Biosynthesis

Biosynthesis of eicosanoids is limited by the availability of substrate and depends primarily on the release of AA, esterified in the sn-2 domain of cell membrane phospholipids or other complex lipids, to the eicosanoid-synthesizing enzymes by acyl hydrolases, most notably phospho-lipase A2. Chemical and physical stimuli activate the Ca2+-dependent translocation of group IV cytosolic PLA2 (cPLA2), which has high affinity for AA, to the membrane, where it hydrolyzes the sn-2 ester bond of membrane phospholipids (particularly phosphatidylcholine and phos-phatidylethanolamine), releasing arachidonate. Multiple additional PLA2 isoforms (group IIA secretory [sPLA2], group V [sPLA2], group VI Ca2+ independent [iPLA2], and group X [sPLA2]) have been characterized. Under nonstimulated conditions, AA liberated by iPLA2 is reincorporated into cell membranes, so there is negligible eicosanoid biosynthesis. While cPLA2 dominates in the acute release of AA, the inducible sPLA2 contributes under conditions of sustained or intense stimulation of AA production. Once liberated, a portion of the AA is metabolized rapidly to oxygenated products by several distinct enzyme systems, including cyclooxygenases, lipoxygenases, and CYPs.

Products of Prostaglandin G/H Synthases

The prostaglandins prostacyclin and thromboxane, collectively termed prostanoids, can be considered analogs of unnatural compounds with the trivial names prostanoic acid and thrombanoic acid, with the structures shown below:

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