phospholipids at the sn-2 position to release free arachidonic acid and lysophospholipid. Arachidonic acid sets in motion a three-pronged cascade that results in the production of eicosanoids - potent mediators of inflammation. Lysophospholipid, the other substrate released by Pla2g4a activity, can be used in the production of platelet-activating factor (PAF), also a potent mediator of inflammation. The membrane translocation of Pla2g4a is dependent on Ca2+ which binds to the C2 domain at the N-terminus of the enzyme. The C2 domains are Ca2+ and phospholipid binding domains. The C-terminus catalytic domain has several phosphorylation sites; although mutations of these sites impair the activity of the enzyme, the mechanism of Pla2ga4 activation by phosphorylation is not well understood. The mitogen activated kinase (MAPK) Mknk1 is involved in the serine phosphorylation of Pla2g4a. Binding of annexins can inhibit the activity of the enzyme; annexin 1 (Anxa1) binds to the C2 domain of the enzyme. Binding of vimentin, on the other hand, promotes arachidonic acid release. The role of other interactors is less well defined [ Click to see the crystal structure of cPLA2]. Once released, arachidonic acid is metabolized via three routes: the cyclooxygenase mediated pathway leads to the production of prostanoids, the lipooxygenase mediated pathway leads to the production of leukotrienes and the cytochrome P450 monooxygenase mediated pathway leads to the production of hydroxyeicosatetraenoic (HETE) and epoxyeicosatrienoic acids (EET). In the cyclooxygenase mediated pathway, arachidonic acid is the substrate of Ptgs1 and Ptgs2 cyclooxygenases, better known as Cox-1 and Cox-2. Both Cox-1 and 2 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. Cox 1 is a constitutive enzyme whereas Cox 2 is inducible. Cox 2 can also act upon the endogenous endocannabinoids providing a route for their degradation. Click, to see the structure of Cox-1; click to see Cox-2 in complex with a selective inhibitor. PHG2 produced in the second reaction is the substrate for various, cell specific prostaglandin synthases to produce the final prostaglandins, prostacyclin and thromboxane, collectively known as prostanoids. The prostanoids bind to and 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 Cox enzymes and the prostanoid receptors are targets for drug development. Various non-selective non-steroidal anti-inflammatory (NSAIDs) drugs such as indomethacin or diclofenac and selective Cox-2 inhibitors such as celecoxib or meloxicam, target the cyclooxygenases, specifically the first reaction. On the other hand paracetamol, also known as acetaminophen, a widely used analgesic and antipyretic drug, inhibits the second reaction of both enzymes. 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)