Overview: Prostaglandin (PG) G/H synthase, most commonly referred to as cyclooxygenase [COX, (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate,hydrogen-donor : oxygen oxidoreductase] activity, catalyses the formation of PG G2 from arachidonic acid. Hydroperoxidase activity inherent in the enzyme catalyses the formation of PGH2 from PGG2. COX-1 and -2 can be nonselectively inhibited by ibuprofen, ketoprofen, naproxen, indometacin and paracetamol (acetaminophen).
Subsequent to the formation of PGH2, the cytochrome P450 activities (see page S215) thromboxane synthase (CYP5A1, EC 5.3.99.5, ENSG00000059377) and prostacyclin synthase (CYP8A1, EC 5.3.99.4, ENSG00000124212) generate thromboxane A2 and prostacyclin (PGI2), respectively. Additionally, multiple enzyme activities are able to generate prostaglandin E2, prostaglandin D2 and prostaglandin F2α (see tables).
| Nomenclature | COX-1 | COX-2 |
| Other names | Prostaglandin G2/H2 synthase-1 | Prostaglandin G2/H2 synthase-2 |
| Ensembl ID | ENSG00000095303 | ENSG00000073756 |
| EC | 1.14.99.1 | 1.4.99.1 |
| Substrates | Arachidonic acid | Arachidonic acid, docosahexaenoic acid (see Smith, 2008) |
| Selective inhibitors | FR122047 (7.5, Ochi et al., 2000), valeroylsalicylate (Bhattacharyya et al., 1995) | Diclofenac (6.7), celecoxib (5.1), rofecoxib (4.3), valdecoxib, parecoxib, etoricoxib, lumiracoxib |
| Nomenclature | mPGES1 | mPGES2 | cPGES | L-PGDS | H-PGDS |
| Other names | Prostaglandin E synthase, microsomal glutathione S-transferase 1-like 1, MGST1-L1, p53-induced gene 12 protein p53-induced gene 12; PIG12 | Prostaglandin E synthase 2, microsomal prostaglandin E synthase 2, mPGES-2 | Cytosolic prostaglandin E2 synthase, prostaglandin E synthase 3, telomerase-binding protein p23, hsp90 co-chaperone, progesterone receptor complex p23 | Lipocalin-type prostaglandin-D synthase, prostaglandin D2 synthase, prostaglandin H2 D-isomerase, glutathione-independent PGD synthetase, β-trace protein, cerebrin-28 | Hematopoietic prostaglandin D synthase, glutathione-requiring prostaglandin D synthase, glutathione-dependent PGD synthetase, prostaglandin-H2 D-isomerase |
| EC | 5.3.99.3 | 5.3.99.3 | 5.3.99.3 | 5.3.99.2 | 5.3.99.2 |
| Ensembl ID | ENSG00000148344 | ENSG00000148334 | ENSG00000110958 | ENSG00000107317 | ENSG00000163106 |
Prostaglandin D2 can be metabolised to 9α,11β-prostaglandin F2α through the multifunctional enzyme activity AKR1C3. Prostaglandin E2 can be metabolised to 9α,11α-prostaglandin F2α through the 9-ketoreductase activity of CBR1.
| Nomenclature | AKR1C3 | CBR1 |
| Other names | Aldo-keto reductase family 1 member C3, prostaglandin F synthase, PGFS, trans-1,2-dihydrobenzene-1,2-diol dehydrogenase, 3α-hydroxysteroid dehydrogenase type 2, 3α-HSD type 2, testosterone 17β-dehydrogenase 5, 17β-hydroxysteroid dehydrogenase type 5, 17β-HSD 5, dihydrodiol dehydrogenase type I, dihydrodiol dehydrogenase 3, chlordecone reductase homolog HAKRb, HA1753 | Carbonyl reductase [NADPH] 1, prostaglandin E2 9-reductase, prostaglandin 9-ketoreductase, NADPH-dependent carbonyl reductase 1, 15-hydroxyprostaglandin dehydrogenase [NADP+] |
| EC | 1.1.1.188, 1.3.1.20, 1.1.1.213, 1.1.1.63, 1.1.1.64 | 1.1.1.197, 1.1.1.184, 1.1.1.189 |
| Ensembl ID | ENSG00000196139 | ENSG00000159228 |
| Inhibitors | Flufenamic acid, indometacin (Matsuura et al., 1998), flavonoids (Skarydova et al., 2009) | – |
Glossary
Abbreviations:
- FR122047
1-([4,5-bis{methoxyphenyl}-2-thazoyl]carbonyl)-4-methyl)piperazine hydrochloride
Further Reading
Blobaum AL, Marnett LJ (2007). Structural and functional basis of cyclooxygenase inhibition. J Med Chem50: 1425–1441.
Cha YI, DuBois RN (2007). NSAIDs and cancer prevention: targets downstream of COX-2. Annu Rev Med58: 239–252.
Eisinger AL, Prescott SM, Jones DA, Stafforini DM (2007). The role of cyclooxygenase-2 and prostaglandins in colon cancer. Prostaglandins Other Lipid Mediat82: 147–154.
Grosser T, Fries S, FitzGerald GA (2006). Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest116: 4–15.
Kang YJ, Mbonye UR, DeLong CJ, Wada M, Smith WL (2007). Regulation of intracellular cyclooxygenase levels by gene transcription and protein degradation. Prog Lipid Res46: 108–125.
Maxwell SR, Payne RA, Murray GD, Webb DJ (2006). Selectivity of NSAIDs for COX-2 and cardiovascular outcome. Br J Clin Pharmacol62: 243–245.
O'Banion MK (2009). Prostaglandin E2 synthases in neurologic homeostasis and disease. Prostaglandins Other Lipid Mediat, in press.
Samuelsson B, Morgenstern R, Jakobsson PJ (2007). Membrane prostaglandin E synthase-1: a novel therapeutic target. Pharmacol Rev59: 207–224.
Smith WL (2008). Nutritionally essential fatty acids and biologically indispensable cyclooxygenases. Trends Biochem Sci33: 27–37.
Smyth EM, Grosser T, Wang M, Yu Y, FitzGerald GA (2009). Prostanoids in health and disease. J Lipid Res50(Suppl.): S423–S428.
References
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