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 important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain. Non-steroidal anti-inflammatory drugs, 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.

Function [edit]

COX converts arachidonic acid (AA, an ω-6 PUFA) to prostaglandin H₂ (PGH₂), the precursor of the series-2 prostanoids. The enzyme contains two active sites: a heme with peroxidase activity, responsible for the reduction of PGG₂ to PGH₂, and a cyclooxygenase site, where arachidonic acid is converted into the hydroperoxy endoperoxide prostaglandin G₂ (PGG₂). The reaction proceeds through H atom abstraction from arachidonic acid by a tyrosine radical generated by the peroxidase active site. Two O₂ molecules then react with the arachidonic acid radical, yielding PGG₂.

At present, three COX isoenzymes are known: COX-1, COX-2, and COX-3. COX-3 is a splice variant of COX-1, which retains intron one and has a frameshift mutation; thus some prefer the name COX-1b or COX-1 variant (COX-1v).^[3]

Different tissues express varying levels of COX-1 and COX-2. Although both enzymes act basically in the same fashion, selective inhibition can make a difference in side-effects. COX-1 is considered a constitutive enzyme, being found in most mammalian cells. COX-2, on the other hand, is undetectable in most normal tissues. It is an inducible enzyme, becoming abundant in activated macrophages and other cells at sites of inflammation. More recently, it has been shown to be upregulated in various carcinomas and to have a central role in tumorigenesis.

Both COX-1 and -2 (also known as PGHS-1 and -2) also oxygenate two other essential fatty acids – DGLA (ω-6) and EPA (ω-3) – to give the series-1 and series-3 prostanoids, which are less inflammatory than those of series-2. DGLA and EPA are competitive inhibitors with AA for the COX pathways. This inhibition is a major mode of action in the way that dietary sources of DGLA and EPA (e.g., borage, fish oil) reduce inflammation.^[4]

The cyclooxygenase reaction mechanism.

Pharmacology [edit]

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 [edit]

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 [edit]

Selectivity for COX-2 is the main feature of celecoxib, rofecoxib, 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 for heart attack, thrombosis, and stroke through an increase of thromboxane unbalanced by prostacyclin (which is reduced by COX-2 inhibition).^{[citation needed]} 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 [edit]

Culinary 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 contain a natural inhibitor of COX.^[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]

Cardiovascular side-effects of COX inhibitors [edit]

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^[11] 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 have been proposed as a reasonable alternative for the treatment of rheumatoid arthritis e.g. cod liver oil and other conditions as a consequence of the fact that they provide less cardiovascular risk than other treatments including NSAIDs.^[8]

See also [edit]

• COX-2 selective inhibitor
• PTGS2
• Cyclooxygenase 2 inhibitors: drug discovery and development

References [edit]

External links [edit]

• The Cyclooxygenase Protein
• Cyclooxygenase at the US National Library of Medicine Medical Subject Headings (MeSH)
• GONUTS Page: Cyclooxygenase