Biosynthesis and metabolism of leukotrienes

Leukotrienes are metabolites of arachidonic acid derived from the action of 5-LO (5-lipoxygenase). The immediate product of 5-LO is LTA₄ (leukotriene A₄), which is enzymatically converted into either LTB₄ (leukotriene B₄) by LTA₄ hydrolase or LTC₄ (leukotriene C₄) by LTC₄ synthase. The regulation of leukotriene production occurs at various levels, including expression of 5-LO, translocation of 5-LO to the perinuclear region and phosphorylation to either enhance or inhibit the activity of 5-LO. Several other proteins, including cPLA₂α (cytosolic phospholipase A₂α) and FLAP (5-LO-activating protein) also assemble at the perinuclear region before production of LTA₄. LTC₄ synthase is an integral membrane protein that is present at the nuclear envelope; however, LTA₄ hydrolase remains cytosolic. Biologically active LTB₄ is metabolized by ω-oxidation carried out by specific cytochrome P450s (CYP4F) followed by β-oxidation from the ω-carboxy position and after CoA ester formation. Other specific pathways of leukotriene metabolism include the 12-hydroxydehydrogenase/15-oxo-prostaglandin-13-reductase that forms a series of conjugated diene metabolites that have been observed to be excreted into human urine. Metabolism of LTC₄ occurs by sequential peptide cleavage reactions involving a γ-glutamyl transpeptidase that forms LTD₄ (leukotriene D₄) and a membrane-bound dipeptidase that converts LTD₄ into LTE₄ (leukotriene E₄) before ω-oxidation. These metabolic transformations of the primary leukotrienes are critical for termination of their biological activity, and defects in expression of participating enzymes may be involved in specific genetic disease.