the reaction proceeds via hydrogen abstraction, peroxide cleavage, radical rearrangement, and epoxide formation. To initiate the reaction the ferrous LOX is first activated by peroxide-dependent oxidation to a ferric form. The lipohydroperoxidase activity is initiatedwhen a lipid hydroperoxide (ROOH) is bound at the active site of the enzyme. The enzyme then catalyzes a homolytic cleavage of the hydroperoxy bond, which leads to the formation of an oxygen-centered alkoxy radical, a hydroxyl and oxidizes the ferrous iron to a ferric form. Then the enzyme binds a linoleic acid molecule (or an alterative reductant such as guaiacol) and releases a carbon-centered linoleic radical. This reaction reduces the ferric LOX back to its ferrous form to start the next catalytic cycle. The released radical intermediates may then initiate free radical secondary reactions leading to the formation of mixed oxygenated and non-oxygenated linoleic acid dimer
in the brain, the principal 12/15-LOX metabolites of arachidonate are (5Z,8Z,10E,14Z)-(12S)-12-hydroperoxyicosa-5,8,10,14-tetraenoate, cf. EC 1.13.11.31, and (5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
the major reaction products are identified as(8S,15S,5Z,9E,11Z,13E)-8,15-dihydroperoxy-5,9,11,13-eicosatetraenoic acid (8S,15S-DiHpETE) and (5S,15S,6E,8Z,11Z,13E)-5,15-dihydroperoxy-6,8,11,13-eicosatetraenoic acid (5S,15S-DiHPETE) and the stereochemistry of the reaction is compatible with an inverse substrate orientation
enzyme substrate specificity, overview. The ALOX15 enzyme activity is not restricted to free polyenoic fatty acids since phospholipids and even biomembranes and lipoproteins are suitable ALOX15 substrates. The ALOX15 orthologue is capable of converting hydroperoxy fatty acids to epoxy leukotrienes. Product specificity with polyenoic acids and with complex substrates, and alteration of product specificity by substrate modification. Intraenzyme oxygen movement
in the brain, the principal 12/15-LOX metabolites of arachidonate are (5Z,8Z,10E,14Z)-(12S)-12-hydroperoxyicosa-5,8,10,14-tetraenoate, cf. EC 1.13.11.31, and (5Z,8Z,11Z,13E)-(15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
the major reaction products are identified as(8S,15S,5Z,9E,11Z,13E)-8,15-dihydroperoxy-5,9,11,13-eicosatetraenoic acid (8S,15S-DiHpETE) and (5S,15S,6E,8Z,11Z,13E)-5,15-dihydroperoxy-6,8,11,13-eicosatetraenoic acid (5S,15S-DiHPETE) and the stereochemistry of the reaction is compatible with an inverse substrate orientation
certain oxazole-4-carbonitrile based LOX inhibitors share a high inhibitory potency for human and mouse ALOX15 but hardly inhibit other mammalian LOX-isoforms
ALOX15 is usually present as catalytically silent ferrous enzyme. To initiate fatty acid oxygenation, the enzyme must first be oxidized to a ferric form capable of initiating hydrogen abstraction. Unfortunately, single activation of the enzyme is not sufficient to keep it running, since during catalysis small quantities of radical intermediates might escape from the active site leaving the enzyme in an inactive ferrous (Fe2+) form. To keep the reaction at quasistationary levels, repeated enzyme activation is required and the primary oxygenation products appear to serve as enzyme activators. In this sense, the LOX exhibits autocatalytic properties
increased expression of 12/15-LOX, predominantly in neurons, and elevated production of 12(S)-hydroperoxyicosatetraenoate and 15(S)-hydroperoxyicosatetraenoate in ischemic brain
primary cortical neurons, increased expression of 12/15-LOX, predominantly in neurons, and elevated production of 12(S)-hydroperoxyicosatetraenoate and 15(S)-hydroperoxyicosatetraenoate in ischemic brain
12/15-lipoxygenase metabolites of arachidonic acid activate PPARgamma, involvement of 12(S)- and 15(S)-hydroperoxyicosatetraenoate in the regulation of PPARgamma following cerebral ischemia and effects on ischemia-induced inflammatory response. 12(S)-HETE and 15(S)-HETE elicit neuroprotection in rats exposed to focal ischemia. PPARgamma is a member of the nuclear hormone receptorfamily of ligand-dependent transcription factors. PPARgamma regulates genes that are implicated in adipocyte differentiation, lipid and glucose metabolism, and insulin sensitivity
lipoxygenases (LOX) form a family of lipid peroxidizing enzymes, which are implicated in a number of physiological processes and in the pathogenesis of inflammatory, hyperproliferative and neurodegenerative diseases. Physiological roles of ALOX15, detailed overview