Cyclooxygenase: Wikis

  

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prostaglandin-endoperoxide synthase
Identifiers
EC number 1.14.99.1
CAS number 9055-65-6
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures
Gene Ontology AmiGO / EGO
cyclooxygenase 1
PROSTAGLANDIN H2 SYNTHASE-1 COMPLEX.png
Crystallographic structure of prostaglandin H2 synthase-1 complex with flurbiprofen.[1]
Identifiers
Symbol PTGS1
Alt. symbols COX-1
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
cyclooxygenase 2
Cyclooxygenase-2.png
Cyclooxygenase-2 (Prostaglandin Synthase-2) in complex with a COX-2 selective inhibitor.[2]
Identifiers
Symbol PTGS2
Alt. symbols COX-2
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. Non-steroidal anti-inflammatory drugs, such as aspirin and ibuprofen, exert their effects through inhibition of COX. The names "prostaglandin synthase (PHS)" and "prostaglandin endoperoxide synthetase (PES)" are still used to refer to COX.

Contents

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.

At present, 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).[3]

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. 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. More recently, it has been shown to be upregulated in various carcinomas and to have a central role in tumorigenesis.

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.[citation needed]

Enzyme cyclooxygenase (box: first step in creating prostaglandins from fatty acids).[4]  
The cyclooxygenase reaction mechanism.  

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 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

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.

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 is evidence that indicates that there might be an increase in the risk for heart attack, thrombosis, and stroke through an 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.

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.[5][6] Culinary mushrooms, like Maitake, may be able to partially inhibit COX-1 and COX-2.[7][8]

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[9] 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.

See also

References

  1. ^ PDB 1CQE; Picot D, Loll PJ, Garavito RM (January 1994). "The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1". Nature 367 (6460): 243–9. doi:10.1038/367243a0. PMID 8121489. 
  2. ^ PDB 6COX; Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC (1996). "Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents". Nature 384 (6610): 644–8. doi:10.1038/384644a0. PMID 8967954. 
  3. ^ 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:10.1073/pnas.162468699. PMID 12242329. 
  4. ^ 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 2009-03-31. 
  5. ^ 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:10.1073/pnas.222543099. PMID 12374850. 
  6. ^ Soberman RJ, Christmas P (April 2003). "The organization and consequences of eicosanoid signaling". J. Clin. Invest. 111 (8): 1107–13. doi:10.1172/JCI18338. PMID 12697726. 
  7. ^ Zhang, Y; Mills, GL; Nair, MG (2002). "Cyclooxygenase inhibitory and antioxidant compounds from the mycelia of the edible mushroom Grifola frondosa". Journal of agricultural and food chemistry 50 (26): 7581–5. doi:10.1021/jf0257648. PMID 12475274.  edit
  8. ^ Zhang, Y; Mills, GL; Nair, MG (2003). "Cyclooxygenase inhibitory and antioxidant compounds from the fruiting body of an edible mushroom, Agrocybe aegerita". Phytomedicine : international journal of phytotherapy and phytopharmacology 10 (5): 386–90. PMID 12834003.  edit
  9. ^ 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:10.1136/bmj.332.7553.1302. 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.

External links








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