Cyclooxygenase
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Cyclooxygenase (COX) is an enzyme (EC 1.14.99.1) that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain. Non-steroidal anti-inflammatory drugs, such as aspirin and ibuprofen, exert their effects through inhibition of COX. The names "prostaglandin synthase" and "prostaglandin synthetase" are still used to refer to COX.
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[edit] Function
COX converts arachidonic acid (AA, an ω-6 PUFA) to prostaglandin H2 (PGH2), the precursor of the series-2 prostanoids. The enzyme contains two active sites: a heme with peroxidase activity, responsible for the reduction of PGG2 to PGH2, and a cyclooxygenase site, where arachidonic acid is converted into the hydroperoxy endoperoxide prostaglandin G2 (PGG2). The reaction proceeds through H atom abstraction from arachidonic acid by a tyrosine radical generated by the peroxidase active site. Two O2 molecules then react with the arachidonic acid radical, yielding PGG2.
Currently three COX isoenzymes are known: COX-1, COX-2, and COX-3. COX-3 is a 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).[1]
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 inducible enzyme, becoming abundant in activated macrophages and other cells at sites of inflammation.
Both COX-1 and -2 (also known as PGHS-1 and -2) also oxygenate two other essential fatty acids – DGLA (ω-6) and EPA (ω-3) – to give the series-1 and series-3 prostanoids, which are less inflammatory than those of series-2. DGLA and EPA are competitive inhibitors 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.
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![Enzyme cyclooxygenase (box: first step in creating prostaglandins from fatty acids).[2]](/wiki/File:Cyclooxygenase_(COX).JPG)
[edit] Pharmacology
In terms of their molecular biology, COX-1 and COX-2 are of similar molecular weight, approximately 70 and 72 kDa 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 Val523 residue in COX-2 allows access to a hydrophobic side-pocket in the enzyme (which Ile523 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.
[edit] Classical NSAIDs
The main COX inhibitors are the non-steroidal anti-inflammatory drugs (NSAIDs).
The classical COX inhibitors are not selective and inhibit all types of COX, and cause peptic ulceration and dyspepsia. It is believed that such lack of selectivity is caused by 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.
[edit] 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, 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 are evidence which indicates that there might be an increase in the risk for heart attack, thrombosis and stroke through a relative increase in thromboxane. The sale of Rofecoxib (brand name Vioxx) was banned in 2004 because of such concerns. Some other COX-2 selective NSAIDs, such as celecoxib and etoricoxib, are still on the market.
[edit] 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.[3][4]
[edit] Cardiovascular side effects of COX inhibitors
COX-2 inhibitors have been found to increase the risk of atherothrombosis even with short term use. A 2006 analysis of 138 randomised trials and almost 150 000 participants[5] 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.
[edit] References
- ^ 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". Proc. Natl. Acad. Sci. U.S.A. 99 (21): 13926–31. doi:. PMID 12242329.
- ^ Goodsell DS (2001-05-01). "Cyclooxygenase". RCSB Protein Data Bank. http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb17_1.html. Retrieved on 2009-03-31.
- ^ Warner TD, Mitchell JA (October 2002). "Cyclooxygenase-3 (COX-3): filling in the gaps toward a COX continuum?". Proc. Natl. Acad. Sci. U.S.A. 99 (21): 13371–3. doi:. PMID 12374850.
- ^ Soberman RJ, Christmas P (April 2003). "The organization and consequences of eicosanoid signaling". J. Clin. Invest. 111 (8): 1107–13. doi:. PMID 12697726.
- ^ Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C (June 2006). "Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials". BMJ 332 (7553): 1302–8. doi:. PMID 16740558.
[edit] 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. Theoretical Chemistry Accounts, 110, 345-351.
[edit] See also
[edit] External links
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