| 词条 | Cyclooxygenase |
| 释义 |
| Name = prostaglandin-endoperoxide synthase | EC_number = 1.14.99.1 | CAS_number = 9055-65-6 | IUBMB_EC_number = 1/14/99/1 | GO_code = 0004666 | image = | width = | caption = }}{{infobox protein |Name=cyclooxygenase 1 |caption=Crystallographic structure of prostaglandin H2 synthase-1 complex with flurbiprofen.[1] |image= PROSTAGLANDIN H2 SYNTHASE-1 COMPLEX.png |width= |HGNCid=9604 |Symbol=PTGS1 |AltSymbols=COX-1 |EntrezGene=5742 |OMIM=176805 |RefSeq=NM_080591 |UniProt=P23219 |PDB=1CQE |ECnumber=1.14.99.1 |Chromosome=9 |Arm=q |Band=32 |LocusSupplementaryData=-q33.3 }}{{infobox protein |Name=cyclooxygenase 2 |caption= Cyclooxygenase-2 (Prostaglandin Synthase-2) in complex with a COX-2 selective inhibitor.[2] |image=Cyclooxygenase-2.png |width= |HGNCid=9605 |Symbol=PTGS2 |AltSymbols=COX-2 |EntrezGene=5743 |OMIM=600262 |RefSeq=NM_000963 |UniProt=P35354 |PDB=6COX |ECnumber=1.14.99.1 |Chromosome=1 |Arm=q |Band=25.2 |LocusSupplementaryData=-25.3 }}Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, {{EC_number|1.14.99.1}}) that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as prostacyclin, from arachidonic acid.[3]Pharmaceutical inhibition of COX can provide relief from the symptoms of inflammation and pain.[3] Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, exert their effects through inhibition of COX. Those that are specific to the COX-2 isozyme are called COX-2 inhibitors. The active metabolite (AM404) of paracetamol believed to provide most or all of its analgesic effects is a COX inhibitor and this is believed to provide part of its effect.[4] In medicine, the root symbol "COX" is encountered more often than "PTGS". In genetics, "PTGS" is officially used for this family of genes and proteins, because the root symbol "COX" was already used for the cytochrome c oxidase family. Thus the two isozymes found in humans, PTGS1 and PTGS2, are frequently called COX-1 and COX-2 in the 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. PharmacologyIn 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{{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 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 NSAIDsSelectivity 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). {{Citation needed|date=March 2013}} 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 inhibitionCulinary mushrooms, like maitake, may be able to partially inhibit COX-1 and COX-2.[5][6] A variety of flavonoids have been found to inhibit COX-2.[7] Fish oils provide alternative fatty acids to arachidonic acid. These acids can be turned into some anti-inflammatory prostacyclins by COX instead of pro-inflammatory prostaglandins.[8]Hyperforin has been shown to inhibit COX-1 around 3-18 times as much as aspirin.[9]Calcitriol (vitamin D) significantly inhibits the expression of the COX-2 gene.[10]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.[11] Cardiovascular side-effects of COX inhibitorsCOX-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[12] 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.[8] Effects of COX on the immune systemInhibition of COX-2 using celecoxib has been shown to reduce the immunosuppressive TGFβ expression in hepatocytes attentuating EMT in human hepatocellular carcinoma[13] See also
References1. ^{{PDB|1CQE}}; {{cite journal | vauthors = Picot D, Loll PJ, Garavito RM | title = The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1 | journal = Nature | volume = 367 | issue = 6460 | pages = 243–9 | date = January 1994 | pmid = 8121489 | doi = 10.1038/367243a0 }} 2. ^{{PDB|6COX}}; {{cite journal | vauthors = Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC | title = Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents | journal = Nature | volume = 384 | issue = 6610 | pages = 644–8 | year = 1996 | pmid = 8967954 | doi = 10.1038/384644a0 }} 3. ^1 {{cite book | vauthors = Litalien C, Beaulieu P | chapter = Chapter 117 – Molecular Mechanisms of Drug Actions: From Receptors to Effectors | veditors = Fuhrman BP, Zimmerman JJ |title=Pediatric Critical Care |date=2011 |publisher=Elsevier Saunders |location=Philadelphia, PA |isbn=978-0-323-07307-3 | doi = 10.1016/B978-0-323-07307-3.10117-X |pages=1553–1568 |edition=4th |quote=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. ^{{cite journal | vauthors = Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM | title = Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system | journal = The Journal of Biological Chemistry | volume = 280 | issue = 36 | pages = 31405–12 | date = September 2005 | pmid = 15987694 | doi = 10.1074/jbc.M501489200 | url = http://www.jbc.org/content/280/36/31405.full.pdf | format = pdf }} 5. ^{{cite journal | vauthors = Zhang Y, Mills GL, Nair MG | title = Cyclooxygenase inhibitory and antioxidant compounds from the mycelia of the edible mushroom Grifola frondosa | journal = Journal of Agricultural and Food Chemistry | volume = 50 | issue = 26 | pages = 7581–5 | date = December 2002 | pmid = 12475274 | doi = 10.1021/jf0257648 }} 6. ^{{cite journal | vauthors = Zhang Y, Mills GL, Nair MG | title = Cyclooxygenase inhibitory and antioxidant compounds from the fruiting body of an edible mushroom, Agrocybe aegerita | journal = Phytomedicine | volume = 10 | issue = 5 | pages = 386–90 | year = 2003 | pmid = 12834003 | doi = 10.1078/0944-7113-00272 }} 7. ^{{cite journal | vauthors = O'Leary KA, de Pascual-Teresa S, de Pascual-Tereasa S, Needs PW, Bao YP, O'Brien NM, Williamson G | title = Effect of flavonoids and vitamin E on cyclooxygenase-2 (COX-2) transcription | journal = Mutation Research | volume = 551 | issue = 1-2 | pages = 245–54 | date = July 2004 | pmid = 15225597 | doi = 10.1016/j.mrfmmm.2004.01.015 }} 8. ^1 {{cite journal | vauthors = Cleland LG, James MJ, Proudman SM | title = Fish oil: what the prescriber needs to know | journal = Arthritis Research & Therapy | volume = 8 | issue = 1 | pages = 202 | year = 2006 | pmid = 16542466 | pmc = 1526555 | doi = 10.1186/ar1876 }} 9. ^{{cite journal | vauthors = Albert D, Zündorf I, Dingermann T, Müller WE, Steinhilber D, Werz O | title = Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase | journal = Biochemical Pharmacology | volume = 64 | issue = 12 | pages = 1767–75 | date = December 2002 | pmid = 12445866 | doi = 10.1016/s0006-2952(02)01387-4 }} 10. ^{{cite journal | vauthors = Moreno J, Krishnan AV, Peehl DM, Feldman D | title = Mechanisms of vitamin D-mediated growth inhibition in prostate cancer cells: inhibition of the prostaglandin pathway | journal = Anticancer Research | volume = 26 | issue = 4A | pages = 2525–30 | date = July–August 2006 | pmid = 16886660 | doi = | url = http://ar.iiarjournals.org/content/26/4A/2525.abstract }} 11. ^{{cite journal | vauthors = Wallace JL | title = Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself? | journal = Physiological Reviews | volume = 88 | issue = 4 | pages = 1547–65 | date = October 2008 | pmid = 18923189 | doi = 10.1152/physrev.00004.2008 | url = http://physrev.physiology.org/content/88/4/1547.long }} 12. ^{{cite journal | vauthors = Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C | title = Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials | journal = BMJ | volume = 332 | issue = 7553 | pages = 1302–8 | date = June 2006 | pmid = 16740558 | pmc = 1473048 | doi = 10.1136/bmj.332.7553.1302 }} 13. ^{{cite journal | vauthors = Ogunwobi OO, Wang T, Zhang L, Liu C | title = Cyclooxygenase-2 and Akt mediate multiple growth-factor-induced epithelial-mesenchymal transition in human hepatocellular carcinoma | journal = Journal of Gastroenterology and Hepatology | volume = 27 | issue = 3 | pages = 566–78 | date = March 2012 | pmid = 22097969 | pmc = 3288221 | doi = 10.1111/j.1440-1746.2011.06980.x }} External links
3 : Prostaglandins|EC 1.14.99|Integral membrane proteins |
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