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P05979 (PGH1_SHEEP) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 135. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Prostaglandin G/H synthase 1

EC=1.14.99.1
Alternative name(s):
Cyclooxygenase-1
Short name=COX-1
Prostaglandin H2 synthase 1
Short name=PGH synthase 1
Short name=PGHS-1
Short name=PHS 1
Prostaglandin-endoperoxide synthase 1
Gene names
Name:PTGS1
Synonyms:COX1
OrganismOvis aries (Sheep) [Reference proteome]
Taxonomic identifier9940 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeCaprinaeOvis

Protein attributes

Sequence length600 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the generation of thromboxane A2 (TXA2), which promotes platelet activation and aggregation, vasoconstriction and proliferation of vascular smooth muscle cells. Ref.8

Catalytic activity

Arachidonate + AH2 + 2 O2 = prostaglandin H2 + A + H2O.

Cofactor

Binds 1 heme B (iron-protoporphyrin IX) group per subunit. Ref.5

Pathway

Lipid metabolism; prostaglandin biosynthesis.

Subunit structure

Homodimer.

Subcellular location

Endoplasmic reticulum membrane; Multi-pass membrane protein. Microsome membrane; Multi-pass membrane protein.

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.

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.

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.

Sequence similarities

Belongs to the prostaglandin G/H synthase family.

Contains 1 EGF-like domain.

Ontologies

Keywords
   Biological processFatty acid biosynthesis
Fatty acid metabolism
Lipid biosynthesis
Lipid metabolism
Prostaglandin biosynthesis
Prostaglandin metabolism
   Cellular componentEndoplasmic reticulum
Membrane
Microsome
   DomainEGF-like domain
Signal
Transmembrane
Transmembrane helix
   LigandHeme
Iron
Metal-binding
   Molecular functionDioxygenase
Oxidoreductase
Peroxidase
   PTMDisulfide bond
Glycoprotein
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processprostaglandin biosynthetic process

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of blood pressure

Inferred from sequence or structural similarity. Source: UniProtKB

response to oxidative stress

Inferred from electronic annotation. Source: InterPro

   Cellular_componentcytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

endoplasmic reticulum membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

integral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

intracellular membrane-bounded organelle

Inferred from sequence or structural similarity. Source: UniProtKB

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functiondioxygenase activity

Inferred from electronic annotation. Source: UniProtKB-KW

heme binding

Inferred from electronic annotation. Source: InterPro

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

peroxidase activity

Inferred from electronic annotation. Source: UniProtKB-KW

prostaglandin-endoperoxide synthase activity

Inferred from electronic annotation. Source: UniProtKB-EC

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2424
Chain25 – 600576Prostaglandin G/H synthase 1
PRO_0000023871

Regions

Transmembrane74 – 829Helical
Transmembrane86 – 927Helical
Transmembrane97 – 1059Helical
Transmembrane108 – 12215Helical
Domain32 – 7039EGF-like

Sites

Active site2071Proton acceptor
Active site3851For cyclooxygenase activity Ref.6
Metal binding3881Iron (heme axial ligand)
Site1041Not glycosylated
Site5301Aspirin-acetylated serine

Amino acid modifications

Glycosylation681N-linked (GlcNAc...) Ref.7
Glycosylation1441N-linked (GlcNAc...) Ref.7
Glycosylation4101N-linked (GlcNAc...) Ref.7
Disulfide bond36 ↔ 47
Disulfide bond37 ↔ 159
Disulfide bond41 ↔ 57
Disulfide bond59 ↔ 69
Disulfide bond569 ↔ 575

Natural variations

Natural variant971R → H.
Natural variant1641G → D.
Natural variant4561R → Q.
Natural variant5201E → K.
Natural variant5201E → Q.
Natural variant5251M → I.

Experimental info

Mutagenesis3851Y → F: Abolishes cyclooxygenase activity.
Sequence conflict1 – 33MSR → MV in AAA31511. Ref.3
Sequence conflict51S → G AA sequence Ref.2
Sequence conflict63 – 9028GYSGP…PSFIH → AIPAPTAPSRRYGPGSGRLC GPAPLSST in AAA31576. Ref.1
Sequence conflict921M → L in CAA68719. Ref.2
Sequence conflict921M → L in AAA31511. Ref.3
Sequence conflict1931G → S in CAA68719. Ref.2
Sequence conflict5401C → E AA sequence Ref.4

Secondary structure

............................................................................................................ 600
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P05979 [UniParc].

Last modified June 1, 1994. Version 2.
Checksum: 1B76E659BBA4353A

FASTA60068,791
        10         20         30         40         50         60 
MSRQSISLRF PLLLLLLSPS PVFSADPGAP APVNPCCYYP CQHQGICVRF GLDRYQCDCT 

        70         80         90        100        110        120 
RTGYSGPNCT IPEIWTWLRT TLRPSPSFIH FMLTHGRWLW DFVNATFIRD TLMRLVLTVR 

       130        140        150        160        170        180 
SNLIPSPPTY NIAHDYISWE SFSNVSYYTR ILPSVPRDCP TPMGTKGKKQ LPDAEFLSRR 

       190        200        210        220        230        240 
FLLRRKFIPD PQGTNLMFAF FAQHFTHQFF KTSGKMGPGF TKALGHGVDL GHIYGDNLER 

       250        260        270        280        290        300 
QYQLRLFKDG KLKYQMLNGE VYPPSVEEAP VLMHYPRGIP PQSQMAVGQE VFGLLPGLML 

       310        320        330        340        350        360 
YATIWLREHN RVCDLLKAEH PTWGDEQLFQ TARLILIGET IKIVIEEYVQ QLSGYFLQLK 

       370        380        390        400        410        420 
FDPELLFGAQ FQYRNRIAME FNQLYHWHPL MPDSFRVGPQ DYSYEQFLFN TSMLVDYGVE 

       430        440        450        460        470        480 
ALVDAFSRQP AGRIGGGRNI DHHILHVAVD VIKESRVLRL QPFNEYRKRF GMKPYTSFQE 

       490        500        510        520        530        540 
LTGEKEMAAE LEELYGDIDA LEFYPGLLLE KCHPNSIFGE SMIEMGAPFS LKGLLGNPIC 

       550        560        570        580        590        600 
SPEYWKASTF GGEVGFNLVK TATLKKLVCL NTKTCPYVSF HVPDPRQEDR PGVERPPTEL 

« Hide

References

[1]"Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence."
Dewitt D.L., Smith W.L.
Proc. Natl. Acad. Sci. U.S.A. 85:1412-1416(1988) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
Tissue: Seminal vesicle.
[2]"Primary structure of sheep prostaglandin endoperoxide synthase deduced from cDNA sequence."
Yokoyama C., Takai T., Tanabe T.
FEBS Lett. 231:347-351(1988) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
[3]"Isolation and characterization of the complementary DNA for sheep seminal vesicle prostaglandin endoperoxide synthase (cyclooxygenase)."
Merlie J., Fagan D., Mudd J., Needleman P.
J. Biol. Chem. 263:3550-3553(1988) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]"Isolation and covalent structure of the aspirin-modified, active-site region of prostaglandin synthetase."
Roth G.J., Machuga E.T., Ozols J.
Biochemistry 22:4672-4675(1983) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 523-544.
[5]"The aspirin and heme-binding sites of ovine and murine prostaglandin endoperoxide synthases."
Dewitt D.L., El-Harith E.A., Kraemer S.A., Andrews M.J., Yao E.F., Armstrong R.L., Smith W.L.
J. Biol. Chem. 265:5192-5198(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: HEME-BINDING SITE.
[6]"Tyrosine 385 of prostaglandin endoperoxide synthase is required for cyclooxygenase catalysis."
Shimokawa T., Kulmacz R.J., Dewitt D.L., Smith W.L.
J. Biol. Chem. 265:20073-20076(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: ACTIVE SITE TYR-385.
[7]"N-glycosylation of prostaglandin endoperoxide synthases-1 and -2 and their orientations in the endoplasmic reticulum."
Otto J.C., Dewitt D.L., Smith W.L.
J. Biol. Chem. 268:18234-18242(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION AT ASN-68; ASN-144 AND ASN-410, ABSENCE OF GLYCOSYLATION AT ASN-104.
[8]"Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition."
Marnett L.J., Rowlinson S.W., Goodwin D.C., Kalgutkar A.S., Lanzo C.A.
J. Biol. Chem. 274:22903-22906(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AND INHIBITION BY NSAIDS.
[9]"The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1."
Picot D., Loll P.J., Garavito R.M.
Nature 367:243-249(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.5 ANGSTROMS).
[10]"The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase."
Loll P.J., Picot D., Garavito R.M.
Nat. Struct. Biol. 2:637-643(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.4 ANGSTROMS).
[11]"Synthesis and use of iodinated antiinflammatory drug analogs as crystallographic probes of the prostaglandin H2 synthase cyclooxygenase active site."
Loll P.J., Picot D., Ekabo O., Garavito R.M.
Biochemistry 35:7330-7340(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.5 ANGSTROMS).
[12]"The productive conformation of arachidonic acid bound to prostaglandin synthase."
Malkowski M.G., Ginell S.L., Smith W.L., Garavito R.M.
Science 289:1933-1937(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS).
[13]"Mutational and X-ray crystallographic analysis of the interaction of dihomo-gamma-linolenic acid with prostaglandin endoperoxide H synthases."
Thuresson E.D., Malkowski M.G., Lakkides K.M., Rieke C.J., Mulichak A.M., Ginell S.L., Garavito R.M., Smith W.L.
J. Biol. Chem. 276:10358-10365(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS).
[14]"Structural analysis of NSAID binding by prostaglandin H2 synthase: time-dependent and time-independent inhibitors elicit identical enzyme conformations."
Selinsky B.S., Gupta K., Sharkey C.T., Loll P.J.
Biochemistry 40:5172-5180(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.61 ANGSTROMS).
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
J03599 mRNA. Translation: AAA31576.1.
Y00750 mRNA. Translation: CAA68719.1.
M18243 mRNA. Translation: AAA31511.1.
PIRA28960.
A29947.
S00561.
RefSeqNP_001009476.1. NM_001009476.1.
UniGeneOar.445.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1CQEX-ray3.10A/B21-600[»]
1DIYX-ray3.00A32-584[»]
1DJJmodel-A25-600[»]
1EBVX-ray3.20A33-583[»]
1EQGX-ray2.61A/B21-600[»]
1EQHX-ray2.70A/B21-600[»]
1FE2X-ray3.00A25-600[»]
1HT5X-ray2.75A/B33-583[»]
1HT8X-ray2.69A/B33-583[»]
1IGXX-ray3.10A25-600[»]
1IGZX-ray2.90A25-600[»]
1PGEX-ray3.50A/B25-600[»]
1PGFX-ray4.50A/B25-600[»]
1PGGX-ray4.50A/B25-600[»]
1PRHX-ray3.50A/B33-586[»]
1PTHX-ray3.40A/B25-600[»]
1Q4GX-ray2.00A/B32-584[»]
1U67X-ray3.10A1-600[»]
2AYLX-ray2.00A/B32-584[»]
2OYEX-ray2.85P1-600[»]
2OYUX-ray2.70P1-600[»]
3KK6X-ray2.75A/B32-584[»]
3N8VX-ray3.05A/B32-584[»]
3N8WX-ray2.75A/B32-584[»]
3N8XX-ray2.75A/B32-584[»]
3N8YX-ray2.60A/B32-584[»]
3N8ZX-ray2.90A/B32-584[»]
4O1ZX-ray2.40A/B32-600[»]
ProteinModelPortalP05979.
SMRP05979. Positions 32-584.
ModBaseSearch...
MobiDBSearch...

Chemistry

BindingDBP05979.
ChEMBLCHEMBL2949.

Protein family/group databases

PeroxiBase4121. OarPGHS01.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID443551.

Organism-specific databases

CTD5742.

Phylogenomic databases

HOVERGENHBG000366.

Enzyme and pathway databases

BRENDA1.14.99.1. 4472.
SABIO-RKP05979.
UniPathwayUPA00662.

Family and domain databases

Gene3D1.10.640.10. 1 hit.
InterProIPR000742. EG-like_dom.
IPR010255. Haem_peroxidase.
IPR002007. Haem_peroxidase_animal.
IPR019791. Haem_peroxidase_animal_subgr.
[Graphical view]
PfamPF03098. An_peroxidase. 1 hit.
[Graphical view]
PRINTSPR00457. ANPEROXIDASE.
SMARTSM00181. EGF. 1 hit.
[Graphical view]
SUPFAMSSF48113. SSF48113. 1 hit.
PROSITEPS50026. EGF_3. 1 hit.
PS50292. PEROXIDASE_3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP05979.

Entry information

Entry namePGH1_SHEEP
AccessionPrimary (citable) accession number: P05979
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1988
Last sequence update: June 1, 1994
Last modified: July 9, 2014
This is version 135 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways