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Cyclooxygenase

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Title: Cyclooxygenase  
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Subject: Eicosanoid, COX-2 inhibitor, Prostacyclin synthase, Prostaglandin, Ibuprofen
Collection: Ec 1.14.99, Integral Membrane Proteins, Prostaglandins
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Cyclooxygenase

prostaglandin-endoperoxide synthase
Identifiers
EC number 1.14.99.1
CAS number 9055-65-6
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
cyclooxygenase 1
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 (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), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (EC 1.14.99.1) that is responsible for formation of prostanoids, including prostaglandins such as prostacyclin and thromboxane.

The abbreviation "COX" is more often encountered in medicine. In genetics, the "PTGS" symbol is officially used for the prostaglandin-endoperoxide synthase (cyclooxygenase) family of genes and proteins, because the stem "COX" was already used for the cytochrome c oxidase family of genes and proteins.

Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain. Non-steroidal anti-inflammatory drugs (NSAID), 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

  • Pharmacology 1
    • Classical NSAIDs 1.1
    • Newer NSAIDs 1.2
    • Natural COX inhibition 1.3
    • Cardiovascular side-effects of COX inhibitors 1.4
  • See also 2
  • References 3
  • External links 4

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. 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 renal failure, and there is evidence that indicates an increase in the risk of heart attack, thrombosis, and stroke through an increase of thromboxane unbalanced by prostacyclin (which is reduced by COX-2 inhibition). 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.[3][4]

A variety of flavonoids have been found to inhibit COX-2.[5]

Fish oils contain a natural inhibitor of COX.[6]

Hyperforin has been shown to inhibit COX-1 around 3-18 times as much as aspirin.[7]

Calcitriol (vitamin D) significantly inhibits the expression of the COX-2 gene.[8]

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.[9]

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[10] 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.

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.[6]

See also

References

  1. ^ ​; 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.  
  2. ^ ​; 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.  
  3. ^ Zhang Y, Mills GL, Nair MG (December 2002). "Cyclooxygenase inhibitory and antioxidant compounds from the mycelia of the edible mushroom Grifola frondosa". J. Agric. Food Chem. 50 (26): 7581–5.  
  4. ^ Zhang Y, Mills GL, Nair MG (2003). "Cyclooxygenase inhibitory and antioxidant compounds from the fruiting body of an edible mushroom, Agrocybe aegerita". Phytomedicine 10 (5): 386–90.  
  5. ^ O'Leary KA, de Pascual-Tereasa S, Needs PW, Bao YP, O'Brien NM, Williamson G (July 2004). "Effect of flavonoids and vitamin E on cyclooxygenase-2 (COX-2) transcription". Mutat. Res. 551 (1–2): 245–54.  
  6. ^ a b Fish oil: what the prescriber needs to know by Leslie G Cleland, Michael J James, and Susanna M Proudman http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1526555/
  7. ^ Albert D, Zündorf I, Dingermann T, Müller WE, Steinhilber D, Werz O. (December 2002). "Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase". Biochemical Pharmacology. 15;64(12):1767-75. PMID 12445866
  8. ^ Moreno J, Krishnan AV, Peehl DM, Feldman D. (July–August 2006). "Mechanisms of vitamin D-mediated growth inhibition in prostate cancer cells: inhibition of the prostaglandin pathway.". Anticancer Res. 26 (4A): 2525–2530.  
  9. ^ Wallace JL (October 2008). "Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself?". Physiol. Rev. 88 (4): 1547–65.  
  10. ^ 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.  

External links

  • The Cyclooxygenase Protein
  • Cyclooxygenase at the US National Library of Medicine Medical Subject Headings (MeSH)
  • GONUTS Page: Cyclooxygenase
  • Cyclooxygenase: Proteopedia, life in 3D
  • A discussion of the enzymatic mechanism, including interactive 3D models
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