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{{Infobox_gene}}
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{{redirect|COX-1|mitochondrial cytochrome c oxidase subunit 1 (cox1)|MT-CO1}}
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'''Cyclooxygenase 1''' (COX-1), also known as '''prostaglandin G/H synthase 1''', '''prostaglandin-endoperoxide synthase 1''' or '''prostaglandin H2 synthase 1''', is an [[enzyme]] that in humans is encoded by the ''PTGS1'' [[gene]].<ref name="pmid2512924">{{cite journal | vauthors = Yokoyama C, Tanabe T | title = Cloning of human gene encoding prostaglandin endoperoxide synthase and primary structure of the enzyme | journal = Biochemical and Biophysical Research Communications | volume = 165 | issue = 2 | pages = 888–94 | date = December 1989 | pmid = 2512924 | doi = 10.1016/S0006-291X(89)80049-X }}</ref><ref name="pmid1907252">{{cite journal | vauthors = Funk CD, Funk LB, Kennedy ME, Pong AS, Fitzgerald GA | title = Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment | journal = FASEB Journal | volume = 5 | issue = 9 | pages = 2304–12 | date = June 1991 | pmid = 1907252 | doi = }}</ref> In humans it is one of two [[cyclooxygenase]]s.
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== History ==
{{GNF_Protein_box
Cyclooxygenase (COX) is the central enzyme in the biosynthetic pathway to prostaglandins from [[arachidonic acid]]. This protein was isolated more than 40 years ago and [[Clone (genetics)|cloned]] in 1988.<ref name="pmid12973429">{{cite journal | vauthors = Bakhle YS | title = Structure of COX-1 and COX-2 enzymes and their interaction with inhibitors | journal = Drugs of Today | volume = 35 | issue = 4-5 | pages = 237–50 | year = 1999 | pmid = 12973429 | doi =  10.1358/dot.1999.35.4-5.552200}}</ref><ref name="pmid9773924">{{cite journal | vauthors = Sakamoto C | title = Roles of COX-1 and COX-2 in gastrointestinal pathophysiology | journal = Journal of Gastroenterology | volume = 33 | issue = 5 | pages = 618–24 | date = October 1998 | pmid = 9773924 | doi = 10.1007/s005350050147 }}</ref>
| image = PBB_Protein_PTGS1_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1cqe.
| PDB = {{PDB2|1cqe}}, {{PDB2|1diy}}, {{PDB2|1ebv}}, {{PDB2|1eqg}}, {{PDB2|1eqh}}, {{PDB2|1fe2}}, {{PDB2|1ht5}}, {{PDB2|1ht8}}, {{PDB2|1igx}}, {{PDB2|1igz}}, {{PDB2|1pge}}, {{PDB2|1pgf}}, {{PDB2|1pgg}}, {{PDB2|1prh}}, {{PDB2|1pth}}, {{PDB2|1q4g}}, {{PDB2|1u67}}, {{PDB2|2ayl}}
| Name = Prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)
| HGNCid = 9604
| Symbol = PTGS1
| AltSymbols =; COX1; COX3; PCOX1; PGG/HS; PGHS-1; PGHS1; PHS1; PTGHS
| OMIM = 176805
| ECnumber =
| Homologene = 743
| MGIid = 97797
  | GeneAtlas_image1 = PBB_GE_PTGS1_215813_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_PTGS1_205127_at_tn.png
| GeneAtlas_image3 = PBB_GE_PTGS1_205128_x_at_tn.png
| Function = {{GNF_GO|id=GO:0004601 |text = peroxidase activity}} {{GNF_GO|id=GO:0004666 |text = prostaglandin-endoperoxide synthase activity}} {{GNF_GO|id=GO:0005506 |text = iron ion binding}} {{GNF_GO|id=GO:0016491 |text = oxidoreductase activity}} {{GNF_GO|id=GO:0016702 |text = oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005792 |text = microsome}} {{GNF_GO|id=GO:0016020 |text = membrane}}
| Process = {{GNF_GO|id=GO:0001516 |text = prostaglandin biosynthetic process}} {{GNF_GO|id=GO:0006629 |text = lipid metabolic process}} {{GNF_GO|id=GO:0006633 |text = fatty acid biosynthetic process}} {{GNF_GO|id=GO:0008217 |text = blood pressure regulation}} {{GNF_GO|id=GO:0030216 |text = keratinocyte differentiation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5742
    | Hs_Ensembl = ENSG00000095303
    | Hs_RefseqProtein = NP_000953
    | Hs_RefseqmRNA = NM_000962
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 9
    | Hs_GenLoc_start = 124173050
    | Hs_GenLoc_end = 124197802
    | Hs_Uniprot = P23219
    | Mm_EntrezGene = 19224
    | Mm_Ensembl = ENSMUSG00000047250
    | Mm_RefseqmRNA = NM_008969
    | Mm_RefseqProtein = NP_032995
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 2
    | Mm_GenLoc_start = 36052509
    | Mm_GenLoc_end = 36074278
    | Mm_Uniprot = Q3TJN9
  }}
}}
'''Prostaglandin-endoperoxide synthase 1''' (also known as '''prostaglandin H2 synthase 1''', '''cyclooxygenase-1''', and '''COX-1'''), gene name '''PTGS1''', is a human protein.


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== Gene and isozymes ==
{{PBB_Summary
There are two [[isozymes]] of COX encoded by distinct gene products: a constitutive COX-1 (this enzyme) and an inducible [[COX-2]], which differ in their regulation of expression and tissue distribution. The expression of these two transcripts is differentially regulated by relevant [[cytokine]]s and [[growth factor]]s.<ref>{{cite web |title=Entrez Gene: PTGS1 prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase) |url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5742 |accessdate=}}</ref> This gene encodes COX-1, which regulates [[angiogenesis]] in [[endothelial]] cells. COX-1 is also involved in [[cell signaling]] and maintaining tissue [[Homeostasis#Biological|homeostasis]]. A splice variant of COX-1 termed [[COX-3]] was identified in the CNS of dogs, but does not result in a functional protein in humans. Two smaller COX-1-derived proteins (the partial COX-1 proteins PCOX-1A and PCOX-1B) have also been discovered, but their precise roles are yet to be described.<ref name="CDRETES1">{{cite journal | vauthors = Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL | title = COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 21 | pages = 13926–31 | date = October 2002 | pmid = 12242329 | pmc = 129799 | doi = 10.1073/pnas.162468699 }}</ref>
| section_title =  
| summary_text = [[Prostaglandin]]-endoperoxide [[synthase]] (PTGS), also known as [[cyclooxygenase]], is the key enzyme in prostaglandin biosynthesis, and acts both as a [[dioxygenase]] and as a [[peroxidase]]. There are two [[isozymes]] of PTGS: a constitutive PTGS1 and an inducible PTGS2, which differ in their regulation of expression and tissue distribution. This gene encodes PTGS1, which regulates [[angiogenesis]] in [[endothelial]] cells, and is inhibited by nonsteroidal anti-inflammatory drugs such as [[aspirin]]. Recent research has shown that the inhibition of COX-1 is the main reason why [[aspirin]] is effective at reducing cardiac events (as opposed to [[aspirin]]'s anti-platelet aggregation effects).  PTGS1 is thought to be involved in cell-cell signaling and maintaining tissue homeostasis. [[Alternative splicing]] of this gene generates two transcript variants called COX-1 and COX-3. The expression of these two transcripts is differentially regulated by relevant [[cytokine]]s and [[growth factor]]s.<ref>{{cite web | title = Entrez Gene: PTGS1 prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5742| accessdate = }}</ref>
}}


==See also==
== Function ==
[[Prostaglandin]]-endoperoxide [[synthase]] (PTGS), also known as [[cyclooxygenase]] (COX), is the key enzyme in prostaglandin biosynthesis. It converts free arachidonic acid, released from membrane phospholipids at the sn-2 ester binding site by the enzymatic activity of phospholipase A2, to prostaglandin (PG) H2. The reaction involves both cyclooxygenase ([[dioxygenase]]) and hydroperoxidase ([[peroxidase]]) activity. The cyclooxygenase activity incorporates two oxygen molecules into arachidonic acid or alternate polyunsaturated fatty acid substrates, such as [[linoleic acid]] and [[eicosapentaenoic acid]]. Metabolism of [[arachidonic acid]] forms a labile intermediate peroxide, [[PGG2]], which is reduced to the corresponding alcohol, PGH2, by the enzyme’s hydroperoxidase activity.
 
While metabolizing arachidonic acid primarily to PGG2, COX-1 also converts this fatty acid to small amounts of a racemic mixture of [[15-Hydroxyicosatetraenoic acid]]s (i.e., 15-HETEs) composed of ~22% 15(''R'')-HETE and ~78% 15(''S'')-HETE [[stereoisomers]] as well as a small amount of 11(''R'')-HETE.<ref>{{cite journal | vauthors = Mulugeta S, Suzuki T, Hernandez NT, Griesser M, Boeglin WE, Schneider C | title = Identification and absolute configuration of dihydroxy-arachidonic acids formed by oxygenation of 5S-HETE by native and aspirin-acetylated COX-2 | journal = Journal of Lipid Research | volume = 51 | issue = 3 | pages = 575–85 | date = March 2010 | pmid = 19752399 | pmc = 2817587 | doi = 10.1194/jlr.M001719 }}</ref> The two 15-HETE stereoisomers have intrinsic biological activities but, perhaps more importantly, can be further metabolized to a major class of anti-inflammatory agents, the [[lipoxins]].<ref>{{cite journal | vauthors = Serhan CN | title = Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution | journal = Prostaglandins, Leukotrienes, and Essential Fatty Acids | volume = 73 | issue = 3-4 | pages = 141–62 | year = 2005 | pmid = 16005201 | doi = 10.1016/j.plefa.2005.05.002 }}</ref> In addition, PGG2 and PGH2 rearrange non-enzymatically to a mixture of [[12-Hydroxyheptadecatrienoic acid]]s viz.,1 2-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid (i.e. 12-HHT) and 12-(S)-hydroxy-5Z,8Z,10E-heptadecatrienoic acid plus [[Malonyldialdehyde]].<ref>{{cite journal | vauthors = Wlodawer P, Samuelsson B | title = On the organization and mechanism of prostaglandin synthetase | journal = The Journal of Biological Chemistry | volume = 248 | issue = 16 | pages = 5673–8 | date = August 1973 | pmid = 4723909 }}</ref><ref>{{cite journal | vauthors = Hamberg M, Samuelsson B | title = Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 71 | issue = 9 | pages = 3400–4 | date = September 1974 | pmid = 4215079 | pmc = 433780 | doi=10.1073/pnas.71.9.3400}}</ref><ref>{{cite journal | vauthors = John H, Cammann K, Schlegel W | title = Development and review of radioimmunoassay of 12-S-hydroxyheptadecatrienoic acid | journal = Prostaglandins & Other Lipid Mediators | volume = 56 | issue = 2-3 | pages = 53–76 | date = June 1998 | pmid = 9785378 | doi=10.1016/s0090-6980(98)00043-4}}</ref> and can be metabolized by [[CYP2S1]] to 12-HHT<ref>{{cite journal | vauthors = Bui P, Imaizumi S, Beedanagari SR, Reddy ST, Hankinson O | title = Human CYP2S1 metabolizes cyclooxygenase- and lipoxygenase-derived eicosanoids | journal = Drug Metabolism and Disposition | volume = 39 | issue = 2 | pages = 180–90 | date = February 2011 | pmid = 21068195 | pmc = 3033693 | doi = 10.1124/dmd.110.035121 }}</ref><ref>{{cite journal | vauthors = Frömel T, Kohlstedt K, Popp R, Yin X, Awwad K, Barbosa-Sicard E, Thomas AC, Lieberz R, Mayr M, Fleming I | title = Cytochrome P4502S1: a novel monocyte/macrophage fatty acid epoxygenase in human atherosclerotic plaques | journal = Basic Research in Cardiology | volume = 108 | issue = 1 | pages = 319 | date = January 2013 | pmid = 23224081 | doi = 10.1007/s00395-012-0319-8 }}</ref> (see [[12-Hydroxyheptadecatrienoic acid]]). These alternate metabolites of COX-1 may contribute to its activities.
 
COX-1 promotes the production of the natural mucus lining that protects the inner stomach and contributes to reduced acid secretion and reduced pepsin content.<ref name="pmid18549814">{{cite journal | vauthors = Laine L, Takeuchi K, Tarnawski A | title = Gastric mucosal defense and cytoprotection: bench to bedside | journal = Gastroenterology | volume = 135 | issue = 1 | pages = 41–60 | year = 2008 | pmid = 18549814 | doi = 10.1053/j.gastro.2008.05.030 }}</ref><ref>{{cite book | editor-last1 = Fauci | editor-first1 = Anthony S. | editor-first2 = Eugene | editor-last2 = Braunwald  | editor-first3 = Dennis L. | editor-last3 = Kasper  | editor-first4 = Stephen L. | editor-last4 = Hauser | editor-first5 = Dan L. | editor-last5 = Longo  | editor-first6 = J. Larry | editor-last6 = Jameson  | editor-first7 = Joseph | editor-last7 = Loscalzo | name-list-format = vanc | title = Harrison's Principles of Internal Medicine | date = 2008 | publisher = McGraw-Hill Medical | location = New York | isbn = 978-0-07-146633-2| edition = 17th | page = 661 }}</ref> COX-1 is normally present in a variety of areas of the body, including not only the stomach but any site of inflammation.
 
== Clinical significance ==
COX-1 is inhibited by [[nonsteroidal anti-inflammatory drug]]s (NSAIDs) such as [[aspirin]]. [[Thromboxane A2]], the major product of COX-1 in platelets, induces platelet aggregation.<ref>{{cite book | last1 = Parker | first1 = Keith L. | last2 = Brunton | first2 = Laurence L. | last3 = Lazo | first3 =John S. | name-list-format = vanc | title = Goodman & Gilman's The Pharmacological Basis of Therapeutics | date = 2005 | publisher = McGraw-Hill Medical Publishing Division | location = New York | isbn = 0-07-142280-3 | page = 1126 | edition =11th }}</ref><ref>{{cite book | editor-last1 = Fauci | editor-first1 = Anthony S. | editor-first2 = Eugene | editor-last2 = Braunwald  | editor-first3 = Dennis L. | editor-last3 = Kasper  | editor-first4 = Stephen L. | editor-last4 = Hauser | editor-first5 = Dan L. | editor-last5 = Longo  | editor-first6 = J. Larry | editor-last6 = Jameson  | editor-first7 = Joseph | editor-last7 = Loscalzo | name-list-format = vanc | title = Harrison's Principles of Internal Medicine | date = 2008 | publisher = McGraw-Hill Medical | location = New York | isbn = 978-0-07-146633-2| edition = 17th | chapter = Chapter 112. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs | last = Weitz | first = Jeffrey I }}</ref> The inhibition of COX-1 is sufficient to explain why low dose [[aspirin]] is effective at reducing cardiac events.
 
== See also ==
* [[Arachidonic acid]]
* [[Cyclooxygenase]]
* [[Cyclooxygenase]]
* [[Prostaglandin-endoperoxide synthase 2|Cyclooxygenase 2]]
* [[NSAID]]
* [[Discovery and development of cyclooxygenase 2 inhibitors|Discovery and development of COX-2 selective inhibitors]]
* [[COX-2 selective inhibitor]]


==References==
== References ==
{{reflist|2}}
{{reflist|33em}}
==Further reading==
 
{{refbegin | 2}}
== Further reading ==
{{PBB_Further_reading
{{refbegin|33em}}
| citations =
* {{cite journal | vauthors = Richards JA, Petrel TA, Brueggemeier RW | title = Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 80 | issue = 2 | pages = 203–12 | date = February 2002 | pmid = 11897504 | doi = 10.1016/S0960-0760(01)00187-X }}
*{{cite journal | author=Richards JA, Petrel TA, Brueggemeier RW |title=Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells. |journal=J. Steroid Biochem. Mol. Biol. |volume=80 |issue= 2 |pages= 203-12 |year= 2002 |pmid= 11897504 |doi= }}
* {{cite journal | vauthors = Wu T, Wu H, Wang J, Wang J | title = Expression and cellular localization of cyclooxygenases and prostaglandin E synthases in the hemorrhagic brain | journal = Journal of Neuroinflammation | volume = 8 | pages = 22 | year = 2011 | pmid = 21385433 | pmc = 3062590 | doi = 10.1186/1742-2094-8-22 }}
*{{cite journal | author=Jain S, Khuri FR, Shin DM |title=Prevention of head and neck cancer: current status and future prospects. |journal=Current problems in cancer |volume=28 |issue= 5 |pages= 265-86 |year= 2004 |pmid= 15375804 |doi= }}
* {{cite journal | vauthors = Jain S, Khuri FR, Shin DM | title = Prevention of head and neck cancer: current status and future prospects | journal = Current Problems in Cancer | volume = 28 | issue = 5 | pages = 265–86 | year = 2004 | pmid = 15375804 | doi = 10.1016/j.currproblcancer.2004.05.003 }}
*{{cite journal | author=Bingham S, Beswick PJ, Blum DE, ''et al.'' |title=The role of the cylooxygenase pathway in nociception and pain. |journal=Semin. Cell Dev. Biol. |volume=17 |issue= 5 |pages= 544-54 |year= 2007 |pmid= 17071117 |doi= 10.1016/j.semcdb.2006.09.001 }}
* {{cite journal | vauthors = Bingham S, Beswick PJ, Blum DE, Gray NM, Chessell IP | title = The role of the cylooxygenase pathway in nociception and pain | journal = Seminars in Cell & Developmental Biology | volume = 17 | issue = 5 | pages = 544–54 | date = October 2006 | pmid = 17071117 | doi = 10.1016/j.semcdb.2006.09.001 }}
*{{cite journal | author=Diaz A, Reginato AM, Jimenez SA |title=Alternative splicing of human prostaglandin G/H synthase mRNA and evidence of differential regulation of the resulting transcripts by transforming growth factor beta 1, interleukin 1 beta, and tumor necrosis factor alpha. |journal=J. Biol. Chem. |volume=267 |issue= 15 |pages= 10816-22 |year= 1992 |pmid= 1587858 |doi= }}
* {{cite journal | vauthors = Diaz A, Reginato AM, Jimenez SA | title = Alternative splicing of human prostaglandin G/H synthase mRNA and evidence of differential regulation of the resulting transcripts by transforming growth factor beta 1, interleukin 1 beta, and tumor necrosis factor alpha | journal = The Journal of Biological Chemistry | volume = 267 | issue = 15 | pages = 10816–22 | date = May 1992 | pmid = 1587858 | doi =  }}
*{{cite journal | author=Takahashi Y, Ueda N, Yoshimoto T, ''et al.'' |title=Immunoaffinity purification and cDNA cloning of human platelet prostaglandin endoperoxide synthase (cyclooxygenase). |journal=Biochem. Biophys. Res. Commun. |volume=182 |issue= 2 |pages= 433-8 |year= 1992 |pmid= 1734857 |doi=  }}
* {{cite journal | vauthors = Takahashi Y, Ueda N, Yoshimoto T, Yamamoto S, Yokoyama C, Miyata A, Tanabe T, Fuse I, Hattori A, Shibata A | title = Immunoaffinity purification and cDNA cloning of human platelet prostaglandin endoperoxide synthase (cyclooxygenase) | journal = Biochemical and Biophysical Research Communications | volume = 182 | issue = 2 | pages = 433–8 | date = January 1992 | pmid = 1734857 | doi = 10.1016/0006-291X(92)91750-K }}
*{{cite journal | author=Funk CD, Funk LB, Kennedy ME, ''et al.'' |title=Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. |journal=FASEB J. |volume=5 |issue= 9 |pages= 2304-12 |year= 1991 |pmid= 1907252 |doi= }}
* {{cite journal | vauthors = Vane JR, Mitchell JA, Appleton I, Tomlinson A, Bishop-Bailey D, Croxtall J, Willoughby DA | title = Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 6 | pages = 2046–50 | date = March 1994 | pmid = 7510883 | pmc = 43306 | doi = 10.1073/pnas.91.6.2046 }}
*{{cite journal | author=Yokoyama C, Tanabe T |title=Cloning of human gene encoding prostaglandin endoperoxide synthase and primary structure of the enzyme. |journal=Biochem. Biophys. Res. Commun. |volume=165 |issue= 2 |pages= 888-94 |year= 1990 |pmid= 2512924 |doi= }}
* {{cite journal | vauthors = Mollace V, Colasanti M, Rodino P, Lauro GM, Nistico G | title = HIV coating gp 120 glycoprotein-dependent prostaglandin E2 release by human cultured astrocytoma cells is regulated by nitric oxide formation | journal = Biochemical and Biophysical Research Communications | volume = 203 | issue = 1 | pages = 87–92 | date = August 1994 | pmid = 7521167 | doi = 10.1006/bbrc.1994.2152 }}
*{{cite journal | author=Vane JR, Mitchell JA, Appleton I, ''et al.'' |title=Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=91 |issue= 6 |pages= 2046-50 |year= 1994 |pmid= 7510883 |doi= }}
* {{cite journal | vauthors = Inoue H, Yokoyama C, Hara S, Tone Y, Tanabe T | title = Transcriptional regulation of human prostaglandin-endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in vascular endothelial cells. Involvement of both nuclear factor for interleukin-6 expression site and cAMP response element | journal = The Journal of Biological Chemistry | volume = 270 | issue = 42 | pages = 24965–71 | date = October 1995 | pmid = 7559624 | doi = 10.1074/jbc.270.42.24965 }}
*{{cite journal | author=Mollace V, Colasanti M, Rodino P, ''et al.'' |title=HIV coating gp 120 glycoprotein-dependent prostaglandin E2 release by human cultured astrocytoma cells is regulated by nitric oxide formation. |journal=Biochem. Biophys. Res. Commun. |volume=203 |issue= 1 |pages= 87-92 |year= 1994 |pmid= 7521167 |doi= 10.1006/bbrc.1994.2152 }}
* {{cite journal | vauthors = Ren Y, Loose-Mitchell DS, Kulmacz RJ | title = Prostaglandin H synthase-1: evaluation of C-terminus function | journal = Archives of Biochemistry and Biophysics | volume = 316 | issue = 2 | pages = 751–7 | date = February 1995 | pmid = 7864630 | doi = 10.1006/abbi.1995.1100 }}
*{{cite journal | author=Inoue H, Yokoyama C, Hara S, ''et al.'' |title=Transcriptional regulation of human prostaglandin-endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in vascular endothelial cells. Involvement of both nuclear factor for interleukin-6 expression site and cAMP response element. |journal=J. Biol. Chem. |volume=270 |issue= 42 |pages= 24965-71 |year= 1995 |pmid= 7559624 |doi= }}
* {{cite journal | vauthors = Picot D, Loll PJ, Garavito RM | title = The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1 | journal = Nature | volume = 367 | issue = 6460 | pages = 243–9 | date = January 1994 | pmid = 8121489 | doi = 10.1038/367243a0 }}
*{{cite journal | author=Ren Y, Loose-Mitchell DS, Kulmacz RJ |title=Prostaglandin H synthase-1: evaluation of C-terminus function. |journal=Arch. Biochem. Biophys. |volume=316 |issue= 2 |pages= 751-7 |year= 1995 |pmid= 7864630 |doi= }}
* {{cite journal | vauthors = Kosaka T, Miyata A, Ihara H, Hara S, Sugimoto T, Takeda O, Takahashi E, Tanabe T | title = Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2 | journal = European Journal of Biochemistry / FEBS | volume = 221 | issue = 3 | pages = 889–97 | date = May 1994 | pmid = 8181472 | doi = 10.1111/j.1432-1033.1994.tb18804.x }}
*{{cite journal | author=Picot D, Loll PJ, Garavito RM |title=The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. |journal=Nature |volume=367 |issue= 6460 |pages= 243-9 |year= 1994 |pmid= 8121489 |doi= 10.1038/367243a0 }}
* {{cite journal | vauthors = Otto JC, DeWitt DL, Smith WL | title = N-glycosylation of prostaglandin endoperoxide synthases-1 and -2 and their orientations in the endoplasmic reticulum | journal = The Journal of Biological Chemistry | volume = 268 | issue = 24 | pages = 18234–42 | date = August 1993 | pmid = 8349699 | doi =  }}
*{{cite journal | author=Kosaka T, Miyata A, Ihara H, ''et al.'' |title=Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2. |journal=Eur. J. Biochem. |volume=221 |issue= 3 |pages= 889-97 |year= 1994 |pmid= 8181472 |doi=  }}
* {{cite journal | vauthors = O'Neill GP, Ford-Hutchinson AW | title = Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues | journal = FEBS Letters | volume = 330 | issue = 2 | pages = 156–60 | date = September 1993 | pmid = 8365485 | doi = 10.1016/0014-5793(93)80263-T }}
*{{cite journal | author=Otto JC, DeWitt DL, Smith WL |title=N-glycosylation of prostaglandin endoperoxide synthases-1 and -2 and their orientations in the endoplasmic reticulum. |journal=J. Biol. Chem. |volume=268 |issue= 24 |pages= 18234-42 |year= 1993 |pmid= 8349699 |doi= }}
* {{cite journal | vauthors = Corasaniti MT, Melino G, Navarra M, Garaci E, Finazzi-Agrò A, Nisticò G | title = Death of cultured human neuroblastoma cells induced by HIV-1 gp120 is prevented by NMDA receptor antagonists and inhibitors of nitric oxide and cyclooxygenase | journal = Neurodegeneration | volume = 4 | issue = 3 | pages = 315–21 | date = September 1995 | pmid = 8581564 | doi = 10.1016/1055-8330(95)90021-7 }}
*{{cite journal | author=O'Neill GP, Ford-Hutchinson AW |title=Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. |journal=FEBS Lett. |volume=330 |issue= 2 |pages= 156-60 |year= 1993 |pmid= 8365485 |doi= }}
* {{cite journal | vauthors = Ballif BA, Mincek NV, Barratt JT, Wilson ML, Simmons DL | title = Interaction of cyclooxygenases with an apoptosis- and autoimmunity-associated protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 11 | pages = 5544–9 | date = May 1996 | pmid = 8643612 | pmc = 39283 | doi = 10.1073/pnas.93.11.5544 }}
*{{cite journal | author=Corasaniti MT, Melino G, Navarra M, ''et al.'' |title=Death of cultured human neuroblastoma cells induced by HIV-1 gp120 is prevented by NMDA receptor antagonists and inhibitors of nitric oxide and cyclooxygenase. |journal=Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration |volume=4 |issue= 3 |pages= 315-21 |year= 1996 |pmid= 8581564 |doi= }}
* {{cite journal | vauthors = Hla T | title = Molecular characterization of the 5.2 KB isoform of the human cyclooxygenase-1 transcript | journal = Prostaglandins | volume = 51 | issue = 1 | pages = 81–5 | date = January 1996 | pmid = 8900446 | doi = 10.1016/0090-6980(95)00158-1 }}
*{{cite journal | author=Ballif BA, Mincek NV, Barratt JT, ''et al.'' |title=Interaction of cyclooxygenases with an apoptosis- and autoimmunity-associated protein. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=93 |issue= 11 |pages= 5544-9 |year= 1996 |pmid= 8643612 |doi= }}
* {{cite journal | vauthors = Mahida YR, Beltinger J, Makh S, Göke M, Gray T, Podolsky DK, Hawkey CJ | title = Adult human colonic subepithelial myofibroblasts express extracellular matrix proteins and cyclooxygenase-1 and -2 | journal = The American Journal of Physiology | volume = 273 | issue = 6 Pt 1 | pages = G1341-8 | date = December 1997 | pmid = 9435560 | doi =  }}
*{{cite journal | author=Hla T |title=Molecular characterization of the 5.2 KB isoform of the human cyclooxygenase-1 transcript. |journal=Prostaglandins |volume=51 |issue= 1 |pages= 81-5 |year= 1996 |pmid= 8900446 |doi=  }}
* {{cite journal | vauthors = Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN | title = Cyclooxygenase regulates angiogenesis induced by colon cancer cells | journal = Cell | volume = 93 | issue = 5 | pages = 705–16 | date = May 1998 | pmid = 9630216 | doi = 10.1016/S0092-8674(00)81433-6 }}
*{{cite journal | author=Mahida YR, Beltinger J, Makh S, ''et al.'' |title=Adult human colonic subepithelial myofibroblasts express extracellular matrix proteins and cyclooxygenase-1 and -2. |journal=Am. J. Physiol. |volume=273 |issue= 6 Pt 1 |pages= G1341-8 |year= 1998 |pmid= 9435560 |doi= }}
*{{cite journal  | author=Tsujii M, Kawano S, Tsuji S, ''et al.'' |title=Cyclooxygenase regulates angiogenesis induced by colon cancer cells. |journal=Cell |volume=93 |issue= 5 |pages= 705-16 |year= 1998 |pmid= 9630216 |doi=  }}
}}
{{refend}}
{{refend}}


{{protein-stub}}
{{PDB Gallery|geneid=5742}}
{{Eicosanoid metabolism enzymes}}
{{Prostanoidergics}}
 


[[Category:Prostaglandins]]
[[Category:Peripheral membrane proteins]]
[[Category:Peripheral membrane proteins]]
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Latest revision as of 07:33, 10 January 2019

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Identifiers
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Orthologs
SpeciesHumanMouse
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"COX-1" redirects here. For mitochondrial cytochrome c oxidase subunit 1 (cox1), see MT-CO1.

Cyclooxygenase 1 (COX-1), also known as prostaglandin G/H synthase 1, prostaglandin-endoperoxide synthase 1 or prostaglandin H2 synthase 1, is an enzyme that in humans is encoded by the PTGS1 gene.[1][2] In humans it is one of two cyclooxygenases.

History

Cyclooxygenase (COX) is the central enzyme in the biosynthetic pathway to prostaglandins from arachidonic acid. This protein was isolated more than 40 years ago and cloned in 1988.[3][4]

Gene and isozymes

There are two isozymes of COX encoded by distinct gene products: a constitutive COX-1 (this enzyme) and an inducible COX-2, which differ in their regulation of expression and tissue distribution. The expression of these two transcripts is differentially regulated by relevant cytokines and growth factors.[5] This gene encodes COX-1, which regulates angiogenesis in endothelial cells. COX-1 is also involved in cell signaling and maintaining tissue homeostasis. A splice variant of COX-1 termed COX-3 was identified in the CNS of dogs, but does not result in a functional protein in humans. Two smaller COX-1-derived proteins (the partial COX-1 proteins PCOX-1A and PCOX-1B) have also been discovered, but their precise roles are yet to be described.[6]

Function

Prostaglandin-endoperoxide synthase (PTGS), also known as cyclooxygenase (COX), is the key enzyme in prostaglandin biosynthesis. It converts free arachidonic acid, released from membrane phospholipids at the sn-2 ester binding site by the enzymatic activity of phospholipase A2, to prostaglandin (PG) H2. The reaction involves both cyclooxygenase (dioxygenase) and hydroperoxidase (peroxidase) activity. The cyclooxygenase activity incorporates two oxygen molecules into arachidonic acid or alternate polyunsaturated fatty acid substrates, such as linoleic acid and eicosapentaenoic acid. Metabolism of arachidonic acid forms a labile intermediate peroxide, PGG2, which is reduced to the corresponding alcohol, PGH2, by the enzyme’s hydroperoxidase activity.

While metabolizing arachidonic acid primarily to PGG2, COX-1 also converts this fatty acid to small amounts of a racemic mixture of 15-Hydroxyicosatetraenoic acids (i.e., 15-HETEs) composed of ~22% 15(R)-HETE and ~78% 15(S)-HETE stereoisomers as well as a small amount of 11(R)-HETE.[7] The two 15-HETE stereoisomers have intrinsic biological activities but, perhaps more importantly, can be further metabolized to a major class of anti-inflammatory agents, the lipoxins.[8] In addition, PGG2 and PGH2 rearrange non-enzymatically to a mixture of 12-Hydroxyheptadecatrienoic acids viz.,1 2-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid (i.e. 12-HHT) and 12-(S)-hydroxy-5Z,8Z,10E-heptadecatrienoic acid plus Malonyldialdehyde.[9][10][11] and can be metabolized by CYP2S1 to 12-HHT[12][13] (see 12-Hydroxyheptadecatrienoic acid). These alternate metabolites of COX-1 may contribute to its activities.

COX-1 promotes the production of the natural mucus lining that protects the inner stomach and contributes to reduced acid secretion and reduced pepsin content.[14][15] COX-1 is normally present in a variety of areas of the body, including not only the stomach but any site of inflammation.

Clinical significance

COX-1 is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin. Thromboxane A2, the major product of COX-1 in platelets, induces platelet aggregation.[16][17] The inhibition of COX-1 is sufficient to explain why low dose aspirin is effective at reducing cardiac events.

See also

References

  1. ↑ Yokoyama C, Tanabe T (December 1989). "Cloning of human gene encoding prostaglandin endoperoxide synthase and primary structure of the enzyme". Biochemical and Biophysical Research Communications. 165 (2): 888–94. doi:10.1016/S0006-291X(89)80049-X. PMID 2512924.
  2. ↑ Funk CD, Funk LB, Kennedy ME, Pong AS, Fitzgerald GA (June 1991). "Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment". FASEB Journal. 5 (9): 2304–12. PMID 1907252.
  3. ↑ Bakhle YS (1999). "Structure of COX-1 and COX-2 enzymes and their interaction with inhibitors". Drugs of Today. 35 (4–5): 237–50. doi:10.1358/dot.1999.35.4-5.552200. PMID 12973429.
  4. ↑ Sakamoto C (October 1998). "Roles of COX-1 and COX-2 in gastrointestinal pathophysiology". Journal of Gastroenterology. 33 (5): 618–24. doi:10.1007/s005350050147. PMID 9773924.
  5. ↑ "Entrez Gene: PTGS1 prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)".
  6. ↑ Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL (October 2002). "COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression". Proceedings of the National Academy of Sciences of the United States of America. 99 (21): 13926–31. doi:10.1073/pnas.162468699. PMC 129799. PMID 12242329.
  7. ↑ Mulugeta S, Suzuki T, Hernandez NT, Griesser M, Boeglin WE, Schneider C (March 2010). "Identification and absolute configuration of dihydroxy-arachidonic acids formed by oxygenation of 5S-HETE by native and aspirin-acetylated COX-2". Journal of Lipid Research. 51 (3): 575–85. doi:10.1194/jlr.M001719. PMC 2817587. PMID 19752399.
  8. ↑ Serhan CN (2005). "Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 73 (3–4): 141–62. doi:10.1016/j.plefa.2005.05.002. PMID 16005201.
  9. ↑ Wlodawer P, Samuelsson B (August 1973). "On the organization and mechanism of prostaglandin synthetase". The Journal of Biological Chemistry. 248 (16): 5673–8. PMID 4723909.
  10. ↑ Hamberg M, Samuelsson B (September 1974). "Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets". Proceedings of the National Academy of Sciences of the United States of America. 71 (9): 3400–4. doi:10.1073/pnas.71.9.3400. PMC 433780. PMID 4215079.
  11. ↑ John H, Cammann K, Schlegel W (June 1998). "Development and review of radioimmunoassay of 12-S-hydroxyheptadecatrienoic acid". Prostaglandins & Other Lipid Mediators. 56 (2–3): 53–76. doi:10.1016/s0090-6980(98)00043-4. PMID 9785378.
  12. ↑ Bui P, Imaizumi S, Beedanagari SR, Reddy ST, Hankinson O (February 2011). "Human CYP2S1 metabolizes cyclooxygenase- and lipoxygenase-derived eicosanoids". Drug Metabolism and Disposition. 39 (2): 180–90. doi:10.1124/dmd.110.035121. PMC 3033693. PMID 21068195.
  13. ↑ Frömel T, Kohlstedt K, Popp R, Yin X, Awwad K, Barbosa-Sicard E, Thomas AC, Lieberz R, Mayr M, Fleming I (January 2013). "Cytochrome P4502S1: a novel monocyte/macrophage fatty acid epoxygenase in human atherosclerotic plaques". Basic Research in Cardiology. 108 (1): 319. doi:10.1007/s00395-012-0319-8. PMID 23224081.
  14. ↑ Laine L, Takeuchi K, Tarnawski A (2008). "Gastric mucosal defense and cytoprotection: bench to bedside". Gastroenterology. 135 (1): 41–60. doi:10.1053/j.gastro.2008.05.030. PMID 18549814.
  15. ↑ Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. (2008). Harrison's Principles of Internal Medicine (17th ed.). New York: McGraw-Hill Medical. p. 661. ISBN 978-0-07-146633-2.
  16. ↑ Parker KL, Brunton LL, Lazo JS (2005). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill Medical Publishing Division. p. 1126. ISBN 0-07-142280-3.
  17. ↑ Weitz JI (2008). "Chapter 112. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs". In Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's Principles of Internal Medicine (17th ed.). New York: McGraw-Hill Medical. ISBN 978-0-07-146633-2.

Further reading

  • Richards JA, Petrel TA, Brueggemeier RW (February 2002). "Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells". The Journal of Steroid Biochemistry and Molecular Biology. 80 (2): 203–12. doi:10.1016/S0960-0760(01)00187-X. PMID 11897504.
  • Wu T, Wu H, Wang J, Wang J (2011). "Expression and cellular localization of cyclooxygenases and prostaglandin E synthases in the hemorrhagic brain". Journal of Neuroinflammation. 8: 22. doi:10.1186/1742-2094-8-22. PMC 3062590. PMID 21385433.
  • Jain S, Khuri FR, Shin DM (2004). "Prevention of head and neck cancer: current status and future prospects". Current Problems in Cancer. 28 (5): 265–86. doi:10.1016/j.currproblcancer.2004.05.003. PMID 15375804.
  • Bingham S, Beswick PJ, Blum DE, Gray NM, Chessell IP (October 2006). "The role of the cylooxygenase pathway in nociception and pain". Seminars in Cell & Developmental Biology. 17 (5): 544–54. doi:10.1016/j.semcdb.2006.09.001. PMID 17071117.
  • Diaz A, Reginato AM, Jimenez SA (May 1992). "Alternative splicing of human prostaglandin G/H synthase mRNA and evidence of differential regulation of the resulting transcripts by transforming growth factor beta 1, interleukin 1 beta, and tumor necrosis factor alpha". The Journal of Biological Chemistry. 267 (15): 10816–22. PMID 1587858.
  • Takahashi Y, Ueda N, Yoshimoto T, Yamamoto S, Yokoyama C, Miyata A, Tanabe T, Fuse I, Hattori A, Shibata A (January 1992). "Immunoaffinity purification and cDNA cloning of human platelet prostaglandin endoperoxide synthase (cyclooxygenase)". Biochemical and Biophysical Research Communications. 182 (2): 433–8. doi:10.1016/0006-291X(92)91750-K. PMID 1734857.
  • Vane JR, Mitchell JA, Appleton I, Tomlinson A, Bishop-Bailey D, Croxtall J, Willoughby DA (March 1994). "Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation". Proceedings of the National Academy of Sciences of the United States of America. 91 (6): 2046–50. doi:10.1073/pnas.91.6.2046. PMC 43306. PMID 7510883.
  • Mollace V, Colasanti M, Rodino P, Lauro GM, Nistico G (August 1994). "HIV coating gp 120 glycoprotein-dependent prostaglandin E2 release by human cultured astrocytoma cells is regulated by nitric oxide formation". Biochemical and Biophysical Research Communications. 203 (1): 87–92. doi:10.1006/bbrc.1994.2152. PMID 7521167.
  • Inoue H, Yokoyama C, Hara S, Tone Y, Tanabe T (October 1995). "Transcriptional regulation of human prostaglandin-endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in vascular endothelial cells. Involvement of both nuclear factor for interleukin-6 expression site and cAMP response element". The Journal of Biological Chemistry. 270 (42): 24965–71. doi:10.1074/jbc.270.42.24965. PMID 7559624.
  • Ren Y, Loose-Mitchell DS, Kulmacz RJ (February 1995). "Prostaglandin H synthase-1: evaluation of C-terminus function". Archives of Biochemistry and Biophysics. 316 (2): 751–7. doi:10.1006/abbi.1995.1100. PMID 7864630.
  • Picot D, Loll PJ, Garavito RM (January 1994). "The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1". Nature. 367 (6460): 243–9. doi:10.1038/367243a0. PMID 8121489.
  • Kosaka T, Miyata A, Ihara H, Hara S, Sugimoto T, Takeda O, Takahashi E, Tanabe T (May 1994). "Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2". European Journal of Biochemistry / FEBS. 221 (3): 889–97. doi:10.1111/j.1432-1033.1994.tb18804.x. PMID 8181472.
  • Otto JC, DeWitt DL, Smith WL (August 1993). "N-glycosylation of prostaglandin endoperoxide synthases-1 and -2 and their orientations in the endoplasmic reticulum". The Journal of Biological Chemistry. 268 (24): 18234–42. PMID 8349699.
  • O'Neill GP, Ford-Hutchinson AW (September 1993). "Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues". FEBS Letters. 330 (2): 156–60. doi:10.1016/0014-5793(93)80263-T. PMID 8365485.
  • Corasaniti MT, Melino G, Navarra M, Garaci E, Finazzi-Agrò A, Nisticò G (September 1995). "Death of cultured human neuroblastoma cells induced by HIV-1 gp120 is prevented by NMDA receptor antagonists and inhibitors of nitric oxide and cyclooxygenase". Neurodegeneration. 4 (3): 315–21. doi:10.1016/1055-8330(95)90021-7. PMID 8581564.
  • Ballif BA, Mincek NV, Barratt JT, Wilson ML, Simmons DL (May 1996). "Interaction of cyclooxygenases with an apoptosis- and autoimmunity-associated protein". Proceedings of the National Academy of Sciences of the United States of America. 93 (11): 5544–9. doi:10.1073/pnas.93.11.5544. PMC 39283. PMID 8643612.
  • Hla T (January 1996). "Molecular characterization of the 5.2 KB isoform of the human cyclooxygenase-1 transcript". Prostaglandins. 51 (1): 81–5. doi:10.1016/0090-6980(95)00158-1. PMID 8900446.
  • Mahida YR, Beltinger J, Makh S, Göke M, Gray T, Podolsky DK, Hawkey CJ (December 1997). "Adult human colonic subepithelial myofibroblasts express extracellular matrix proteins and cyclooxygenase-1 and -2". The American Journal of Physiology. 273 (6 Pt 1): G1341–8. PMID 9435560.
  • Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN (May 1998). "Cyclooxygenase regulates angiogenesis induced by colon cancer cells". Cell. 93 (5): 705–16. doi:10.1016/S0092-8674(00)81433-6. PMID 9630216.
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