View source for Cyclooxygenase

{{redirect|COX||Cox (disambiguation)}}
{{enzyme
| Name = prostaglandin-endoperoxide synthase
| EC_number = 1.14.99.1
| CAS_number = 9055-65-6
| IUBMB_EC_number = 1/14/99/1
| GO_code = 0004666
| image = 
| width = 
| caption = 
}}
{{infobox protein
|Name=[[PTGS1|cyclooxygenase 1]]
|caption=Crystallographic structure of prostaglandin H2 synthase-1 complex with [[flurbiprofen]].<ref name="pmid8121489">{{PDB|1CQE}}; {{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 }}</ref>
|image= PROSTAGLANDIN H2 SYNTHASE-1 COMPLEX.png
|width=
|HGNCid=9604
|Symbol=[[PTGS1]]
|AltSymbols=COX-1
|EntrezGene=5742
|OMIM=176805
|RefSeq=NM_080591
|UniProt=P23219
|PDB=1CQE
|ECnumber=1.14.99.1
|Chromosome=9
|Arm=q
|Band=32
|LocusSupplementaryData=-q33.3
}}
{{infobox protein
|Name=[[PTGS2|cyclooxygenase 2]]
|caption= Cyclooxygenase-2 (Prostaglandin Synthase-2) in complex with a COX-2 selective inhibitor.<ref name="pmid8967954">{{PDB|6COX}}; {{cite journal | vauthors = Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC | title = Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents | journal = Nature | volume = 384 | issue = 6610 | pages = 644–8 | year = 1996 | pmid = 8967954 | doi = 10.1038/384644a0 }}</ref>
|image=Cyclooxygenase-2.png
|width=
|HGNCid=9605
|Symbol=[[PTGS2]]
|AltSymbols=COX-2
|EntrezGene=5743
|OMIM=600262
|RefSeq=NM_000963
|UniProt=P35354
|PDB=6COX
|ECnumber=1.14.99.1
|Chromosome=1
|Arm=q
|Band=25.2
|LocusSupplementaryData=-25.3
}}

'''Cyclooxygenase''' ('''COX'''), officially known as '''prostaglandin-endoperoxide [[synthase]]''' (PTGS), is an [[enzyme]] (specifically, a family of [[isozyme]]s, {{EC_number|1.14.99.1}}) that is responsible for formation of [[prostanoid]]s, including [[thromboxane]] and [[prostaglandin]]s such as [[prostacyclin]], from [[arachidonic acid]].<ref name = "Litalien_2011">{{cite book | vauthors = Litalien C, Beaulieu P | chapter = Chapter 117 – Molecular Mechanisms of Drug Actions: From Receptors to Effectors | veditors = Fuhrman BP, Zimmerman JJ |title=Pediatric Critical Care |date=2011 |publisher=Elsevier Saunders |location=Philadelphia, PA |isbn=978-0-323-07307-3 | doi = 10.1016/B978-0-323-07307-3.10117-X |pages=1553–1568 |edition=4th |quote=Arachidonic acid is a component of membrane phospholipids released either in a one-step process, after phospholipase A2 (PLA2) action, or a two-step process, after phospholipase C and DAG lipase actions. Arachidonic acid is then metabolized by cyclooxygenase (COX) and 5-lipoxygenase, resulting in the synthesis of prostaglandins and leukotrienes, respectively. These intracellular messengers play an important role in the regulation of signal transduction implicated in pain and inflammatory responses. }}</ref>

[[Pharmaceutical drug|Pharmaceutical]] inhibition of ''COX'' can provide relief from the symptoms of [[inflammation]] and [[pain]].<ref name="Litalien_2011" /> [[Nonsteroidal anti-inflammatory drug]]s (NSAIDs), such as [[aspirin]] and [[ibuprofen]], exert their effects through inhibition of COX. Those that are specific to the COX-2 isozyme are called [[COX-2 inhibitor]]s. The active metabolite ([[AM404]]) of [[paracetamol]] believed to provide most or all of its analgesic effects is a COX inhibitor and this is believed to provide part of its effect.<ref name="pmid15987694">{{cite journal | vauthors = Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM | title = Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system | journal = The Journal of Biological Chemistry | volume = 280 | issue = 36 | pages = 31405–12 | date = September 2005 | pmid = 15987694 | doi = 10.1074/jbc.M501489200 | url = http://www.jbc.org/content/280/36/31405.full.pdf | format = pdf }}</ref>

In [[medicine]], the [[gene nomenclature#Symbol and name|root symbol]] "COX" is encountered more often than "PTGS". In [[genetics]], "PTGS" is officially used for this family of [[gene]]s and [[protein]]s, because the root symbol "COX" was already used for the [[cytochrome c oxidase]] family. Thus the two isozymes found in humans, [[PTGS1]] and [[PTGS2]], are frequently called COX-1 and COX-2 in the [[medical literature]]. The names "prostaglandin synthase (PHS)", "prostaglandin synthetase (PHS)", and "prostaglandin-endoperoxide synthetase (PES)" are older terms still sometimes used to refer to COX.

== Pharmacology ==

In terms of their molecular biology, ''COX-1'' and ''COX-2'' are of similar molecular weight, approximately 70 and 72 k[[dalton (unit)|Da]], respectively, and having 65% amino acid sequence homology and near-identical catalytic sites. The most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution of [[isoleucine]] at position 523 in ''COX-1'' with [[valine]] in ''COX-2''. The smaller Val<sub>523</sub> residue in ''COX-2'' allows access to a [[hydrophobic]] side-pocket in the enzyme (which Ile<sub>523</sub> sterically hinders). Drug molecules, such as DuP-697 and the coxibs derived from it, bind to this alternative site and are considered to be selective inhibitors of ''COX-2''.

=== Classical NSAIDs ===

{{See also|Mechanism of action of aspirin}}
The main ''COX'' inhibitors are the [[non-steroidal anti-inflammatory drug]]s (NSAIDs).

The classical ''COX'' inhibitors are not selective and inhibit all types of ''COX''. The resulting inhibition of [[prostaglandin]] and [[thromboxane]] synthesis has the effect of reduced inflammation, as well as antipyretic, antithrombotic and analgesic effects. The most frequent adverse effect of NSAIDs is irritation of the gastric mucosa as [[prostaglandin]]s normally have a protective role in the gastrointestinal tract. Some NSAIDs are also acidic which may cause additional damage to the gastrointestinal tract.

=== Newer NSAIDs ===

Selectivity for ''COX-2'' is the main feature of [[celecoxib]], [[etoricoxib]], and other members of this drug class.  Because COX-2 is usually specific to inflamed tissue, there is much less gastric irritation associated with COX-2 inhibitors, with a decreased risk of peptic ulceration. The selectivity of COX-2 does not seem to negate other side-effects of NSAIDs, most notably an increased risk of [[renal failure]], and there is evidence that indicates an increase in the risk of [[myocardial infarction|heart attack]], [[thrombosis]], and [[stroke]] through an increase of [[thromboxane]] unbalanced by prostacyclin (which is reduced by COX-2 inhibition). {{Citation needed|date=March 2013}} [[Rofecoxib]] (brand name [[Vioxx]]) was withdrawn in 2004 because of such concerns. Some other COX-2 selective NSAIDs, such as [[celecoxib]], and [[etoricoxib]], are still on the market.

=== Natural COX inhibition ===

Culinary mushrooms, like [[maitake]], may be able to partially inhibit COX-1 and COX-2.<ref name="pmid12475274">{{cite journal | vauthors = Zhang Y, Mills GL, Nair MG | title = Cyclooxygenase inhibitory and antioxidant compounds from the mycelia of the edible mushroom Grifola frondosa | journal = Journal of Agricultural and Food Chemistry | volume = 50 | issue = 26 | pages = 7581–5 | date = December 2002 | pmid = 12475274 | doi = 10.1021/jf0257648 }}</ref><ref name="pmid12834003">{{cite journal | vauthors = Zhang Y, Mills GL, Nair MG | title = Cyclooxygenase inhibitory and antioxidant compounds from the fruiting body of an edible mushroom, Agrocybe aegerita | journal = Phytomedicine | volume = 10 | issue = 5 | pages = 386–90 | year = 2003 | pmid = 12834003 | doi = 10.1078/0944-7113-00272 }}</ref>

A variety of [[flavonoid]]s have been found to inhibit COX-2.<ref name="pmid15225597">{{cite journal | vauthors = O'Leary KA, de Pascual-Teresa S, de Pascual-Tereasa S, Needs PW, Bao YP, O'Brien NM, Williamson G | title = Effect of flavonoids and vitamin E on cyclooxygenase-2 (COX-2) transcription | journal = Mutation Research | volume = 551 | issue = 1-2 | pages = 245–54 | date = July 2004 | pmid = 15225597 | doi = 10.1016/j.mrfmmm.2004.01.015 }}</ref>

[[Fish oils]] provide alternative fatty acids to arachidonic acid. These acids can be turned into some anti-inflammatory [[prostacyclins]] by COX instead of pro-inflammatory [[prostaglandins]].<ref name="fish_oils">{{cite journal | vauthors = Cleland LG, James MJ, Proudman SM | title = Fish oil: what the prescriber needs to know | journal = Arthritis Research & Therapy | volume = 8 | issue = 1 | pages = 202 | year = 2006 | pmid = 16542466 | pmc = 1526555 | doi = 10.1186/ar1876 }}</ref>

[[Hyperforin]] has been shown to inhibit COX-1 around 3-18 times as much as aspirin.<ref>{{cite journal | vauthors = Albert D, Zündorf I, Dingermann T, Müller WE, Steinhilber D, Werz O | title = Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase | journal = Biochemical Pharmacology | volume = 64 | issue = 12 | pages = 1767–75 | date = December 2002 | pmid = 12445866 | doi = 10.1016/s0006-2952(02)01387-4 }}</ref>

[[Calcitriol]] ([[vitamin D]]) significantly inhibits the expression of the COX-2 gene.<ref name="pmid16886660">{{cite journal | vauthors = Moreno J, Krishnan AV, Peehl DM, Feldman D | title = Mechanisms of vitamin D-mediated growth inhibition in prostate cancer cells: inhibition of the prostaglandin pathway | journal = Anticancer Research | volume = 26 | issue = 4A | pages = 2525–30 | date = July–August 2006 | pmid = 16886660 | doi =  | url = http://ar.iiarjournals.org/content/26/4A/2525.abstract }}</ref>

Caution should be exercised in combining low dose aspirin with COX-2 inhibitors due to potential increased damage to the gastric mucosa.  COX-2 is upregulated when COX-1 is suppressed with aspirin, which is thought to be important in enhancing mucosal defense mechanisms and lessening the erosion by aspirin.<ref>{{cite journal | vauthors = Wallace JL | title = Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself? | journal = Physiological Reviews | volume = 88 | issue = 4 | pages = 1547–65 | date = October 2008 | pmid = 18923189 | doi = 10.1152/physrev.00004.2008 | url = http://physrev.physiology.org/content/88/4/1547.long }}</ref>

=== Cardiovascular side-effects of COX inhibitors ===

COX-2 inhibitors have been found to increase the risk of [[Thrombosis|atherothrombosis]] even with short-term use. A 2006 analysis of 138 randomised trials and almost 150 000 participants<ref name="pmid16740558">{{cite journal | vauthors = Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C | title = Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials | journal = BMJ | volume = 332 | issue = 7553 | pages = 1302–8 | date = June 2006 | pmid = 16740558 | pmc = 1473048 | doi = 10.1136/bmj.332.7553.1302 }}</ref> showed that selective ''COX-2'' inhibitors are associated with a moderately increased risk of vascular events, mainly due to a twofold increased risk of [[myocardial infarction]], and also that high-dose regimens of some traditional NSAIDs (such as [[diclofenac]] and [[ibuprofen]], but not [[naproxen]]) are associated with a similar increase in risk of vascular events.

Fish oils (e.g., [[cod liver oil]]) have been proposed as a reasonable alternative for the treatment of [[rheumatoid arthritis]] and other conditions as a consequence of the fact that they provide less cardiovascular risk than other treatments including NSAIDs.<ref name='fish_oils'/>

=== Effects of COX on the immune system ===
Inhibition of COX-2 using celecoxib has been shown to reduce the immunosuppressive TGFβ expression in hepatocytes attentuating EMT in human hepatocellular carcinoma<ref name="pmid22097969">{{cite journal | vauthors = Ogunwobi OO, Wang T, Zhang L, Liu C | title = Cyclooxygenase-2 and Akt mediate multiple growth-factor-induced epithelial-mesenchymal transition in human hepatocellular carcinoma | journal = Journal of Gastroenterology and Hepatology | volume = 27 | issue = 3 | pages = 566–78 | date = March 2012 | pmid = 22097969 | pmc = 3288221 | doi = 10.1111/j.1440-1746.2011.06980.x }}</ref>

== See also ==
* [[Arachidonic acid]]
* [[PTGS1|Cyclooxygenase 1]]
* [[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]]
* [[COX-3]] (not functional in humans)

== References ==
{{reflist|33em}}

== External links ==
* [http://macromoleculeinsights.com/cox.php The Cyclooxygenase Protein]
* {{MeshName|Cyclooxygenase}}
* [http://gowiki.tamu.edu/wiki/index.php/cyclooxygenase GONUTS Page: Cyclooxygenase]
* [http://proteopedia.org/wiki/index.php/Cyclooxygenase Cyclooxygenase: Proteopedia, life in 3D]
* [http://homepage.ufp.pt/pedros/science/cox/cox.htm: A discussion of the enzymatic mechanism, including interactive 3D models]{{dead link|date=August 2017 |bot=InternetArchiveBot |fix-attempted=yes }}

{{Metabolism of complex lipids}}
{{Prostanoidergics}}
{{Dioxygenases}}
{{Enzymes}}
{{Portal bar|Molecular and Cellular Biology|border=no}}

[[Category:Prostaglandins]]
[[Category:EC 1.14.99]]
[[Category:Integral membrane proteins]]