The synthesis of
leukotrienes begins with the activation of cytosolic
phospholipase A2 (cPLA2). CPLA2
hydrolyses and releases
arachidonic acid from membrane phospholipid. The next step is the formation of an unstable
epoxide LTA4. This occurs via an intermediate compound
5-HPETE, which is formed by the
oxygenation of arachidonic acid at its fifth carbon position. This reaction is
catalysed by
5-lipoxygenase, which is translocated from the
cytosol to the
cell membrane following cell activation. For the reaction to occur it is necessary for 5-lipoxygenase activating protein to be present. This binds free arachidonic acid and activates 5-lipoxygenase by acting as an arachidonic acid transfer protein.
LTA4 is the intermediate for the formation of the stable products of arachidonic acid metabolism by lipoxygenase. Enzymatic hydrolysis of LTA4 forms LTB4, while leukotriene C4 synthase conjugates LTA4 with glutathione, at the C-6 position, to form LTC4.
Once formed, a specific carrier transports LTC4 to the extracellular compartment. It is here that it is converted sequentially to LTD4 and LTE4 by cleavage of first glutamic acid and then glycine from the glutathione moiety of LTC4. The first reaction is catalysed by gamma-glutamyltranspeptidase and the remaining peptide bond in LTD4 is hydrolysed by dipeptidase to give LTE4.