Editing Cyclooxygenase

{{cs1 config|name-list-style=vanc}}
{{Short description|Class of enzymes}}
{{redirect|COX||Cox (disambiguation)}}
{{infobox enzyme
| Name       = Prostaglandin-endoperoxide synthase
| EC_number  = 1.14.99.1
| CAS_number = 9055-65-6
| 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 | bibcode = 1994Natur.367..243P | s2cid = 4340064 }}</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 | bibcode = 1996Natur.384..644K | s2cid = 4326310 }}</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 biosynthesis of [[prostanoid]]s, including [[thromboxane]] and [[prostaglandin]]s such as [[prostacyclin]], from [[arachidonic acid]]. A member of the [[animal heme-dependent peroxidases|animal-type heme peroxidase]] family, it is also known as '''prostaglandin G/H synthase'''. The specific reaction catalyzed is the conversion from arachidonic acid to [[prostaglandin H2]] via a short-living [[prostaglandin G2]] intermediate.<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 | url = https://archive.org/details/pediatriccritica00mdbr | url-access = limited |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=[https://archive.org/details/pediatriccritica00mdbr/page/n1557 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><ref>{{cite journal | vauthors = Liu J, Seibold SA, Rieke CJ, Song I, Cukier RI, Smith WL | title = Prostaglandin endoperoxide H synthases: peroxidase hydroperoxide specificity and cyclooxygenase activation | journal = The Journal of Biological Chemistry | volume = 282 | issue = 25 | pages = 18233–44 | date = June 2007 | pmid = 17462992 | doi = 10.1074/jbc.M701235200 | doi-access = free }}</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]] is a COX inhibitor, a fact to which some or all of its [[Analgesic|therapeutic effect]] has been attributed.<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 | s2cid = 10837155 | url = http://www.jbc.org/content/280/36/31405.full.pdf | doi-access = free }}</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 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.

== Biology ==
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. Both proteins have three domains: an N-terminal [[EGF-like domain]], a small 4-helical membrane anchor, and a core heme-peroxidase catalytic domain. Both form dimers.<ref>{{cite journal | vauthors = Nina M, Bernèche S, Roux B | title = Anchoring of a monotopic membrane protein: the binding of prostaglandin H2 synthase-1 to the surface of a phospholipid bilayer | journal = European Biophysics Journal | volume = 29 | issue = 6 | pages = 439–54 | date = 2000 | pmid = 11081405 | doi = 10.1007/PL00006649 | s2cid = 6317524 }}</ref> The membrane anchor fixes the proteins into the [[endoplasmic reticulum]] (ER) and [[microsome]] membrane.<ref name=uniprotboth>{{UniProt|P23219}}, {{UniProt|P35354}}. ''UniProt''</ref>

== Pharmacology ==

COX is a common target for anti-inflammatory drugs.  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.<ref name="pmid8967954"/>

=== Classical NSAIDs ===

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

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 prostaglandins 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 [[kidney 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).<ref>Kumar, V., Abbas, A. K., & Aster, J. C. (2017). Robbins Basic Pathology (10th ed.). Elsevier - Health Sciences Division.
</ref>  [[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 | doi-access = free }}</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 | url = http://ar.iiarjournals.org/content/26/4A/2525.abstract | access-date = 2013-03-12 | archive-date = 2017-04-25 | archive-url = https://web.archive.org/web/20170425063418/http://ar.iiarjournals.org/content/26/4A/2525.abstract | url-status = live }}</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 |last=Wallace |first=John L. |date=October 2008 |title=Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself? |url=https://pubmed.ncbi.nlm.nih.gov/18923189/ |journal=Physiological Reviews |volume=88 |issue=4 |pages=1547–1565 |doi=10.1152/physrev.00004.2008 |issn=0031-9333 |pmid=18923189}}</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.

This evidence, however, has been contradicted by the 2016 PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen) trial<ref name="pmid27959716">{{cite journal | vauthors = Nissen SE, Yeomans ND, Solomon DH, Luscher TF, Libby P, Husni ME, Graham DY, Borer JS, Wisniewski LM, Wolski KE, Qiuqing W, Menon V, Ruschitzka F, Gaffney M, Beckerman B, Berger MF, Weihang B, Lincoff AM | title = Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis | journal = NEJM | volume = 375 | issue = 26 | date = December 2016 | pmid = 27959716 | doi = 10.1056/NEJMoa1611593 }}</ref> of 24,081 participants, which shows a lower incidence of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke for Celecoxib as compared to both Naproxen and Ibuprofen.

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 attenuating 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 ==
* [[Cyclooxygenase-1]]
* [[Cyclooxygenase-2]]
* [[Cyclooxygenase-3]] (not functional in humans)
* [[Discovery and development of cyclooxygenase 2 inhibitors|Discovery and development of COX-2 selective inhibitors]]

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

== External links ==
* {{usurped|1=[https://web.archive.org/web/20071007185051/http://macromoleculeinsights.com/cox.php The Cyclooxygenase Protein]}}
* {{MeshName|Cyclooxygenase}}
* [https://web.archive.org/web/20120219145840/http://gowiki.tamu.edu/wiki/index.php/cyclooxygenase GONUTS Page: Cyclooxygenase]
* [http://proteopedia.org/wiki/index.php/Cyclooxygenase Cyclooxygenase: Proteopedia, life in 3D]
* [https://web.archive.org/web/20131013055255/http://homepage.ufp.pt/pedros/science/cox/cox.htm A discussion of the enzymatic mechanism, including interactive 3D models]

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

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