Biosynthesis
Two families of enzymes catalyze fatty acid oxygenation to produce the eicosanoids:
- Cyclooxygenase, or COX, generates the prostanoids.
- Lipoxygenase, or LOX, in several forms. 5-lipoxygenase (5-LO) generates the leukotrienes.
Eicosanoids are not stored within cells, but are synthesized as required. They derive from the fatty acids that make up the cell membrane and nuclear membrane.
Eicosanoid biosynthesis begins when a cell is activated by mechanical trauma, cytokines, growth factors or other stimuli. (The stimulus may even be an eicosanoid from a neighboring cell; the pathways are complex.) This triggers the release of a phospholipase at the cell membrane. The phospholipase travels to the nuclear membrane. There, the phospholipase catalyzes ester hydrolysis of phospholipid (by A2) or diacylglycerol (by phospholipase C). This frees a 20-carbon essential fatty acid. This hydrolysis appears to be the rate-determining step for eicosanoid formation.
The fatty acids may be released by any of several phospholipases. Of these, type IV cytosolic phospholipase A2 (cPLA2) is the key actor, as cells lacking cPLA2 are generally devoid of eicosanoid synthesis. The phospholipase cPLA2 is specific for phospholipids that contain AA, EPA or GPLA at the SN2 position. Interestingly, cPLA2 may also release the lysophospholipid that becomes platelet-activating factor.
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