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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 tissue distribution of phospholipid hydroperoxide glutathione peroxidase (PHGPX) was studied in rats of different ages. In the same samples the activities of Se-dependent glutathione peroxidase (GPX), and non-Se-dependent glutathione peroxidase (non Se-GPX) were also determined using specific substrates for each enzyme. Enzymatically generated phospholipid hydroperoxides were used as substrate for PHGPX, hydrogen peroxide for GPX, and cumene hydroperoxide for non-Se-GPX (after correction for the activity of GPX on this substrate). PHGPX specific activity in different organs is as follows: liver = kidney greater than heart = lung = brain greater than muscle. Furthermore, this activity is reasonably constant in different age groups, with a lower specific activity observed only in kidney and liver of young animals. GPX activity is expressed as follows: liver greater than kidney greater than heart greater than lung greater than brain = muscle, and substantial age-dependent differences have been observed (adult greater than old greater than young). Non-Se-GPX activity was present in significant amount only in liver greater than lung greater than heart and only in adult animals. These results suggest a tissue- and age-specific expression of different peroxidases.
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PMID:Phospholipid hydroperoxide glutathione peroxidase: specific activity in tissues of rats of different age and comparison with other glutathione peroxidases. 280 65

The present review deals with the chemical properties of selenium in relation to its antioxidant properties and its reactivity in biological systems. The interaction of selenite with thiols and glutathione and the reactivity of selenocompounds with hydroperoxides are described. After a short survey on distribution, metabolism and organification of selenium, the role of this element as a component of the two seleno-dependent glutathione peroxidases is described. The main features of glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase are also reviewed. Both enzymes reduce different hydroperoxides to the corresponding alcohols and the major difference is the reduction of lipid hydroperoxides in membrane matrix catalyzed only by the phospholipid hydroperoxide glutathione peroxidase. However, in spite of the different specificity for the peroxidic substrates, the kinetic mechanism of both glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase seems identical and proceeds through a tert-uni ping pong mechanism. In the reaction cycle, indeed, as supported by the kinetic data, the oxidation of the ionized selenol by the hydroperoxide yields a selenenic acid that in turn is reduced back by two reactions with reduced glutathione. Special emphasis has been given to the role of selenium-dependent glutathione peroxidases in the prevention of membrane lipid peroxidation. While glutathione peroxidase is able to reduce hydrogen peroxide and other hydroperoxides possibly present in the soluble compartment of the cell, this enzyme fails to inhibit microsomal lipid peroxidation induced by NADPH or ascorbate and iron complexes. On the other hand, phospholipid hydroperoxide glutathione peroxidase, by reducing the phospholipid hydroperoxides in the membranes, actively prevents lipid peroxidation, provided a normal content of vitamin E is present in the membranes. In fact, by preventing the free radical generation from lipid hydroperoxides, phospholipid hydroperoxide glutathione peroxidase decreases the vitamin E requirement necessary to inhibit lipid peroxidation. Finally, the possible regulatory role of the selenoperoxidases on the arachidonic acid cascade enzymes (cyclooxygenase and lipoxygenase) is discussed.
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PMID:The role of selenium peroxidases in the protection against oxidative damage of membranes. 331 19

The effects of Triton X-100, deoxycholate, and fatty acids were studied on the two steps of the ping-pong reaction catalyzed by Se-dependent glutathione peroxidases. The study was carried out by analyzing the single progression curves where the specific glutathione oxidation was monitored using glutathione reductase and NADPH. While the "classic" glutathione peroxidase was inhibited only by Triton, the newly discovered "phospholipid hydroperoxide glutathione peroxidase" was inhibited by deoxycholate and by unsaturated fatty acids. The kinetic analysis showed that in the case of glutathione peroxidase only the interaction of the lipophilic peroxidic substrate was hampered by Triton, indicating that the enzyme is not active at the interface. Phospholipid hydroperoxide glutathione peroxidase activity measured with linoleic acid hydroperoxide as substrate, on the other hand, was not stimulated by the Triton concentrations which have been shown to stimulate the activity on phospholipid hydroperoxides. Furthermore a slight inhibition was apparent at high Triton concentrations and the effect could be attributed to a surface dilution of the substrate. Deoxycholate and unsaturated fatty acids were not inhibitory on glutathione peroxidase but inhibited both steps of the peroxidic reaction of phospholipid hydroperoxide glutathione peroxidase, in the presence of either amphiphilic or hydrophilic substrates. This inhibition pattern suggests an interaction of anionic detergents with the active site of this enzyme. These results are in agreement with the different roles played by these peroxidases in the control of lipid peroxide concentrations in the cells. While glutathione peroxidase reduces the peroxides in the water phase (mainly hydrogen peroxide), the new peroxidase reduces the amphyphilic peroxides, possibly at the water-lipid interface.
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PMID:Different effects of Triton X-100, deoxycholate, and fatty acids on the kinetics of glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase. 380 Mar 87

Our previous studies have implicated the selenium metabolite selenodiglutathione (SDG) in the growth inhibitory effects of selenite in vitro. Other work has suggested that reactive oxygen species, the superoxide anion and hydrogen peroxide, may be implicated in selenite toxicity. In this study the mechanism of growth inhibition by SDG and H2O2 has been compared in a mammary cell line, C57. Both SDG and H2O2 had a rapid effect on C57 cells and markedly reduced cloning efficiency within 1 h. However, the mechanisms involved seem to be different, as judged by the following observations: (i) An SDG-resistant cell line (B19) derived from C57 cells is cross-resistant to selenite, but not H2O2; (ii) SDG reduces the levels of the mRNAs for phospholipid hydroperoxide glutathione peroxidase and cytosolic glutathione peroxidase, whereas H2O2 has no effect; (iii) SDG induces both 560 kb and 50 kb DNA fragments, whereas H2O2 only induces 560 kb DNA fragments. This is of interest, since formation of high molecular weight DNA fragments has been recognized as a characteristic of apoptosis.
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PMID:The selenium metabolite selenodiglutathione induces cell death by a mechanism distinct from H2O2 toxicity. 761 92

We report a transient adaptation to the oxidative stress of hydrogen peroxide (H2O2) exposure in several mammalian cell lines: Chinese hamster ovary fibroblast (CHO) cells, HA-1 cells (a defined CHO subclone), C3H 10T1/2 cells (embryonic mouse fibroblasts), V79 cells (Chinese hamster lung fibroblasts), and Clone 9 liver cells (rat liver epithelial cells). Up to 40-fold adaptive increases in resistance to H2O2 challenge occurred following pretreatment with relatively low H2O2 "priming" doses, from as little as 1.9% cell viability for untreated cells to as much as 76.5% viability for H2O2 pretreated cells. Detailed studies with HA-1 cells revealed the following pattern of responses to H2O2: very low H2O2 concentrations of 0.1 to 0.5 mumol/10(7) cells (3 to 15 microM) stimulated cell growth by 25 to 45%; low H2O2 concentrations of 2-5 mumol/10(7) cells (120 to 150 microM) induced a temporary growth-arrest, a lengthening of cell cycle from 18 h to approximately 26 h, and marked adaptive increases in H2O2 resistance; intermediate H2O2 concentrations of 9 to 14 mumol/10(7) cells (250 to 400 microM) caused permanent growth-arrest (i.e., permanent loss of replicative or divisional competence) with no evidence of necrosis; high H2O2 concentrations of 30 mumol/10(7) cells or greater (> or = 1 mM) caused an apoptotic-like necrotic cell death and destruction. The adaptive response to low H2O2 concentrations of 2-5 mumol/10(7) (120 to 150 microM) was maximal 18 h after pretreatment of HA-1 cells, declined thereafter toward baseline sensitivity, and was observed with both 7-day fix and stain procedures and clonogenic viability assays. Transient adaptation following H2O2 pretreatment of 4.15 mumol/10(7) (150 microM) involved the de novo synthesis of at least 20 proteins and was blocked by the translation inhibitor, cycloheximide. During the 18-h adaptation in HA-1 cells proteins were synthesized in three phases; early (0-4 h), middle (4-8 h), and late (8-15 h). No H2O2 response proteins were synthesized beyond 18 h after pretreatment, by which time adaptation had already maximized. Selective translational inhibition of the early, middle, or late proteins revealed that all three sets were necessary for a maximal adaptive increase in H2O2 resistance. Northern blot and enzyme activity analyses revealed no significant increases in transcription or translation of the classical antioxidant enzymes catalase, glutathione peroxidase, phospholipid hydroperoxide glutathione peroxidase, Cu, Zn superoxide dismutase, or Mn superoxide dismutase in H2O2-adapted HA-1 cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transient adaptation of oxidative stress in mammalian cells. 772 66

The comparative importance of phospholipid hydroperoxide glutathione peroxidase (PHGPx) and of "classic" glutathione peroxidase (GPx) in the reduction of phospholipid hydroperoxides is unclear. Although GPx activity is 500-fold higher than that of PHGPx in rat liver, the reduction of phospholipid hydroperoxides by glutathione (GSH) through GPx may be strongly limited by a low PLA2 activity. We address this issue using a moderately detailed kinetic model of mitochondrial lipid peroxidation in rat liver. The model was based on published data and was subjected to validation as reported in the references. It is analysed by computer simulation and sensitivity analysis. Results suggest that in rat liver mitochondria PHGPx is responsible for almost all phospholipid hydroperoxide reduction. Under physiological conditions, the estimated flux of phospholipid hydroperoxides reduction through PHGPx is about four orders of magnitude higher than the estimated hydrolysis flux through PLA2. On the other hand, virtually all hydrogen peroxide is reduced through GPx. Therefore, a functional complementarity between PHGPx and GPx is suggested. Because the results are qualitatively robust to changes of several orders of magnitude in PLA2 and PHGPx levels, the conclusions may not be limited to mitochondria.
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PMID:PHGPx and phospholipase A2/GPx: comparative importance on the reduction of hydroperoxides in rat liver mitochondria. 852 27

1-linoleoyl lysophosphatidylcholine hydroperoxide is a substrate of GSH peroxidase (GPx) both purified from bovine erythrocytes and nonpurified from rat liver. The initial reaction rate for bovine erythrocyte GPx with 1-linoleoyl lysophosphatidylcholine hydroperoxide is about 76 and 95% of the reaction rate for hydrogen peroxide and linoleic acid hydroperoxide respectively. For rat liver GPx these initial reaction rates are about 66 and 75%, respectively. The rate constants for the reaction of GPx with 1-linoleoyl lysophosphatidylcholine hydroperoxide were calculated to be approximately 3 x 10(7) M-1s-1 and approximately 2 x 10(6) M-1s-1 for the bovine erythrocyte and the rat liver enzymes, respectively. By using kinetic models of lipid peroxidation we found by simulation that: (1) the main source of lysophospholipid hydroperoxides in vivo is the peroxidation of lysophospholipids, both in mitochondrial inner membranes and in endoplasmic reticulum; (2) a specialized enzyme able to reduce directly lysophospholipid hydroperoxides is important for the reduction of these hydroperoxides, because the detoxification of these species mediated by the action of acyl ester bond cleaving enzymes is not efficient; (3) the reduction through GPx predominates over phospholipid hydroperoxide glutathione peroxidase (PHGPx) in mitochondrial inner membranes and in the cytosolic phase of the endoplasmic reticulum; (4) in the luminal phase of endoplasmic reticulum PHGPx is predominant.
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PMID:Role of glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase in the reduction of lysophospholipid hydroperoxides. 911 56

Antioxidant enzyme expression was determined in rat pancreatic islets and RINm5F insulin-producing cells on the level of mRNA, protein, and enzyme activity in comparison with 11 other rat tissues. Although superoxide dismutase expression was in the range of 30% of the liver values, the expression of the hydrogen peroxide-inactivating enzymes catalase and glutathione peroxidase was extremely low, in the range of 5% of the liver. Pancreatic islets but not RINm5F cells expressed an additional phospholipid hydroperoxide glutathione peroxidase that exerted protective effects against lipid peroxidation of the plasma membrane. Regression analysis for mRNA and protein expression and enzyme activities from 12 rat tissues revealed that the mRNA levels determine the enzyme activities of the tissues. The induction of cellular stress by high glucose, high oxygen, and heat shock treatment did not affect antioxidant enzyme expression in rat pancreatic islets or in RINm5F cells. Thus insulin-producing cells cannot adapt the low antioxidant enzyme activity levels to typical situations of cellular stress by an upregulation of gene expression. Through stable transfection, however, we were able to increase catalase and glutathione peroxidase gene expression in RINm5F cells, resulting in enzyme activities more than 100-fold higher than in nontransfected controls. Catalase-transfected RINm5F cells showed a 10-fold greater resistance toward hydrogen peroxide toxicity, whereas glutathione peroxidase overexpression was much less effective. Thus inactivation of hydrogen peroxide through catalase seems to be a step of critical importance for the removal of reactive oxygen species in insulin-producing cells. Overexpression of catalase may therefore be an effective means of preventing the toxic action of reactive oxygen species.
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PMID:Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. 935 19

Glutathione peroxidases (GPx) are characterized by a catalytically active selenium which forms the center of a strictly conserved triad composed of selenocysteine, glutamine, and tryptophan. In order to check the functional relevance of this structural peculiarity, six molecular mutants of phospholipid hydroperoxide glutathione peroxidase (PHGPx) were designed, isolated, and investigated kinetically. Replacement of the selenocysteine in position 46 by cysteine decreased k + 1, i.e., the reaction rate of reduced enzyme with hydroperoxide, by three orders of magnitude. The rate of regeneration of the reduced enzyme by glutathione (k' + 2) was similarly affected. Additional substitution of Gln81 or Trp136 by acid residues resulted in a further decrease of k + 1 by three orders of magnitude, whereas histidine or neutral residues in these positions proved to be less deleterious. The data support the hypothesis that the typical triad of selenocysteine, glutamine, and tryptophan is indeed a novel catalytic center in which the reactivity of selenium is optimized by hydrogen bonding provided by the adjacent glutamine and tryptophan residues.
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PMID:Probing the presumed catalytic triad of a selenium-containing peroxidase by mutational analysis. 955 42


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