Leukotrienes and Chemotaxis — 5-Lipoxygenase Activation and Control

Abstract

The leukotrienes are a group of mediators derived from arachidonic acid through the action of the 5-lipoxygenase enzyme system (Ford-Hutchinson 1990a). This enzyme is present in cells of the myeloid lineage, such as polymorphonuclear leukocytes, eosinophils, mast cells, basophils and macrophages. Following cellular activation, which induces a rise in intracellular calcium, free arachidonic acid is liberated from membrane phospholipids through the action of phospholipases. The rise in intracellular calcium also causes activation of 5-lipoxygenase which can oxygenate arachidonic acid to produce the intermediate, 5-hydroperoxyeicosatetraenoic acid. This intermediate then undergoes a dehydrase step, also catalyzed by 5-lipoxygenase, to produce the unstable epoxide intermediate, leukotriene A4. There are two enzymic routes of metabolism of leukotriene A4. The first involves the addition of water, through the action of leukotriene A4 hydrolase, to produce the dihydroxy fatty acid, leukotriene B4. The second involves the action of another unique enzyme, leukotriene C4 synthase, which catalyzes the conjugation of glutathione with leukotriene A4 to produce the peptidolipid leukotriene C4. Leukotriene C4 is further metabolized through the action of y-glutamyl transferase through loss of L-glutamic acid to probably the most important peptidolipid leukotriene, leukotriene D4. Leukotriene D4 in turn can be metabolized by a dipeptidase through loss of glycine to produce leukotriene E4.