Cyclooxygenase

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"COX" redirects here. For other uses, see Cox (disambiguation).
Prostaglandin-endoperoxide synthase
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Chr. 9 q32-q33.3
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Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, EC 1.14.99.1) that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such as prostacyclin, from arachidonic acid. A member of the animal-type heme peroxidase family, it is also known as prostaglandin G/H synthase. The specific reaction catalyzed is the conversion from arachidonic acid to prostaglandin H2 via a short-living prostaglandin G2 intermediate.[3][4]

COX-2 inhibitors. The active metabolite (AM404) of paracetamol is a COX inhibitor, a fact to which some or all of its therapeutic effect has been attributed.[5]

In medicine, the

PTGS2
, are frequently called COX-1 and COX-2 in medical literature. The names "prostaglandin synthase (PHS)", "prostaglandin synthetase (PHS)", and "prostaglandin-endoperoxide synthetase (PES)" are older terms still sometimes used to refer to COX.

Biology

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. Both proteins have three domains: an N-terminal EGF-like domain, a small 4-helical membrane anchor, and a core heme-peroxidase catalytic domain. Both form dimers.[6] The membrane anchor fixes the proteins into the endoplasmic reticulum (ER) and microsome membrane.[7]

Pharmacology

COX is a common target for anti-inflammatory drugs. The most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution of

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.[2]

Classical NSAIDs

See also: Mechanism of action of aspirin

The main COX inhibitors are the

non-steroidal anti-inflammatory drugs
.

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

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.[9][10]

A variety of flavonoids have been found to inhibit COX-2.[11]

prostaglandins.[12]

Hyperforin has been shown to inhibit COX-1 around 3-18 times as much as aspirin.[13]

Calcitriol (vitamin D) significantly inhibits the expression of the COX-2 gene.[14]

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.[15]

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[16] 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, but not naproxen) 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.[12]

Effects of COX on the immune system

Inhibition of COX-2 using celecoxib has been shown to reduce the immunosuppressive TGFβ expression in hepatocytes attenuating EMT in human hepatocellular carcinoma[17]

See also

References

  1. S2CID 4340064
    .
  2. ^
    S2CID 4326310
    .
  3. ^
    ISBN 978-0-323-07307-3
    . Arachidonic acid is a component of membrane phospholipids released either in a one-step process, after phospholipase A2 (PLA2) action, or a two-step process, after phospholipase C and DAG lipase actions. Arachidonic acid is then metabolized by cyclooxygenase (COX) and 5-lipoxygenase, resulting in the synthesis of prostaglandins and leukotrienes, respectively. These intracellular messengers play an important role in the regulation of signal transduction implicated in pain and inflammatory responses.
  4. PMID 17462992
    .
  5. S2CID 10837155
    .
  6. S2CID 6317524
    .
  7. ^ P23219, P35354. UniProt
  8. ^ Kumar, V., Abbas, A. K., & Aster, J. C. (2017). Robbins Basic Pathology (10th ed.). Elsevier - Health Sciences Division.
  9. PMID 12475274
    .
  10. PMID 12834003
    .
  11. PMID 15225597
    .
  12. ^
    PMID 16542466
    .
  13. PMID 12445866
    .
  14. PMID 16886660
    .
  15. S2CID 448875
    .
  16. PMID 16740558
    .
  17. PMID 22097969
    .

External links
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