activate the prostanoid receptors, G-protein coupled (GPCRs) to elicit a vast range of responses including sensitization to pain, inflammation and fever, immune and cardiovascular functions. The Ptgs1 and Ptgs2 cyclooxygenases, better known as Cox1 and Cox2 are bifunctional enzymes that in addition to the first cyclooxygenase activity, carry out a second, peroxidase activity. In the first reaction arachidonic acid is oxidized to prostaglandin G2 (PGG2) - a reaction dependent on a tyrosine radical on the enzyme, the generation of which involves the peroxidase activity. PGG2 is converted to prostaglandin H2 (PGH2) in the second, peroxidase mediated reaction. PGH2 is the substrate for various, cell specific prostaglandin synthases to produce the final prostaglandins, prostacyclin and thromboxane, collectively known as prostanoids. The formation of prostaglandin D2 (PGD2) is catalyzed by either the hematopoietic prostaglandin D synthase (Hpgds) or the brain specific lipocalin-type synthase (Htgds). Pgd2 activates two receptor types to modulate immune and inflammatory responses; its involvement in nociception is poorly defined. Prostaglandin E2 (PGE2) is one of the most abundant prostanoids and its formation from PGH2 is catalyzed by microsomal or cytosolic prostaglandin E synthases (Ptges) [click to see the structure of a microsomal synthase]. There are four PGE2 receptors and alternative splicing of type 1 and 3 receptors further diversifies the range of responses PGE2 can elicit. Prostaglandin I2 ( PGI2), also known as prostacyclin, is the primary prostaglandin of the endothelial cell and its synthesis is catalyzed by prostaglandin I2 synthase (Ptgis) - a member of the cytochrome P450 superfamily also known as Cyp8a1. PGI2 binds one receptor type to elicit potent vasodilation and anti-thrombic effects that oppose the function of thromboxane. Thromboxane A2 (TXA2) is involved in smooth muscle contraction and proliferation and also in platelet function. Its synthesis is catalyzed by the thromboxane A synthase 1 (Tbxas1), also a member of the cytochrome P450 superfamily, known as Cyp5a1. TXA2 engages one or two receptors. TXA2 and PGI2 are the major prostanoids of the cardiovascular system where they mediate opposite functions. Finally, the formation of prostaglandin F2alpha (PGF2alpha) metabolites, critical for mammalian reproduction, can be catalyzed by members of AKR (aldo-keto reductase) and thioredoxin-like superfamilies that require NAPH or NADPH and thioredoxin, respectively. In addition to the PGH2 derived route, the PGF2alphas can also be derived from PGE2 and PGD2. The PGH2 based route is believed to be the result of Fam213b oxidoreductase activity as well as of Akr1a1 and Akr1b1 activities whereas the formation of PGF2alpha from PGD2 and PGE2 requires the activities of Akr1c3 and Cbr1, respectively [click to see a structure of Akr1c3]. The Cox enzymes are targets of various non-steroidal anti-inflammatory (NSAID) and specific Cox-2 inhibitor drugs that inhibit the first reaction. On the other hand, paracetamol, a widely used analgesic and antipyretic drug, inhibits the second reaction. The prostanoid receptors are also targets for drug development. The expression of Cox and several prostaglandin synthases is deregulated in cancer. The inducible Cox-2 enzyme, responsible for most of prostanoid synthesis during inflammation, is up-regulated in several cancer types as well as other diseases. To see the ontology report for annotations, GViewer and download, click here...(less)