| Prostaglandin-endoperoxide synthase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 1.14.99.1 | ||||||||
| CAS no. | 9055-65-6 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDBPDBePDBsum | ||||||||
| Gene Ontology | AmiGO /QuickGO | ||||||||
| |||||||||
| Cyclooxygenase 1 | |||||||
|---|---|---|---|---|---|---|---|
 Crystallographic structure of prostaglandin H2 synthase-1 complex withflurbiprofen[1] | |||||||
| Identifiers | |||||||
| Symbol | PTGS1 | ||||||
| Alt. symbols | COX-1 | ||||||
| NCBI gene | 5742 | ||||||
| HGNC | 9604 | ||||||
| OMIM | 176805 | ||||||
| PDB | 1CQE | ||||||
| RefSeq | NM_080591 | ||||||
| UniProt | P23219 | ||||||
| Other data | |||||||
| EC number | 1.14.99.1 | ||||||
| Locus | Chr. 9q32-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 | ||||||
| NCBI gene | 5743 | ||||||
| HGNC | 9605 | ||||||
| OMIM | 600262 | ||||||
| PDB | 6COX | ||||||
| RefSeq | NM_000963 | ||||||
| UniProt | P35354 | ||||||
| Other data | |||||||
| EC number | 1.14.99.1 | ||||||
| Locus | Chr. 1q25.2-25.3 | ||||||
| |||||||
Cyclooxygenase (COX), officially known asprostaglandin-endoperoxide synthase (PTGS), is anenzyme (specifically, a family ofisozymes,EC1.14.99.1) that is responsible for biosynthesis ofprostanoids, includingthromboxane andprostaglandins such asprostacyclin, fromarachidonic acid. A member of theanimal-type heme peroxidase family, it is also known asprostaglandin G/H synthase. The specific reaction catalyzed is the conversion from arachidonic acid toprostaglandin H2 via a short-livedprostaglandin G2 intermediate.[3][4]
Pharmaceutical inhibition of COX can provide relief from the symptoms ofinflammation andpain.[3]Nonsteroidal anti-inflammatory drugs (NSAIDs), such asaspirin andibuprofen, exert their effects through inhibition of COX. Those that are specific to theCOX-2 isozyme are calledCOX-2 inhibitors. The active metabolite (AM404) ofparacetamol is a COX inhibitor, a fact to which some or all of itstherapeutic effect has been attributed.[5]
In medicine, theroot symbol "COX" is encountered more often than "PTGS". Ingenetics, "PTGS" is officially used for this family ofgenes andproteins because the root symbol "COX" was already used for thecytochrome c oxidase family. Thus, the two isozymes found in humans,PTGS1 andPTGS2, 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.
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-terminalEGF-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 theendoplasmic reticulum (ER) andmicrosome membrane.[7]
COX is a common target for anti-inflammatory drugs. The most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution ofisoleucine at position 523 in COX-1 withvaline in COX-2. The smaller Val523 residue in COX-2 allows access to ahydrophobic 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]
The main COX inhibitors are thenon-steroidal anti-inflammatory drugs.
The classical COX inhibitors are not selective and inhibit all types of COX. The resulting inhibition ofprostaglandin andthromboxane 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.
Selectivity for COX-2 is the main feature ofcelecoxib,etoricoxib, and other members of this drug class. Since COX-2 is mostly specific to inflammed tissue, selective COX-2 inhibitors avoid irritating the COX-1 enzymes of stomach lining and reduce peptic ulcers. However, selective COX-2 inhibitors reduce the platelet inhibitor prostacyclin, allowing COX-1 enzymes to excessively producethromboxane lipids. Thus, selective COX-2 inhibitors raise the risk of blood clotting, resulting inkidney failure,heart attack,thrombosis, andstroke.[8]Rofecoxib (brand name Vioxx) was withdrawn in 2004 because of such concerns. Some other COX-2 selective NSAIDs, such ascelecoxib and etoricoxib, are still on the market.[9]
Culinary mushrooms, likemaitake, may be able to partially inhibit COX-1 and COX-2.[10][11]
A variety offlavonoids have been found to inhibit COX-2.[12]
Fish oils provide alternative fatty acids to arachidonic acid. These acids can be turned into some anti-inflammatoryprostacyclins by COX instead of pro-inflammatoryprostaglandins.[13]
Hyperforin has been shown to inhibit COX-1 around 3-18 times as much as aspirin.[14]
Calcitriol (vitamin D) significantly inhibits the expression of the COX-2 gene.[15]
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.[16]
COX-2 inhibitors have been found to increase the risk ofatherothrombosis even with short-term use. A 2006 analysis of 138 randomised trials and almost 150,000 participants[17] showed that selective COX-2 inhibitors are associated with a moderately increased risk of vascular events, mainly due to a twofold increased risk ofmyocardial infarction, and also that high-dose regimens of some traditional NSAIDs (such asdiclofenac andibuprofen, but notnaproxen) are associated with a similar increase in risk of vascular events.
This evidence, however, has been contradicted by the 2016 PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen) trial[18] of 24,081 participants, which shows a lower incidence of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke for Celecoxib as compared to both Naproxen and Ibuprofen.
Fish oils (e.g.,cod liver oil) have been proposed as a reasonable alternative for the treatment ofrheumatoid arthritis and other conditions as a consequence of the fact that they provide less cardiovascular risk than other treatments including NSAIDs.[13]
Inhibition of COX-2 using celecoxib has been shown to reduce the immunosuppressive TGFβ expression in hepatocytes attenuating EMT in human hepatocellular carcinoma[19]
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.
