P05979 (PGH1_SHEEP) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Ovis aries (Sheep)

Taxonomic identifier

9940 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Laurasiatheria › Cetartiodactyla › Ruminantia › Pecora › Bovidae › Caprinae › Ovis

Protein attributes

Sequence length	600 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	May play an important role in regulating or promoting cell proliferation in some normal and neoplastically transformed cells.
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	This enzyme acts both as a dioxygenase and as a peroxidase. This enzyme is the target of nonsteroidal anti-inflammatory drugs such as aspirin.
Sequence similarities	Belongs to the prostaglandin G/H synthase family. Contains 1 EGF-like domain.

Ontologies

Keywords
Biological process	Fatty acid biosynthesis Fatty acid metabolism Lipid biosynthesis Lipid metabolism Prostaglandin biosynthesis Prostaglandin metabolism
Cellular component	Endoplasmic reticulum Membrane Microsome
Domain	EGF-like domain Signal Transmembrane Transmembrane helix
Ligand	Heme Iron Metal-binding
Molecular function	Dioxygenase Oxidoreductase Peroxidase
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological_process	prostaglandin 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_component	cytoplasm Inferred from sequence or structural similarity. Source: UniProtKB endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	heme binding Inferred from electronic annotation. Source: InterPro metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen 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: EC
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 24

24

Chain

25 – 600

576

Prostaglandin G/H synthase 1

PRO_0000023871

Regions

Transmembrane

74 – 82

9

Helical

Transmembrane

86 – 92

7

Helical

Transmembrane

97 – 105

9

Helical

Transmembrane

108 – 122

15

Helical

Domain

32 – 70

39

EGF-like

Sites

Active site

207

1

Proton acceptor

Active site

385

1

For cyclooxygenase activity Ref.6

Metal binding

388

1

Iron (heme axial ligand)

Site

104

1

Not glycosylated

Site

530

1

Aspirin-acetylated serine

Amino acid modifications

Glycosylation

68

1

N-linked (GlcNAc...) Ref.7

Glycosylation

144

1

N-linked (GlcNAc...) Ref.7

Glycosylation

410

1

N-linked (GlcNAc...) Ref.7

Disulfide bond

36 ↔ 47

Disulfide bond

37 ↔ 159

Disulfide bond

41 ↔ 57

Disulfide bond

59 ↔ 69

Disulfide bond

569 ↔ 575

Natural variations

Natural variant

97

1

R → H.

Natural variant

164

1

G → D.

Natural variant

456

1

R → Q.

Natural variant

520

1

E → K.

Natural variant

520

1

E → Q.

Natural variant

525

1

M → I.

Experimental info

Mutagenesis

385

1

Y → F: Abolishes cyclooxygenase activity.

Sequence conflict

1 – 3

3

MSR → MV in AAA31511. Ref.3

Sequence conflict

5

1

S → G AA sequence Ref.2

Sequence conflict

63 – 90

28

GYSGP…PSFIH → AIPAPTAPSRRYGPGSGRLC GPAPLSST in AAA31576. Ref.1

Sequence conflict

92

1

M → L in CAA68719. Ref.2

Sequence conflict

92

1

M → L in AAA31511. Ref.3

Sequence conflict

193

1

G → S in CAA68719. Ref.2

Sequence conflict

540

1

C → E AA sequence Ref.4

Secondary structure

1

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600

Helix Strand Turn

Details...

Helix

35 – 38

4

Beta strand

46 – 50

5

Turn

51 – 53

3

Beta strand

54 – 58

5

Beta strand

62 – 65

4

Turn

66 – 69

4

Helix

74 – 82

9

Helix

86 – 93

8

Helix

97 – 103

7

Helix

108 – 121

14

Beta strand

130 – 133

4

Beta strand

134 – 136

3

Helix

139 – 143

5

Beta strand

149 – 152

4

Beta strand

159 – 161

3

Beta strand

164 – 167

4

Helix

174 – 181

8

Helix

196 – 206

11

Turn

207 – 209

3

Turn

214 – 216

3

Beta strand

220 – 222

3

Beta strand

227 – 229

3

Helix

231 – 234

4

Helix

238 – 244

7

Beta strand

255 – 257

3

Beta strand

260 – 262

3

Turn

266 – 268

3

Helix

281 – 283

3

Beta strand

288 – 291

4

Helix

292 – 294

3

Helix

296 – 319

24

Helix

325 – 346

22

Helix

348 – 353

6

Helix

363 – 366

4

Beta strand

367 – 369

3

Helix

379 – 384

6

Helix

388 – 390

3

Beta strand

393 – 397

5

Beta strand

400 – 402

3

Helix

404 – 407

4

Helix

413 – 417

5

Helix

419 – 428

10

Beta strand

434 – 438

5

Turn

442 – 444

3

Helix

445 – 457

13

Helix

463 – 469

7

Helix

478 – 482

5

Beta strand

483 – 485

3

Helix

486 – 495

10

Helix

498 – 500

3

Helix

503 – 509

7

Beta strand

517 – 519

3

Helix

520 – 535

16

Helix

538 – 540

3

Turn

542 – 544

3

Helix

547 – 550

4

Helix

553 – 560

8

Helix

564 – 569

6

Beta strand

572 – 574

3

Sequences

	Sequence		Length	Mass (Da)
	P05979 [UniParc]. Last modified June 1, 1994. Version 2. Checksum: 1B76E659BBA4353A	FASTA	600	68,791
	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

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]	"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).
[9]	"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).
[10]	"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).
[11]	"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).
[12]	"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).
[13]	"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.

PIR

A28960.
A29947.
S00561.

RefSeq

NP_001009476.1. NM_001009476.1.

UniGene

Oar.445.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1CQE	X-ray	3.10	A/B	21-600	[»]
1DIY	X-ray	3.00	A	32-584	[»]
1DJJ	model	-	A	25-600	[»]
1EBV	X-ray	3.20	A	33-583	[»]
1EQG	X-ray	2.61	A/B	21-600	[»]
1EQH	X-ray	2.70	A/B	21-600	[»]
1FE2	X-ray	3.00	A	25-600	[»]
1HT5	X-ray	2.75	A/B	33-583	[»]
1HT8	X-ray	2.69	A/B	33-583	[»]
1IGX	X-ray	3.10	A	25-600	[»]
1IGZ	X-ray	2.90	A	25-600	[»]
1PGE	X-ray	3.50	A/B	25-600	[»]
1PGF	X-ray	4.50	A/B	25-600	[»]
1PGG	X-ray	4.50	A/B	25-600	[»]
1PRH	X-ray	3.50	A/B	33-586	[»]
1PTH	X-ray	3.40	A/B	25-600	[»]
1Q4G	X-ray	2.00	A/B	32-584	[»]
1U67	X-ray	3.10	A	1-600	[»]
2AYL	X-ray	2.00	A/B	32-584	[»]
2OYE	X-ray	2.85	P	1-600	[»]
2OYU	X-ray	2.70	P	1-600	[»]
3KK6	X-ray	2.75	A/B	32-584	[»]
3N8V	X-ray	3.05	A/B	32-584	[»]
3N8W	X-ray	2.75	A/B	32-584	[»]
3N8X	X-ray	2.75	A/B	32-584	[»]
3N8Y	X-ray	2.60	A/B	32-584	[»]
3N8Z	X-ray	2.90	A/B	32-584	[»]

ProteinModelPortal

P05979.

SMR

P05979. Positions 32-584.

ModBase

Search...

Protein family/group databases

PeroxiBase

4121. OarPGHS01.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

GeneID

443551.

Organism-specific databases

CTD

5742.

Phylogenomic databases

HOVERGEN

HBG000366.

Enzyme and pathway databases

BRENDA

1.14.99.1. 4472.

SABIO-RK

P05979.

UniPathway

UPA00662.

Family and domain databases

Gene3D

1.10.640.10. 1 hit.

InterPro

IPR000742. EG-like_dom.
IPR010255. Haem_peroxidase.
IPR002007. Haem_peroxidase_animal.
IPR019791. Haem_peroxidase_animal_subgr.
[Graphical view]

Pfam

PF03098. An_peroxidase. 1 hit.
[Graphical view]

PRINTS

PR00457. ANPEROXIDASE.

SMART

SM00181. EGF. 1 hit.
[Graphical view]

SUPFAM

SSF48113. Peroxidase_super. 1 hit.

PROSITE

PS00022. EGF_1. False negative.
PS01186. EGF_2. False negative.
PS50026. EGF_3. 1 hit.
PS50292. PEROXIDASE_3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P05979.

ChEMBL

CHEMBL2949.

EvolutionaryTrace

P05979.

Entry information

Entry name

PGH1_SHEEP

Accession

Primary (citable) accession number: P05979

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1988
Last sequence update:	June 1, 1994
Last modified:	April 3, 2013
This is version 128 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program