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Query: UNIPROT:P36969 (phospholipid hydroperoxide glutathione peroxidase)
 344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selenium (Se) is an essential trace element for animals and humans. Its biological role was established following the discovery that Se is a structural component of the active center of the enzyme glutathione peroxidase (GSH-Px). During the last decade remarkable progress has been made in the recognition of the structure and function of several selenoproteins. Cellular GSH-Px was the first enzyme recognized as a selenoprotein. In it Se was found in the form of selenocysteine. The enzyme is a tetrameric protein and is composed of four apparently identical subunits each containing one gram atom of Se. Plasma GSH-Px also has a tetrameric form with identical subunits and with one atom of Se per subunit. It is, however, a glycosylated protein, and is distinct from cellular enzyme. Both enzymes catalyze the reduction of hydrogen peroxide and a variety of organic hydroperoxides by glutathione. A third GSH-Px, called phospholipid hydroperoxide glutathione peroxidase (PHGSH-Px), is a monomeric, membrane-associated enzyme containing one atom of Se per mole of protein. This enzyme destroys esterified lipid hydroperoxides. The fourth known mammalian selenoenzyme is a type I iodothyronine 5'-deiodinase that catalyzes the deiodination of L-thyroxine to the biologically active hormone 3,3',5-triiodothyronine. It is a monomeric enzyme and contains one atom of Se per mole of protein. Selenoprotein P, a fifth known selenoprotein, is a glycosylated, monomeric protein containing ten atoms of Se per molecule. The function of this protein is not known, but it may play a role in Se transport or be connected with a protective activity against free radicals. In all these selenoproteins the Se is incorporated into the protein molecule via the selenocysteinyl-tRNA which recognizes the specific UGA codons in mRNAs to insert selenocysteine into the primary structure of selenoproteins.
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PMID:Mammalian selenoproteins. 148 33

The effect of selenium deprivation on the viability of murine L1210 cells exposed to various exogenous lipid hydroperoxides has been investigated. Selenoperoxidase activities of cells grown for longer than 1 week in 1% serum with no added selenium [Se(-) cells] were less than 10% of the activities of selenium-satisfied controls [Se(+) cells] or selenium-repleted counterparts [Se(-/+) cells]. The enzymes measured were classical glutathione peroxidase (GPX) and phospholipid hydroperoxide glutathione peroxidase (PHGPX). Se(-) cells exhibited a compensatory increase in catalase activity. Dye exclusion and clonal survival assays indicated that Se(-) and Se(+) cells were relatively insensitive to photochemically generated phospholipid hydroperoxides in liposomal form. However, both cell types were sensitive to liposomal cholesterol hydroperoxides, e.g., 7-hydroperoxycholesterol (7-OOH), Se(-) being much more so (LD50 approximately 10 microM) than Se(+) (LD50 approximately 75 microM). By contrast, 7-hydroxycholesterol over a comparable concentration range was minimally toxic to Se(-) and Se(+) cells. Cell killing by 7-OOH was inhibited by desferrioxamine and by butylated hydroxytoluene, suggesting that iron-mediated free radical reactions are involved. The involvement of glutathione in cytoprotection was confirmed by showing that Se(+) cells were more sensitive to 7-OOH after treating with buthionine sulfoximine, an inhibitor of GSH synthesis. Cellular detoxification of 7-OOH is provisionally attributed to PHGPX rather than GPX, since 7-OOH and other cholesterol hydroperoxides were found to be good substrates for PHGPX in a cell free system, but were unreactive with GPX.
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PMID:Lethal damage to murine L1210 cells by exogenous lipid hydroperoxides: protective role of glutathione-dependent selenoperoxidases. 189 56

The general reactivity of membrane lipid hydroperoxides (LOOHs) with the selenoenzyme phospholipid hydroperoxide glutathione peroxidase (PHGPX) has been investigated. When human erythrocyte ghosts (lipid content: 60 wt % phospholipid; 25 wt % cholesterol) were treated with GSH/PHGPX subsequent to rose bengal-sensitized photoperoxidation, iodometrically measured LOOHs were totally reduced to alcohols. Similar treatment with the classic glutathione peroxidase (GPX) produced no effect unless the peroxidized membranes were preincubated with phospholipase A2 (PLA2). However, under these conditions, no more than approximately 60% of the LOOH was reduced; introduction of PHGPX brought the reaction to completion. Thin layer chromatographic analyses revealed that the GPX-resistant (but PHGPX-reactive) LOOH was cholesterol hydroperoxide (ChOOH) consisting mainly of the 5 alpha (singlet oxygen-derived) product. Membrane ChOOHs were reduced by GSH/PHGPX to species that comigrated with borohydride reduction products (diols). Sensitive quantitation of PHGPX-catalyzed ChOOH reduction was accomplished by using [14C]cholesterol-labeled ghosts. Kinetic analyses indicated that the rate of ChOOH decay was approximately 1/6 that of phospholipid hydroperoxide decay. Photooxidized ghosts underwent a large burst of free radical-mediated lipid peroxidation when incubation with ascorbate/iron or xanthine/xanthine oxidase/iron. These reactions were only partially inhibited by PLA2/GSH/GPX treatment, but totally inhibited by GSH/PHGPX treatment, consistent with complete elimination of LOOHs in the latter case. These findings provide important clues as to how ChOOHs are detoxified in cells and add new insights into PHGPX's protective role.
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PMID:Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation. In situ reduction of phospholipid and cholesterol hydroperoxides. 229 13

Lipid hydroperoxides (LOOHs) in various lipid assemblies are shown to be efficiently reduced and deactivated by phospholipid hydroperoxide glutathione peroxidase (PHGPX), the second selenoperoxidase to be identified and characterized. Coupled spectrophotometric analyses in the presence of NADPH, glutathione (GSH), glutathione reductase and Triton X-100 indicated that photochemically generated LOOHs in small unilamellar liposomes are substrates for PHGPX, but not for the classical glutathione peroxidase (GPX). PHGPX was found to be reactive with cholesterol hydroperoxides as well as phospholipid hydroperoxides. Kinetic iodometric analyses during GSH/PHGPX treatment of photoperoxidized liposomes indicated a rapid decay of total LOOH to a residual level of 35-40%; addition of Triton X-100 allowed the reaction to go to completion. The non-reactive LOOHs in intact liposomes were shown to be inaccessible groups on the inner membrane face. In the presence of iron and ascorbate, photoperoxidized liposomes underwent a burst of thiobarbituric acid-detectable lipid peroxidation which could be inhibited by prior GSH/PHGPX treatment, but not by GSH/GPX treatment. Additional experiments indicated that hydroperoxides of phosphatidylcholine, cholesterol and cholesteryl esters in low-density lipoprotein are also good substrates for PHGPX. An important role of PHGPX in cellular detoxification of a wide variety of LOOHs in membranes and internalized lipoproteins is suggested from these findings.
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PMID:Enzymatic reduction of phospholipid and cholesterol hydroperoxides in artificial bilayers and lipoproteins. 238 98

Aurothioglucose (ATG), an inhibitor of selenium-dependent glutathione peroxidase activity, at a concentration of 100 microM, strongly increases lipid peroxidation of rat liver microsomes exposed to either ferrous ion (10 microM) or the combination of ferric ion (10 microM) and ascorbic acid (500 microM), in the presence of reduced glutathione (GSH, 800 microM). This effect was not achieved using heat-inactivated microsomes and was dependent on the presence of GSH. ATG did not affect the lag period associated with ascorbic acid/ferric ion-induced microsomal lipid peroxidation (previously attributed to an undefined GSH-dependent microsomal agent), but did increase the rate of peroxidation subsequent to the lag period. The potent GSH-dependent inhibition of microsomal lipid peroxidation by cytosol (10% of total volume) was completely reversed by ATG (100 microM). ATG similarly reversed an inhibition of phosphatidylcholine hydroperoxide-dependent liposomal peroxidation that has been attributed to phospholipid hydroperoxide glutathione peroxidase (PHGPX), an enzyme distinct from the classical glutathione that cannot utilize intact phospholipids. ATG inhibited, in addition to the classical selenium-dependent glutathione peroxidase, both cytosolic and microsomal (basal and N-ethyl maleimide-stimulated) glutathione S-transferase activities with greater than 80% inhibition achieved at 100 microM ATG. ATG, at concentrations up to 250 microM, did not inhibit PHGPX activity measured by the coupled-enzyme method in the presence of Triton X-100 (0.1%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of aurothioglucose on iron-induced rat liver microsomal lipid peroxidation. 314 31

Regulation of synthesis of the selenoenzymes cytosolic glutathione peroxidase (GSH-Px), phospholipid hydroperoxide glutathione peroxidase (PHGSH-Px) and type-1 iodothyronine 5'-deiodinase (5'IDI) was investigated in liver, thyroid and heart of rats fed on diets containing 0.405, 0.104 (Se-adequate), 0.052, 0.024 or 0.003 mg of Se/kg. Severe Se deficiency (0.003 mg of Se/kg) caused almost total loss of GSH-Px activity and mRNA in liver and heart. 5'IDI activity decreased by 95% in liver and its mRNA by 50%; in the thyroid, activity increased by 15% and mRNA by 95%. PHGSH-Px activity was reduced by 75% in the liver and 60% in the heart but mRNA levels were unchanged; in the thyroid, PHGSH-Px activity was unaffected by Se depletion but its mRNA increased by 52%. Thus there is differential regulation of the three mRNAs and subsequent protein synthesis within and between organs, suggesting both that mechanisms exist to channel Se for synthesis of a particular enzyme and that there is tissue-specific regulation of selenoenzyme mRNAs. During Se depletion, the levels of selenoenzyme mRNA did not necessarily parallel the changes in enzyme activity, suggesting a distinct mechanism for regulating mRNA levels. Nuclear run-off assays with isolated liver nuclei showed severe Se deficiency to have no effect on transcription of the three genes, suggesting that there is post-transcriptional control of the three selenoenzymes, probably involving regulation of mRNA stability.
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PMID:Tissue-specific regulation of selenoenzyme gene expression during selenium deficiency in rats. 748 77

Murine leukemia L1210 cells rendered deficient in glutathione peroxidase (GPX) and phospholipid hydroperoxide glutathione peroxidase (PHGPX) by Se deprivation (L.Se(-) cells) were found to be more sensitive to tert-butyl hydroperoxide (t-BuOOH) cytotoxicity than Se-replete controls (L.Se(+) cells). Human K562 cells, which express PHGPX, but not GPX, were also more sensitive to t-BuOOH in the Se-deficient (K.Se(-)) than Se-satisfied (K.Se(+)) condition. In examining the metabolic basis for selenoperoxidase-dependent resistance, we found that glucose-replete Se(-) cells reduce t-BuOOH to t-butanol far more slowly than Se(+) cells, the ratio of the first-order rate constants approximating that of the GPX activities (L1210 cells) or PHGPX activities (K562 cells). Monitoring peroxide-induced changes in GSH and GSSG gave consistent results; e.g., glucose-depleted L.Se(+) cells exhibited a first order loss of GSH that was substantially faster than that of glucose-depleted L.Se(-) cells. Under the conditions used, peroxide-induced conversion of GSH to GSSG could be stoichiometrically reversed by resupplying D-glucose, indicating that no significant lysis or GSSG efflux and/or interchange had taken place. The apparent first-order rate constant for GSH decay increased progressively for L1210 cells expressing a range of GPX activities from approximately 5% to 100%, demonstrating that peroxide detoxification is strictly dependent on enzyme content. The initial rate of 14CO2 release from D-[1-14C]glucose supplied in the medium was much greater for L.Se(+) or K.Se(+) cells than for their respective Se(-) counterparts, consistent with greater hexose monophosphate shunt activity in the former. These results highlight the importance of selenoperoxidase action in the glutathione cycle as a means by which tumor cells cope with hydroperoxide stress.
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PMID:Selenoperoxidase-dependent glutathione cycle activity in peroxide-challenged leukemia cells. 777 66

Selenium is an essential component in the two antioxidant enzymes glutathione peroxidase (GSH-Px) and phospholipid hydroperoxide glutathione peroxidase (PLGSH-Px). Free oxygen radicals are involved in the inflammatory process seen in rheumatoid arthritis (RA) and are generated mainly through the phagocytic activity of the polymorphonuclear leucocytes. Several experimental studies indicate that selenium is important to the functioning of the immune system and to the inflammatory process. A low selenium status among patients with RA has been reported from areas with both high and low natural selenium intake. The reduction in the serum level is approx. 10%. This reduction is related to the clinical disease activity in arthritis patients in both cross-sectional and longitudinal studies, and selenium concentrations have been found to fluctuate during the disease. Reduced selenium concentrations have been reported in red blood cells, too, and concentrations have been found to be slightly reduced in the polymorphonuclear leucocytes. Studies do not agree on the activity of GSH-Px among RA patients. Thus activity levels have been reported to range from low to high. Those studies that have focused on the subgroup of patients with high persistent disease activity have reported reduced GSH-Px activities in both serum, red blood cells and polymorphonuclear leucocytes. Selenium supplementation using organic selenium compounds in doses of around 250 microgram/day increases the selenium concentration in serum and red blood cells considerably. However, supplementation is not reflected in the selenium level in polymorphonuclear leucocytes from RA patients as opposed to healthy subjects, in whom the level of selenium in polymorphonuclear leucocytes increases. Selenium supplementation increased GSH-Px activity in serum, red blood cells and platelets from RA patients, but in the polymorphonuclear leucocytes the increase was not sufficient to reach the levels of the controls. This apparent lack of de novo synthesis of GSH-Px in polymorphonuclear leucocytes from RA patients may be explained by their inability to increase their selenium content in spite of high levels of available extracellular selenium. this may be in accordance with the lack of anti-arthritic effect of selenium supplementation in controlled clinical studies among RA patients. Several experimental studies have reported inhibition of GSH-Px by antirheumatic drugs, in particular gold. In addition, gold has been found to reduce selenium in rat plasma. These interactions can, however, be modified by increasing the amount of selenium in the feed. Among RA patients there is no clear evidence of an interaction between gold, selenium and GSH-Px.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Selenium and the selenium-dependent glutathione peroxidase in rheumatoid arthritis. 792 58

Oxidative modification of human low-density lipoprotein (LDL) is thought to play an important role in the development of atherosclerosis. LDL oxidizability is believed to be strongly influenced by factors such as (a) content of preexisting lipid hydroperoxides (LOOHs) and (b) content of endogenous antioxidants such as alpha-tocopherol and beta-carotene. The purpose of this study was to examine the prooxidant role of preexisting LDL-LOOHs, using a recently developed method for ultrasensitive and selective LOOH analysis: high-performance liquid chromatography with mercury drop electrochemical detection (HPLC-EC). Exceedingly low detection limits for LDL-LOOHs have been achieved by HPLC-EC, e.g., approximately 100 fmol for cholesteryl ester hydroperoxide (CEOOH). This sensitivity has allowed us to monitor LDL-LOOHs at levels that are undetectable by most other methods. Fresh LDL prepared with the utmost care to prevent autoxidation was found to contain small, yet significant amounts of CEOOH, 6-12 pmol/mg protein. Our data suggest that these peroxides could not have arisen during LDL isolation or sample work-up for HPLC-EC. Incubation with GSH and phospholipid hydroperoxide glutathione peroxidase resulted in nearly complete reduction of the CEOOH. This LDL was found to be much more resistant to Cu(2+)-induced peroxidation than starting material, exhibiting a lag period that was at least six times greater. We have also determined that LDL becomes progressively more susceptible to Cu(2+)-induced lipid peroxidation (as evidenced by a shortened lag) when it is preloaded with increasing amounts of photochemically generated LOOHs. Taken together, these results provide strong support for the idea that preexisting LOOHs in LDL are important determinants of its overall oxidizability.
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PMID:Involvement of preexisting lipid hydroperoxides in Cu(2+)-stimulated oxidation of low-density lipoprotein. 798 64

The complete amino acid sequence of the selenoprotein phospholipid-hydroperoxide glutathione peroxidase (PHGPX) from pig heart has been deduced from the corresponding genomic DNA, the cDNA covering the coding region, and by sequencing the N terminus of the protein. The maximum length of the peptide chain derived from the cDNA amounts to 170 amino acid residues. By protein sequencing the N-terminal residues methionine and cysteine of the deduced sequence were found to be cleaved. The molecular mass of 19,671 Da obtained by laser desorption mass spectroscopy, however, significantly exceeds the mean molecular mass of 19,257.09 calculated for the sequence 3-170 of PHGPX, thus indicating posttranscriptional modification. In contrast to glutathione peroxidase (GPX) the coding area of the PHGPX gene is composed of seven exons. Only the amino acid sequences encoded by the third and fifth exon are highly homologous to GPX sequences. The amino acid residues selenocysteine, tryptophan, and glutamine forming the catalytic site in bovine GPX are conserved in homologous positions of PHGPX, whereas the arginine residues presumed to bind GSH in GPX are not. Gaps in the PHGPX sequence correspond to subunit interaction sites of the tetrameric GPX. The data suggest an identical catalytic mechanism of the selenoperoxidases, a less stringent substrate specificity of PHGPX, and explain the monomeric nature of PHGPX. As in other selenoproteins, the selenocysteine residue of PHGPX is encoded by UGA. The 3'-untranslated region (UTR) of the PHGPX shows a limited consensus with that of GPX and 5'-deiodinase, where it was shown to be responsible for the decoding of UGA as selenocysteine. The 3'-UTR of PHGPX can form a stem/loop as in other mammalian selenoprotein genes. The 5'-UTR and the first intron of the PHGPX gene contain a variety of putative regulatory elements indicating hormonal control.
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PMID:Phospholipid-hydroperoxide glutathione peroxidase. Genomic DNA, cDNA, and deduced amino acid sequence. 812 51


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