Biology:Cyclooxygenase-3

From HandWiki

Cyclooxygenase-3 (COX-3) is an enzyme that is encoded by the PTGS1 (COX1) gene, but is not functional in humans. COX-3 is the third and most recently discovered cyclooxygenase (COX3050) isozyme, while the first two to be discovered were COX-1 and COX-2. The COX-3 isozyme is encoded by the same gene as COX-1, with the difference that COX-3 retains an intron that is not retained in COX-1.[1][2]

The other two cyclooxygenase isozymes are known to convert dihomo-γ-linolenic acid and arachidonic acid into prostaglandins, and are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs).

Transcription

Discovery

The original COX-1/COX-2 model did not fully explain the immune responses of fever and inflammation. Even though COX-2 inhibitors are as active as traditional NSAIDs in inflammatory models, there were still some unexplained issues. For example, the widespread use of the newer generation of COX-2-selective compounds demonstrated that COX-2 also has other physiological roles, e.g. in the maintenance of fluid balance by the kidneys. In addition, the COX-1/COX-2 model did not explain the properties of paracetamol (acetaminophen): although its antipyretic (fever reducing) and analgesic (pain relieving) effects might be explained by inhibition of COX-2, it is not anti-inflammatory. Daniel L. Simmons' group suggested this was because of the presence of a variant of COX-1, which they named COX-3, that would be especially sensitive to paracetamol and related compounds. If this enzyme were particularly expressed in the brain, it could explain both the characteristics of paracetamol, which has been reputed for some time of being a centrally-acting antipyretic.[1][2]

COX-3 was actually discovered in 2002, and been found to be selectively inhibited by paracetamol, phenacetin, antipyrine, aminopyrine, dipyrone, and strongly inhibited by diclofenac, indomethacin, ibuprofen and aspirin in rodent studies.[1][2] Acetaminophen is thought of as a mild analgesic and antipyretic suitable, at best, for mild to moderate pain. Its site of action has recently been identified as a COX-3 isoenzyme, a variant of the COX-1 enzyme.[2][3][4] This discovery raises the possibility of developing more potent and selective drugs targeting the site.

A number of arguments counted against the COX-3 hypothesis: COX-2-selective inhibitors react weakly with the COX-3 enzymatic site, because the site is identical to that in COX-1, but they are as good at reducing fever as older NSAIDs. The fever response has also been clearly associated with a rapid induction of COX-2 expression and an associated increase in prostaglandin E2 production, with no role for COX-1 or a COX-1 gene product (e.g., COX-3). Finally, the sites of COX-3 expression do not appear to fit in well with those sites associated with fever, and the protein should be present within the hypothalamus rather than the cerebral cortex. All these considerations appeared to argue against COX-3 being the site of the antipyretic actions of NSAIDs and COX-2-selective agents. However, the results could be read as showing that paracetamol acts at a different site than the other NSAIDs and that more than one COX isoform contribute to the fever response.[5]


References

  1. ↑ 1.0 1.1 1.2 Botting R (June 2003). "COX-1 and COX-3 inhibitors". Thromb. Res. 110 (5–6): 269–72. doi:10.1016/S0049-3848(03)00411-0. PMID 14592546. 
  2. ↑ 2.0 2.1 2.2 2.3 "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. October 2002. doi:10.1073/pnas.162468699. PMID 12242329. 
  3. ↑ Schwab, Jan M.; Schluesener, Hermann J.; Meyermann, Richard; Serhan, Charles N. (2003). "COX-3 the enzyme and the concept: steps towards highly specialized pathways and precision therapeutics?". Prostaglandins, Leukotrienes, and Essential Fatty Acids 69 (5): 339–343. doi:10.1016/j.plefa.2003.07.003. ISSN 0952-3278. PMID 14580368. 
  4. ↑ Ayoub, Samir S.; Botting, Regina M.; Goorha, Sarita; Colville-Nash, Paul R.; Willoughby, Derek A.; Ballou, Leslie R. (2004-07-27). "Acetaminophen-induced hypothermia in mice is mediated by a prostaglandin endoperoxide synthase 1 gene-derived protein". Proceedings of the National Academy of Sciences of the United States of America 101 (30): 11165–11169. doi:10.1073/pnas.0404185101. ISSN 0027-8424. PMID 15263079. Bibcode: 2004PNAS..10111165A. 
  5. ↑ Berenbaum, Francis (2004). "COX-3: Fact or fancy?" (in en). Joint Bone Spine 71 (6): 451–453. doi:10.1016/j.jbspin.2004.02.003. PMID 15589421. 


Further reading



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Cyclooxygenase-3&oldid=4259330"