Biochemistry of the lipoxygenase pathways in neutrophils

Abstract

Three mammalian lipoxygenases have been reported to date. They catalyze the insertion of oxygen at positions 5, 12, and 15 of various 20-carbon polyunsaturated fatty acids. In the case of arachidonic acid, the immediate products are hydroperoxyeicosatetraenoic acids (HPETEs). HPETEs can undergo different transformations. One reaction is a reduction of the hydroperoxy group yielding the corresponding hydroxyeicosatetraenoic acids (HETEs). In the neutrophils, the major pathway of arachidonic acid metabolism is the 5-lipoxygenase. In these cells the 5-HPETE undergoes a cyclization reaction leading to a 5(6)-epoxy(oxido)eicosatetraenoic acid or leukotriene A4. The 5(6)-epoxy fatty acid can undergo three additional transformations: (a) a nonenzymatic hydrolysis to epimeric dihydroxyeicosatetraenoic acids (diHETEs); (b) stereospecific enzymatic hydrolysis to a specific diHETE, leukotriene B4; or (c) ring opening by reduced glutathione (GSH) to yield a peptidolipid, named leukotriene C4, in which GSH is attached via a sulfoether linkage. The leukotrienes constitute a group of biologically active substances probably involved in allergic and inflammatory reactions. The 5(6)-epoxy-eicosatetraenoic acid and the products derived from it contain a conjugated triene unit; the term leukotriene also denotes the cells (leukocytes) recognized to form these products, mainly the neutrophils, eosinophils, basophils, monocytes, mast cells, and macrophages. In the present article various aspects of the biochemistry of the lipoxygenase pathways of neutrophils are reviewed.