The Selenoenzyme Phospholipid Hydroperoxide Glutathione Peroxidase Controls the Activity of the 15-Lipoxygenase with Complex Substrates and Preserves the Specificity of the Oxygenation Products

Abstract

Mammalian 15-lipoxygenases have been suggested to be involved in cell differentiation and atherogenesis because of their capability of oxygenating polyenoic fatty acids esterified to biomembranes and lipoproteins. We investigated the interaction of the lipid-peroxidizing 15-lipoxygenase and the hydroperoxy lipid-reducing phospholipid hydroperoxide glutathione peroxidase during their reaction with biomembranes and lipoproteins and obtained the following results. 1) Lipoxygenase treatment of submitochondrial membranes led to the formation of hydroperoxyphosphatidylethanolamine and hydroperoxyphosphatidylcholine as indicated by high performance liquid chromatography with chemiluminescence detection. In 15-lipoxygenase-treated low density lipoprotein cholesteryl hydroperoxylinoleate was the major oxygenation product. 2) Phospholipid hydroperoxide glutathione peroxidase was capable of reducing the hydroperoxy lipids formed by the 15-lipoxygenase to their corresponding alcohols. 3) Preincubation of low density lipoprotein and submitochondrial membranes with the phospholipid hydroperoxide glutathione peroxidase completely prevented the lipoxygenase reaction. However, addition of exogenous hydroperoxy lipids restored the oxygenase activity. 4) Short-term incubations of the complex substrates with the 15-lipoxygenase led to a specific pattern of oxidation products which was rendered more unspecific at long-term incubation or at high substrate concentrations. If the phosholipid hydroperoxide glutathione peroxidase was present during the reaction, the specific product pattern was preserved. These data indicate that the phospholipid hydroperoxide glutathione peroxidase is capable of reducing hydroperoxy ester lipids formed by a 15-lipoxygenase, and that it may down-regulate the 15-lipoxygenase pathways in mammalian cells. The specificity of 15-lipoxygenase-derived hydroperoxy lipids depends on their immediate reduction to the corresponding alcohols preventing postcatalytic isomerization.

Cholesterol Hydroperoxide Generation, Translocation, and Reductive Turnover in Biological Systems

“…This is based on knowledge that these enzymes require a low level of pre-existing PLOOH or ChOOH (a peroxide tone) for optimal activity and that GPx4 can negatively affect this. In support of this, it was found, for example, that (i) 5-LOX expression/activity was strongly upregulated in GPx4-deficient (Se-starved) cells, and (ii) 15-LOX-induced lipid peroxidation in membranes and LDL was significantly suppressed by GSH/GPx4 [31,32]. …”

Regulation of inflammation by selenium and selenoproteins: impact on eicosanoid biosynthesis

“…The proposed mechanism was the antioxidant capabilities of GPx4 and the ability to reduce FAHP to hydroxyl derivatives. Others found that GPx4 reduced 15-HPETE to 15-HETE and pre-incubation of endothelial cells with GPx4 could prevent peroxide formation ( 72 ) . Both TrxR and Sepp1 also were shown to have lipid hydryperoxidase activity for 15-HPETE, thus supporting the contention that these selenoproteins can function as antioxidant enzymes against highly reactive hydroperoxy intermediates formed during eicosanoid metabolism ( 35 , 37 ) .…”

Potent and Selective Inhibitors of Human Reticulocyte 12/15-Lipoxygenase as Anti-Stroke Therapies

“…1,2 The nomenclature of the LOX isozymes is loosely based on the carbon position (e.g., 5, 12, or 15) at which they oxidize arachidonic acid to form the corresponding hydroperoxyeicosatetraenoic acid (HpETE), 3 which is reduced to the hydroxyeicosatetraenoic acid (HETE) by intracellular glutathione peroxidases. 4 Human lipoxygenases and their metabolites have been implicated in numerous diseases. 5-LOX has been implicated in cancer, 5 asthma, 6,7 COPD, 8 allergic rhinitis, 9 osteoarthritis, 10,11 and atherosclerosis, 12−14 whereas platelet-type 12-LOX has been implicated in diabetes, 15,16 blood coagulation, 17 psoriasis, 18 and cancer.…”