Evidence for a lipoxygenase mechanism in the biosynthesis of epoxide and dihydroxy leukotrienes from 15(S)-hydroperoxyicosatetraenoic acid by human platelets and porcine leukocytes.
Leukocyte preparations convert the hydroperoxy icosatetraenoic acids 5(S)-HPETE and 15(S)-HPETE to the unstable leukotriene epoxides LTA4 and 14,15-LTA4. In several ways, the conversion of 5- or 15-HPETE to leukotriene epoxide bears a formal mechanistic resemblance to the reaction catalyzed by the 12-lipoxygenase in the conversion of arachidonic acid to 12(S)-HPETE. Points of similarity include enzymatic removal of a hydrogen at carbon 10, double bond isomerization, and formation of a new carbon-to-oxygen bond. In the case of 15(S)-HPETE, two 8,15- and an erythro-14,15-dihydroxy acid (8,15- and 14,15-DiHETEs), which result from incorporation of molecular oxygen into each hydroxyl group, are coproducts in the formation of 14,15-LTA4. These facts prompted us to test the hypothesis that the biosynthesis of 14,15-LTA4 and of 8,15- and 14,15-DiHETEs from 15(S)-HPETE occurs by a mechanism similar to that observed in lipoxygenase reactions. Based on the results presented here, we conclude that the biosynthesis of 14,15-LTA4 and of 8,15- and 14,15-DiHETEs from 15(S)-HPETE occurs via a common intermediate and that, moreover, the formation of these metabolites from 15(S)-HPETE is catalyzed by an enzyme with many mechanistic features in common with the 12-lipoxygenase.
D000818:Animals; D001091:Arachidonate Lipoxygenases; D001095:Arachidonic Acids / Q000096:biosynthesis* / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D017572:Leukotriene A4; D007975:Leukotriene B4 / Q000031:analogs & derivatives* / Q000096:biosynthesis; D015289:Leukotrienes; D008054:Lipid Peroxides / Q000378:metabolism*; D008084:Lipoxygenase / Q000378:metabolism*; D013237:Stereoisomerism; D013552:Swine
D001095:Arachidonic Acids; D017572:Leukotriene A4; D015289:Leukotrienes; D008054:Lipid Peroxides; D007975:Leukotriene B4; C025086:15-hydroperoxy-5,8,11,13-eicosatetraenoic acid; C030723:14,15-leukotriene B4; D001091:Arachidonate Lipoxygenases; D008084:Lipoxygenase