 1 heme b (iron(II)-protoporphyrin IX) group per
subunit. {ECO:0000250|UniProtKB:Q05769};
-!- PATHWAY: Lipid metabolism; prostaglandin biosynthesis.
{ECO:0000250|UniProtKB:P35354}.
-!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:Q05769}.
-!- SUBCELLULAR LOCATION: Microsome membrane; Peripheral membrane
protein. Endoplasmic reticulum membrane; Peripheral membrane
protein.
-!- PTM: S-nitrosylation by NOS2 (iNOS) activates enzyme activity. S-
nitrosylation may take place on different Cys residues in addition
to Cys-525 (By similarity). {ECO:0000250}.
-!- MISCELLANEOUS: The conversion of arachidonate to prostaglandin H2
is a 2 step reaction: a cyclooxygenase (COX) reaction which
converts arachidonate to prostaglandin G2 (PGG2) and a peroxidase
reaction in which PGG2 is reduced to prostaglandin H2 (PGH2). The
cyclooxygenase reaction occurs in a hydrophobic channel in the
core of the enzyme. The peroxidase reaction occurs at a heme-
containing active site located near the protein surface. The
nonsteroidal anti-inflammatory drugs (NSAIDs) binding site
corresponds to the cyclooxygenase active site.
-!- MISCELLANEOUS: Conversion of arachidonate to prostaglandin H2 is
mediated by 2 different isozymes: the constitutive PTGS1 and the
inducible PTGS2. PGHS1 is expressed constitutively and generally
produces prostanoids acutely in response to hormonal stimuli to
fine-tune physiological processes requiring instantaneous,
continuous regulation (e.g. hemostasis). PGHS2 is inducible and
typically produces prostanoids that mediate responses to
physiological stresses such as infection and inflammation.
-!- MISCELLANEOUS: PTGS1 and PTGS2 are the targets of nonsteroidal
anti-inflammatory drugs (NSAIDs) including aspirin and ibuprofen.
Aspirin is able to produce an irreversible inactivation of the
enzyme through a serine acetylation. Inhibition of the PGHSs with
NSAIDs acutely reduces inflammation, pain, and fever, and long-
term use of these drugs reduces fatal thrombotic events, as well
as the development of colon cancer and Alzheimer's disease. PTGS2
is the principal isozyme responsible for production of
inflammatory prostaglandins. New generation PTGSs inhibitors
strive to be selective for PTGS2, to avoid side effects such as
gastrointestinal complications and ulceration.
-!- SIMILARITY: Belongs to the prostaglandin G/H synthase family.
{ECO:0000305}.
-----------------------------------------------------------------------
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Distributed under the Creative Commons Attribution (CC BY 4.0) License
-----------------------------------------------------------------------
EMBL; U68486; AAC48684.1; -; mRNA.
PIR; JC5063; JC5063.
RefSeq; NP_001009432.1; NM_001009432.1.
UniGene; Oar.642; -.
ProteinModelPortal; P79208; -.
SMR; P79208; -.
BindingDB; P79208; -.
ChEMBL; CHEMBL4102; -.
PeroxiBase; 4122; OarPGHS02.
GeneID; 443460; -.
KEGG; oas:443460; -.
CTD; 5743; -.
HOVERGEN; HBG000366; -.
KO; K11987; -.
OrthoDB; 324380at2759; -.
BRENDA; 1.14.99.1; 2668.
SABIO-RK; P79208; -.
UniPathway; UPA00662; -.
PRO; PR:P79208; -.
Proteomes; UP000002356; Unplaced.
GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
GO; GO:0031090; C:organelle membrane; IEA:UniProtKB-SubCell.
GO; GO:0051213; F:dioxygenase activity; IEA:UniProtKB-KW.
GO; GO:0020037; F:heme binding; ISS:UniProtKB.
GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
GO; GO:0004601; F:peroxidase activity; IEA:UniProtKB-KW.
GO; GO:0004666; F:prostaglandin-endoperoxide synthase activity; ISS:UniProtKB.
GO; GO:0019371; P:cyclooxygenase pathway; ISS:UniProtKB.
GO; GO:0006954; P:inflammatory response; IEA:InterPro.
GO; GO:0001516; P:prostaglandin biosynthetic process; ISS:UniProtKB.
GO; GO:0008217; P:regulation of blood pressure; ISS:UniProtKB.
GO; GO:0006979; P:response to oxidative stress; IEA:InterPro.
Gene3D; 1.10.640.10; -; 1.
InterPro; IPR029576; COX-2.
InterPro; IPR000742; EGF-like_dom.
InterPro; IPR019791; Haem_peroxidase_animal.
InterPro; IPR010255; Haem_peroxidase_sf.
InterPro; IPR037120; Haem_peroxidase_sf_animal.
PANTHER; PTHR11903:SF8; PTHR11903:SF8; 1.
Pfam; PF03098; An_peroxidase; 1.
Pfam; PF00008; EGF; 1.
PRINTS; PR00457; ANPEROXIDASE.
SUPFAM; SSF48113; SSF48113; 1.
PROSITE; PS50026; EGF_3; 1.
PROSITE; PS50292; PEROXIDASE_3; 1.
1: Evidence at protein level;
Complete proteome; Dioxygenase; Direct protein sequencing;
Disulfide bond; Endoplasmic reticulum; Fatty acid biosynthesis;
Fatty acid metabolism; Glycoprotein; Heme; Iron; Lipid biosynthesis;
Lipid metabolism; Membrane; Metal-binding; Microsome; Oxidoreductase;
Peroxidase; Prostaglandin biosynthesis; Prostaglandin metabolism;
Reference proteome; S-nitrosylation; Signal.
SIGNAL 1 16 {ECO:0000269|PubMed:7503555}.
CHAIN 17 603 Prostaglandin G/H synthase 2.
/FTId=PRO_0000023880.
DOMAIN 17 54 EGF-like. {ECO:0000255|PROSITE-
ProRule:PRU00076}.
ACT_SITE 192 192 Proton acceptor. {ECO:0000255|PROSITE-
ProRule:PRU00298}.
ACT_SITE 370 370 For cyclooxygenase activity.
{ECO:0000250|UniProtKB:Q05769}.
METAL 373 373 Iron (heme axial ligand).
{ECO:0000255|PROSITE-ProRule:PRU00298}.
BINDING 105 105 Substrate.
{ECO:0000250|UniProtKB:Q05769}.
BINDING 340 340 Substrate.
{ECO:0000250|UniProtKB:Q05769}.
SITE 515 515 Aspirin-acetylated serine.
{ECO:0000250|UniProtKB:P35354}.
CARBOHYD 52 52 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 129 129 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 395 395 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 579 579 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
DISULFID 20 31 {ECO:0000250|UniProtKB:Q05769}.
DISULFID 21 144 {ECO:0000250|UniProtKB:Q05769}.
DISULFID 25 41 {ECO:0000250|UniProtKB:Q05769}.
DISULFID 43 53 {ECO:0000250|UniProtKB:Q05769}.
DISULFID 554 560 {ECO:0000250|UniProtKB:Q05769}.
CONFLICT 99 101 RYV -> GYK (in Ref. 2; AA sequence).
{ECO:0000305}.
CONFLICT 252 252 K -> KH (in Ref. 2; AA sequence).
{ECO:0000305}.
CONFLICT 256 256 V -> N (in Ref. 2; AA sequence).
{ECO:0000305}.
CONFLICT 520 520 Missing (in Ref. 2; AA sequence).
{ECO:0000305}.
CONFLICT 528 528 E -> A (in Ref. 2; AA sequence).
{ECO:0000305}.
SEQUENCE 603 AA; 68969 MW; E27F5E0549BB1C52 CRC64;
MLARALLLCA AVVCGAANPC CSHPCQNRGV CMSVGFDQYK CDCTRTGFYG ENCTTPEFLT
RIKLLLKPTP DTVHYILTHF KGVWNIVNKI SFLRNMIMRY VLTSRSHLIE SPPTYNVHYS
YKSWEAFSNL SYYTRALPPV PDDCPTPMGV KGRKELPDSK EVVKKVLLRR KFIPDPQGTN
LMFAFFAQHF THQFFKTDIE RGPAFTKGKN HGVDLSHVYG ESLERQHNRR LFKDGKMKYQ
MINGEMYPPT VKDTQVEMIY PPHIPEHLKF AVGQEVFGLV PGLMMYATIW LREHNRVCDV
LKQEHPEWGD EQLFQTSRLI LIGETIKIVI EDYVQHLSGY HFKLKFDPEL LFNQQFQYQN
RIAAEFNTLY HWHPLLPDVF QIDGQEYNYQ QFIYNNSVLL EHGVTQFVES FTRQIAGRVA
GRRNLPAAVE KVSKASLDQS REMKYQSFNE YRKRFLLKPY ESFEELTGEK EMAAELEALY
GDIDAMELYP ALLVEKPAPD AIFGETMVEA GAPFSLKGLM GNPICSPEYW KPSTFGGEVG
FKIINTASIQ SLICSNVKGC PFTSFSVQDA HLTKTVTINA SSSHSGLDDI NPTVLLKERS
TEL


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Pathways :
WP1403: AMPK signaling
WP1422: Sphingolipid Metabolism
WP1423: Ganglio Sphingolipid Metabolism
WP1424: Globo Sphingolipid Metabolism
WP1461: Photosynthetic Carbon Reduction
WP1621: Arginine and proline metabolism
WP1708: Terpenoid backbone biosynthesis
WP2199: Seed Development
WP2208: Cardiolipin Biosynthesis
WP2210: Oryzalexin S biosynthesis
WP2211: Geranylgeranyldiphosphate biosynthesis II (plastidic)
WP2248: anthocyanin biosynthesis
WP2340: Thiamine (vitamin B1) biosynthesis and salvage
WP2341: vitamin B1 (thiamin) biosynthesis and salvage pathway
WP296: TCA Cycle - biocyc
WP626: Abscisic Acid Biosynthesis
WP668: Octadecanoid Pathway
WP677: Momilactone biosynthesis
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[PTGES2 C9orf15 PGES2] Prostaglandin E synthase 2 (Membrane-associated prostaglandin E synthase-2) (mPGE synthase-2) (Microsomal prostaglandin E synthase 2) (mPGES-2) (Prostaglandin-H(2) E-isomerase) (EC 5.3.99.3) [Cleaved into: Prostaglandin E synthase 2 truncated form]
[HPGDS GSTS PGDS PTGDS2] Hematopoietic prostaglandin D synthase (H-PGDS) (EC 5.3.99.2) (GST class-sigma) (Glutathione S-transferase) (EC 2.5.1.18) (Glutathione-dependent PGD synthase) (Glutathione-requiring prostaglandin D synthase) (Prostaglandin-H2 D-isomerase)
[PTGDS PDS] Prostaglandin-H2 D-isomerase (EC 5.3.99.2) (Beta-trace protein) (Cerebrin-28) (Glutathione-independent PGD synthase) (Lipocalin-type prostaglandin-D synthase) (Prostaglandin-D2 synthase) (PGD2 synthase) (PGDS) (PGDS2)
[Hpgds Gsts Pgds Ptgds2] Hematopoietic prostaglandin D synthase (H-PGDS) (EC 5.3.99.2) (GST class-sigma) (Glutathione S-transferase) (EC 2.5.1.18) (Glutathione-dependent PGD synthase) (Glutathione-requiring prostaglandin D synthase) (Prostaglandin-H2 D-isomerase)
[] 9,11-endoperoxide prostaglandin H2 reductase (EC 1.1.1.-) (Prostaglandin F2-alpha synthase)
[HPGDS GSTS PGDS PTGDS2] Hematopoietic prostaglandin D synthase (H-PGDS) (EC 5.3.99.2) (GST class-sigma) (Glutathione S-transferase) (EC 2.5.1.18) (Glutathione-dependent PGD synthase) (Glutathione-requiring prostaglandin D synthase) (Prostaglandin-H2 D-isomerase)
[PTGES2 PGES2 QccE-11222] Prostaglandin E synthase 2 (EC 5.3.99.3) (Microsomal prostaglandin E synthase 2) (mPGES-2) [Cleaved into: Prostaglandin E synthase 2 truncated form]
[P100/11E] 9,11-endoperoxide prostaglandin H2 reductase (EC 1.1.1.-) (Prostaglandin F2-alpha synthase)
[PTGIS CYP8 CYP8A1] Prostacyclin synthase (EC 5.3.99.4) (Prostaglandin I2 synthase)
[AKR1C3 DDH1 HSD17B5 KIAA0119 PGFS] Aldo-keto reductase family 1 member C3 (EC 1.-.-.-) (17-beta-hydroxysteroid dehydrogenase type 5) (17-beta-HSD 5) (3-alpha-HSD type II, brain) (3-alpha-hydroxysteroid dehydrogenase type 2) (3-alpha-HSD type 2) (EC 1.1.1.357) (Chlordecone reductase homolog HAKRb) (Dihydrodiol dehydrogenase 3) (DD-3) (DD3) (Dihydrodiol dehydrogenase type I) (HA1753) (Indanol dehydrogenase) (EC 1.1.1.112) (Prostaglandin F synthase) (PGFS) (EC 1.1.1.188) (Testosterone 17-beta-dehydrogenase 5) (EC 1.1.1.239) (EC 1.1.1.64) (Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase) (EC 1.3.1.20)
[] Genome polyprotein [Cleaved into: Protein VP0 (VP4-VP2); Protein VP4 (P1A) (Virion protein 4); Capsid protein VP2 (P1B) (Virion protein 2); Capsid protein VP3 (P1C) (Virion protein 3); Protein VP1-2A (VPX); Capsid protein VP1 (P1D) (Virion protein 1); Assembly signal 2A (pX); Protein 2BC; Protein 2B (P2B); Protein 2C (P2C) (EC 3.6.1.15); Protein 3ABCD (P3); Protein 3ABC; Protein 3AB; Protein 3A (P3A); Viral protein genome-linked (VPg) (Protein 3B) (P3B); Protein 3CD; Protease 3C (P3C) (EC 3.4.22.28) (Picornain 3C); RNA-directed RNA polymerase 3D-POL (P3D-POL) (EC 2.7.7.48)]
[Ptgis Cyp8] Prostacyclin synthase (EC 5.3.99.4) (Prostaglandin I2 synthase)
[Prxl2b Fam213b] Prostamide/prostaglandin F synthase (Prostamide/PG F synthase) (Prostamide/PGF synthase) (EC 1.11.1.20) (Peroxiredoxin-like 2B)
[Ptgis Cyp8] Prostacyclin synthase (EC 5.3.99.4) (Prostaglandin I2 synthase)
[AKR1C3] Aldo-keto reductase family 1 member C3 homolog (EC 1.-.-.-) (17-beta-hydroxysteroid dehydrogenase type 5) (17-beta-HSD 5) (3-alpha-hydroxysteroid dehydrogenase type 2) (3-alpha-HSD type 2) (EC 1.1.1.357) (Indanol dehydrogenase) (EC 1.1.1.112) (Prostaglandin F synthase) (PGFS) (EC 1.1.1.188) (Testosterone 17-beta-dehydrogenase 5) (EC 1.1.1.239) (EC 1.1.1.64) (Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase) (EC 1.3.1.20)
[ptgis ptgisl] Prostacyclin synthase (EC 5.3.99.4) (Prostaglandin I2 synthase) (PGIS)
[PTGIS CYP8] Prostacyclin synthase (EC 5.3.99.4) (Prostaglandin I2 synthase)
[PRXL2B C1orf93 FAM213B] Prostamide/prostaglandin F synthase (Prostamide/PG F synthase) (Prostamide/PGF synthase) (EC 1.11.1.20) (Peroxiredoxin-like 2B) (Protein FAM213B)
[CBR1 CBR CRN SDR21C1] Carbonyl reductase [NADPH] 1 (EC 1.1.1.184) (15-hydroxyprostaglandin dehydrogenase [NADP(+)]) (EC 1.1.1.197) (NADPH-dependent carbonyl reductase 1) (Prostaglandin 9-ketoreductase) (Prostaglandin-E(2) 9-reductase) (EC 1.1.1.189) (Short chain dehydrogenase/reductase family 21C member 1)
[Nos2 Inosl] Nitric oxide synthase, inducible (EC 1.14.13.39) (Inducible NO synthase) (Inducible NOS) (iNOS) (Macrophage NOS) (MAC-NOS) (NOS type II) (Peptidyl-cysteine S-nitrosylase NOS2)
[env] Envelope glycoprotein gp160 (Env polyprotein) [Cleaved into: Surface protein gp120 (SU) (Glycoprotein 120) (gp120); Transmembrane protein gp41 (TM) (Glycoprotein 41) (gp41)]
[PRXL2B FAM213B] Prostamide/prostaglandin F synthase (Prostamide/PG F synthase) (Prostamide/PGF synthase) (EC 1.11.1.20) (Peroxiredoxin-like 2B)
[gag-pol] Gag-Pol polyprotein (Pr160Gag-Pol) [Cleaved into: Matrix protein p17 (MA); Capsid protein p24 (CA); Spacer peptide 1 (SP1) (p2); Nucleocapsid protein p7 (NC); Transframe peptide (TF); p6-pol (p6*); Protease (EC 3.4.23.16) (PR) (Retropepsin); Reverse transcriptase/ribonuclease H (EC 2.7.7.49) (EC 2.7.7.7) (EC 3.1.26.13) (Exoribonuclease H) (EC 3.1.13.2) (p66 RT); p51 RT; p15; Integrase (IN) (EC 2.7.7.-) (EC 3.1.-.-)]
[TK UL23] Thymidine kinase (EC 2.7.1.21)
[Pre C,C C core E PC pre-C pre-C/C PreC preC PreC/C preC/C precore-core HBVgp4] Capsid protein (Core antigen) (Core protein) (HBcAg) (p21.5)
[TBXAS1 CYP5 CYP5A1] Thromboxane-A synthase (TXA synthase) (TXS) (EC 5.3.99.5) (Cytochrome P450 5A1)
[Cbr1 Cbr] Carbonyl reductase [NADPH] 1 (EC 1.1.1.184) (15-hydroxyprostaglandin dehydrogenase [NADP(+)]) (EC 1.1.1.197) (NADPH-dependent carbonyl reductase 1) (Prostaglandin 9-ketoreductase) (Prostaglandin-E(2) 9-reductase) (EC 1.1.1.189)
[fpoF MM_0627] F(420)H(2) dehydrogenase subunit F (EC 1.12.98.3) (EC 1.5.7.2) (Coenzyme F420 oxidoreductase (ferredoxin)) (F(420)H(2)-dependent phenazine dehydrogenase subunit F) (F(420)H(2)-dependent phenazine oxidoreductase subunit F) (FPO subunit F) (Methanophenazine hydrogenase subunit F) (Methanosarcina-phenazine hydrogenase subunit F)
[H2afz H2az] Histone H2A.Z (H2A/z)
[env] Envelope glycoprotein gp160 (Env polyprotein) [Cleaved into: Surface protein gp120 (SU) (Glycoprotein 120) (gp120); Transmembrane protein gp41 (TM) (Glycoprotein 41) (gp41)]

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