Cyclooxygenase
321628
224771214
2008-07-10T10:12:33Z
VolkovBot
3035831
robot Modifying: [[zh:環氧酶]]
{{protein
|Name=[[PTGS1|prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)]]
|caption=
|image=
|width=
|HGNCid=9604
|Symbol=[[PTGS1]]
|AltSymbols=
|EntrezGene=5742
|OMIM=176805
|RefSeq=NM_080591
|UniProt=P23219
|PDB=
|ECnumber=1.14.99.1
|Chromosome=9
|Arm=q
|Band=32
|LocusSupplementaryData=-q33.3
}}
{{protein
|Name=[[PTGS2|prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)]]
|caption=
|image=
|width=
|HGNCid=9605
|Symbol=[[PTGS2]]
|AltSymbols=
|EntrezGene=5743
|OMIM=600262
|RefSeq=NM_000963
|UniProt=P35354
|PDB=
|ECnumber=1.14.99.1
|Chromosome=1
|Arm=q
|Band=25.2
|LocusSupplementaryData=-25.3
}}
'''Cyclooxygenase''' ('''COX''') is an [[enzyme]] ({{EC_number|1.14.99.1}}) that is responsible for formation of important biological mediators called [[prostanoid]]s (including [[prostaglandin]]s, [[prostacyclin]] and [[thromboxane]]). Pharmacological inhibition of ''COX'' can provide relief from the symptoms of [[inflammation]] and [[pain]]; this is the method of action of [[non-steroidal anti-inflammatory drug]]s, such as the well-known [[aspirin]] and [[ibuprofen]]. The names "prostaglandin synthase" and "prostaglandin synthetase" are still sometimes used to refer to the COX enzyme.
== Physiology ==
''See also [[prostaglandin]] and [[eicosanoid]] for more details''
''COX'' converts [[arachidonic acid]] (AA, an [[Omega-6 fatty acid|ω-6]] [[PUFA]]) to [[prostaglandin|prostaglandin H<sub>2</sub>]] (PGH<sub>2</sub>), the precursor of the series-2 [[prostanoid]]s. The enzyme contains two active sites: a [[heme]] with [[peroxidase]] activity, responsible for the reduction of PGG<sub>2</sub> to PGH<sub>2</sub>, and a cyclooxygenase site, where arachidonic acid is converted into the hydroperoxy endoperoxide prostaglandin G<sub>2</sub> (PGG<sub>2</sub>). The reaction proceeds through H atom abstraction from arachidonic acid by a tyrosine radical generated by the [[peroxidase]] active site. Two O<sub>2</sub> molecules then react with the arachidonic acid radical, yielding PGG<sub>2</sub>.
Currently three ''COX'' [[isoenzyme]]s are known—''[[PTGS1|COX-1]]'', ''[[COX-2]]'' and ''[[PTGS1|COX-3]]''. ''COX-3'' is a [[Splicing (genetics)|splice variant]] of COX-1 which retains [[intron]] one and has a [[frameshift mutation]], thus some prefer the name ''COX-1b'' or ''COX-1 variant'' (''COX-1v'').<ref>Chandrasekharan, N.V., Dai, H., Roos, K.L.T. et al. 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, (2002). PMID 12242329.</ref>
Different tissues express varying levels of ''COX-1'' and ''COX-2''. Although both enzymes act basically in the same fashion, selective inhibition can make a difference in terms of side-effects. ''COX-1'' is considered a constitutive enzyme, being found in most mammalian cells. More recently it has been shown to be upregulated in various carcinomas and to have a central role in tumorigenesis. ''COX-2'', on the other hand, is undetectable in most normal tissues. It is an [[adaptive enzyme|inducible enzyme]], becoming abundant in activated [[macrophage]]s and other cells at sites of inflammation.
Both COX-1 and -2 also oxygenate two other essential fatty acids – [[Dihomo-gamma-linolenic acid|DGLA]] (ω-6) and [[Eicosapentaenoic acid|EPA]] (ω-3) – to give the series-1 and series-3 prostanoids, which are less [[inflammation|inflammatory]] than those of series-2. DGLA and EPA are [[competitive inhibitor]]s with AA for the COX pathways. This inhibition is a major mode of action in the way that dietary sources of DGLA and EPA (e.g. [[borage]], [[fish oil]]) reduce inflammation.
[[Image:Cyclooxygenase (COX).JPG|thumb|Enzyme cyclooxygenase (box: first step in creating prostaglandins from fatty acids) ([http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb17_1.html more details...])]]
[[Image:cycloxygenase.gif|thumb|350px|Cyclooxygenase reaction mechanism]]
== 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 relatively 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 (i.e. they inhibit all types of ''COX''), and the main adverse effects of their use are [[peptic ulcer]]ation and [[dyspepsia]]. It is believed that this may be due to the "dual-insult" of NSAIDs - direct irritation of the gastric mucosa (many NSAIDs are acids), and inhibition of [[prostaglandin]] synthesis by ''COX-1''. Prostaglandins have a protective role in the gastrointestinal tract, preventing acid-insult to the mucosa.
=== Newer NSAIDs ===
Selectivity for ''COX-2'' is the main feature of [[celecoxib]], [[rofecoxib]] 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, leading to a decreased risk of peptic ulceration. COX-2-selectivity does not seem to negate other side-effects of NSAIDs (most notably an increased risk of [[renal failure]]), and some results have indicated there might be an increase in the risk for [[myocardial infarction|heart attack]], [[thrombosis]] and [[stroke]] through a relative increase in [[thromboxane]]. [[Rofecoxib]] (brand name [[Vioxx]]) was taken off the market in 2004 because of these concerns. Some other COX-2 selective NSAIDs, such as [[celecoxib]] and [[etoricoxib]], are still on the market.
=== Non-NSAID COX inhibition ===
It has been suggested that [[acetaminophen]], also known as paracetamol, reversibly inhibits ''COX-3'', although there is now some doubt about this theory. ''COX-3'' produces prostanoids in the brain, but does not participate in eicosanoid signalling in inflammation. Acetaminophen thereby may interfere with the perception of pain. Since it has no effect on inflammation, it is not classed as an NSAID.<ref>{{cite journal
|title= Cyclooxygenase-3 (COX-3): Filling in the gaps toward a COX continuum?
| author= Warner, Timothy D. and Mitchell, Jane A.
| url=http://www.pnas.org/cgi/content/extract/99/21/13371
| year = October 8, 2002 | doi= 10.1073/pnas.222543099
| journal =PNAS | volume= 99 | issue=21 | pages=13371–13373
| accessdate = 2007-01-05
|pmid= 12374850}} </ref><ref> {{cite journal | journal =J. Clin. Invest| volume= 111 |pages=1107–1113 |year=2003
| url = http://www.jci.org/cgi/content/full/111/8/1107
|doi = 10.1172/JCI200318338
|title =The organization and consequences of eicosanoid signaling
|author = Soberman, Roy J. and Christmas, Peter
|accessdate = 2007-01-05}}</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>Kearney PM, Baigent C, Godwin J, Halls H, et al. ''Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials.'' BMJ. 2006 Jun 3;332(7553):1302-8. PMID 16740558</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]] are associated with a similar increase in risk of vascular events.
== References ==
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==Further reading==
*Pedro J. Silva, Pedro A. Fernandes and Maria J. Ramos (2003) A theoretical study of radical-only and combined radical/carbocationic mechanisms of arachidonic acid cyclooxygenation by prostaglandin H synthase. [http://dx.doi.org/10.1007/s00214-003-0476-9 Theoretical Chemistry Accounts, 110, 345-351.]
== See also ==
* [[COX-2 selective inhibitor]]
* [[PTGS2]]
==External links==
* [http://macromoleculeinsights.com/cox.php The Cyclooxygenase Protein]
* {{MeshName|Cyclooxygenase}}
{{Oxygenases}}
{{Metabolism of complex lipids}}
[[Category:EC 1.14.99]]
[[Category:Integral membrane proteins]]
[[bs:Ciklooksigenaza]]
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[[ja:シクロオキシゲナーゼ]]
[[pl:Cyklooksygenaza]]
[[pt:Ciclooxigenase]]
[[zh:環氧酶]]