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| PROSTAGLANDIN H2 SYNTHASE-1 COMPLEX | |
| Identifiers | |
| Symbol | PTGS1 |
| Entrez | 5742 |
| HUGO | 9604 |
| OMIM | 176805 |
| PDB | 1CQE |
| RefSeq | NM_080591 |
| UniProt | P23219 |
| Other data | |
| EC number | 1.14.99.1 |
| Locus | Chr. 9 q32-q33.3 |
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| Cyclooxygenase-2 (Prostaglandin Synthase-2) | |
| Identifiers | |
| Symbol | PTGS2 |
| Entrez | 5743 |
| HUGO | 9605 |
| OMIM | 600262 |
| PDB | 6COX |
| RefSeq | NM_000963 |
| UniProt | P35354 |
| Other data | |
| EC number | 1.14.99.1 |
| Locus | Chr. 1 q25.2-25.3 |
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; this is the method of action of non-steroidal anti-inflammatory drugs, 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.
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Physiology
See also prostaglandin and eicosanoid for more details
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 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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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.
Classical NSAIDs
- See also: Mechanism of action of aspirin
The main COX inhibitors are the non-steroidal anti-inflammatory drugs (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 ulceration 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 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.[2][3]
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 [4] 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
- ^ 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.
- ^ Warner, Timothy D. and Mitchell, Jane A. (October 8, 2002). "Cyclooxygenase-3 (COX-3): Filling in the gaps toward a COX continuum?". PNAS 99 (21): 13371–13373. doi:. PMID 12374850. Retrieved on 2007-01-05.
- ^ Soberman, Roy J. and Christmas, Peter (2003). "The organization and consequences of eicosanoid signaling". J. Clin. Invest 111: 1107–1113. doi:. Retrieved on 2007-01-05.
- ^ 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
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.
See also
External links
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Wikipedia content modification information:
- This page was last modified on 26 August 2008, at 13:52.
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