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Pierre Plateau - One of the best experts on this subject based on the ideXlab platform.
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Exposure to Selenomethionine causes selenocysteine misincorporation and protein aggregation in Saccharomyces cerevisiae.
Scientific Reports, 2017Co-Authors: Pierre Plateau, Marc Dauplais, Sylvain Blanquet, Cosmin Saveanu, Roxane Lestini, Laurence Decourty, Alain Jacquier, Myriam LazardAbstract:Selenomethionine, a dietary supplement with beneficial health effects, becomes toxic if taken in excess. To gain insight into the mechanisms of action of Selenomethionine, we screened a collection of ≈5900 Saccharomyces cerevisiae mutants for sensitivity or resistance to growth-limiting amounts of the compound. Genes involved in protein degradation and synthesis were enriched in the obtained datasets, suggesting that Selenomethionine causes a proteotoxic stress. We demonstrate that Selenomethionine induces an accumulation of protein aggregates by a mechanism that requires de novo protein synthesis. Reduction of translation rates was accompanied by a decrease of protein aggregation and of Selenomethionine toxicity. Protein aggregation was supressed in a ∆cys3 mutant unable to synthetize selenocysteine, suggesting that aggregation results from the metabolization of Selenomethionine to selenocysteine followed by translational incorporation in the place of cysteine. In support of this mechanism, we were able to detect random substitutions of cysteinyl residues by selenocysteine in a reporter protein. Our results reveal a novel mechanism of toxicity that may have implications in higher eukaryotes.
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Trans-sulfuration Pathway Seleno-amino Acids Are Mediators of Selenomethionine Toxicity in Saccharomyces cerevisiae.
Journal of Biological Chemistry, 2015Co-Authors: Myriam Lazard, Marc Dauplais, Sylvain Blanquet, Pierre PlateauAbstract:Toxicity of Selenomethionine, an organic derivative of selenium widely used as supplement in human diets, was studied in the model organism Saccharomyces cerevisiae. Several DNA repair-deficient strains hypersensitive to selenide displayed wild-type growth rate properties in the presence of Selenomethionine indicating that selenide and Selenomethionine exert their toxicity via distinct mechanisms. Cytotoxicity of Selenomethionine decreased when the extracellular concentration of methionine or S-adenosylmethionine was increased. This protection resulted from competition between the S- and Se-compounds along the downstream metabolic pathways inside the cell. By comparing the sensitivity to Selenomethionine of mutants impaired in the sulfur amino acid pathway, we excluded a toxic effect of Se-adenosylmethionine, Se-adenosylhomocysteine, or of any compound in the methionine salvage pathway. Instead, we found that Selenomethionine toxicity is mediated by the trans-sulfuration pathway amino acids selenohomocysteine and/or selenocysteine. Involvement of superoxide radicals in Selenomethionine toxicity in vivo is suggested by the hypersensitivity of a Δsod1 mutant strain, increased resistance afforded by the superoxide scavenger manganese, and inactivation of aconitase. In parallel, we showed that, in vitro, the complete oxidation of the selenol function of selenocysteine or selenohomocysteine by dioxygen is achieved within a few minutes at neutral pH and produces superoxide radicals. These results establish a link between superoxide production and trans-sulfuration pathway seleno-amino acids and emphasize the importance of the selenol function in the mechanism of organic selenium toxicity.
Myriam Lazard - One of the best experts on this subject based on the ideXlab platform.
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Exposure to Selenomethionine causes selenocysteine misincorporation and protein aggregation in Saccharomyces cerevisiae.
Scientific Reports, 2017Co-Authors: Pierre Plateau, Marc Dauplais, Sylvain Blanquet, Cosmin Saveanu, Roxane Lestini, Laurence Decourty, Alain Jacquier, Myriam LazardAbstract:Selenomethionine, a dietary supplement with beneficial health effects, becomes toxic if taken in excess. To gain insight into the mechanisms of action of Selenomethionine, we screened a collection of ≈5900 Saccharomyces cerevisiae mutants for sensitivity or resistance to growth-limiting amounts of the compound. Genes involved in protein degradation and synthesis were enriched in the obtained datasets, suggesting that Selenomethionine causes a proteotoxic stress. We demonstrate that Selenomethionine induces an accumulation of protein aggregates by a mechanism that requires de novo protein synthesis. Reduction of translation rates was accompanied by a decrease of protein aggregation and of Selenomethionine toxicity. Protein aggregation was supressed in a ∆cys3 mutant unable to synthetize selenocysteine, suggesting that aggregation results from the metabolization of Selenomethionine to selenocysteine followed by translational incorporation in the place of cysteine. In support of this mechanism, we were able to detect random substitutions of cysteinyl residues by selenocysteine in a reporter protein. Our results reveal a novel mechanism of toxicity that may have implications in higher eukaryotes.
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Trans-sulfuration Pathway Seleno-amino Acids Are Mediators of Selenomethionine Toxicity in Saccharomyces cerevisiae.
Journal of Biological Chemistry, 2015Co-Authors: Myriam Lazard, Marc Dauplais, Sylvain Blanquet, Pierre PlateauAbstract:Toxicity of Selenomethionine, an organic derivative of selenium widely used as supplement in human diets, was studied in the model organism Saccharomyces cerevisiae. Several DNA repair-deficient strains hypersensitive to selenide displayed wild-type growth rate properties in the presence of Selenomethionine indicating that selenide and Selenomethionine exert their toxicity via distinct mechanisms. Cytotoxicity of Selenomethionine decreased when the extracellular concentration of methionine or S-adenosylmethionine was increased. This protection resulted from competition between the S- and Se-compounds along the downstream metabolic pathways inside the cell. By comparing the sensitivity to Selenomethionine of mutants impaired in the sulfur amino acid pathway, we excluded a toxic effect of Se-adenosylmethionine, Se-adenosylhomocysteine, or of any compound in the methionine salvage pathway. Instead, we found that Selenomethionine toxicity is mediated by the trans-sulfuration pathway amino acids selenohomocysteine and/or selenocysteine. Involvement of superoxide radicals in Selenomethionine toxicity in vivo is suggested by the hypersensitivity of a Δsod1 mutant strain, increased resistance afforded by the superoxide scavenger manganese, and inactivation of aconitase. In parallel, we showed that, in vitro, the complete oxidation of the selenol function of selenocysteine or selenohomocysteine by dioxygen is achieved within a few minutes at neutral pH and produces superoxide radicals. These results establish a link between superoxide production and trans-sulfuration pathway seleno-amino acids and emphasize the importance of the selenol function in the mechanism of organic selenium toxicity.
Kazuhito Yokoyama - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of the metabolic chiral inversion of d-Selenomethionine in rats by stable isotope dilution gas chromatography-mass spectrometry.
Journal of pharmaceutical and biomedical analysis, 2015Co-Authors: Takehisa Matsukawa, Hiroshi Hasegawa, Hitomi Goto, Yoshihiko Shinohara, Atsuko Shinohara, Yuki Omori, Kimiyoshi Ichida, Kazuhito YokoyamaAbstract:Abstract The stereoselective pharmacokinetics of Selenomethionine enantiomers in rats has been studied to evaluate the chiral inversion of d -Selenomethionine to the l -enantiomer. After bolus intravenous administration of d - or l -Selenomethionine to rats, the plasma concentrations of these two enantiomers were determined by stereoselective gas chromatography–mass spectrometry with selected ion monitoring. This method involved derivatization of Selenomethionine enantiomers with HCl in methanol to form methyl ester followed by N -acylation with (+)-α-methoxy-α-trifluoromethylphenylacetyl chloride to form the diastereomeric amide, and separation of the diastereomer on GC with an achiral column. Plasma concentrations of administered d - and l -Selenomethionine declined with terminal half-lives of 96 ± 17 min and 91 ± 6 min, respectively. l -Selenomethionine appeared rapidly in plasma after administration of d -Selenomethionine, whereas d -Selenomethionine was not detected in plasma after administration of l -Selenomethionine. The fraction of conversion of d -Selenomethionine to l -Selenomethionine was estimated to be 61.3 ± 14.5%. The present method evaluates the stereoselective pharmacokinetics of Selenomethionine enantiomers, including the estimation of the metabolic chiral inversion.
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Simultaneous determination of Selenomethionine enantiomers in biological fluids by stable isotope dilution gas chromatography–mass spectrometry
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2011Co-Authors: Takehisa Matsukawa, Hiroshi Hasegawa, Yoshihiko Shinohara, Atsuko Shinohara, Kimiyoshi Ichida, Jun Kobayashi, Momoko Chiba, Kazuhito YokoyamaAbstract:Abstract A method for the stereoselective determination of d - and l -enantiomers of Selenomethionine in mouse plasma was developed using gas chromatography–mass spectrometry with selected-ion monitoring (GC–MS-SIM). dl -[ 2 H 3, 82 Se]Selenomethionine was used as analytical internal standard to account for losses associated with the extraction, derivatization and chromatography. Selenomethionine enantiomers in mouse plasma were purified by cation-exchange chromatography using BondElut SCX cartridge and derivatized with HCl in methanol to form methyl ester followed by subsequent N -acylation with optically active (+)-α-methoxy-α-trifluoromethylphenylacetyl chloride to form diastereomeric amide. Quantification was performed by SIM of the molecular-related ions of the diastereomers on the chemical ionization mode. The intra- and inter-day precision for d - and l -Selenomethionine spiked to mouse plasma gave good reproducibility with relative standard deviation of 3% and 3% for d -Selenomethionine and 6% and 3% for l -Selenomethionine, respectively. The estimated amounts were in good agreement with the actual amounts spiked, the intra- and inter-day relative error being 5% and 2% for d -Selenomethionine and 2% and 1% for l -Selenomethionine, respectively. The present method is sensitive enough to determine pharmacokinetics of Selenomethionine enantiomers.
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Synthesis of D- and L-Selenomethionine double-labeled with deuterium and selenium-82.
Chemical & pharmaceutical bulletin, 2010Co-Authors: Takehisa Matsukawa, Hiroshi Hasegawa, Yoshihiko Shinohara, Atsuko Shinohara, Kimiyoshi Ichida, Jun Kobayashi, Momoko Chiba, Kazuhito YokoyamaAbstract:The synthesis of D- and L-Selenomethionine labeled with 82Se and three deuteriums at Se-methyl group (D- and L-[2H3, 82Se]Selenomethionine) was described. D- And L-[2H3, 82Se]Selenomethionine were prepared by condensation of (R)- and (S)-2-amino-4-bromobutylic acid with lithium [2H3, 82Se]methaneselenolate, which was prepared from metal 82Se and [2H3]methyl iodide. The optical purities of D- and L-[2H3, 82Se]Selenomethionine were determined by HPLC with a chiral stationary phase column and were found more than 99% ee. The chemical ionization mass spectra showed that the molecular related ion for N-isobutyloxycarbonyl ethyl ester derivatives of [2H3, 82Se]Selenomethionine did not overlap with the m/z values known from that of non-labeled Selenomethionine.
Ryszard Lobinski - One of the best experts on this subject based on the ideXlab platform.
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determination of Selenomethionine and selenocysteine in human serum using speciated isotope dilution capillary hplc inductively coupled plasma collision cell mass spectrometry
Analytical Chemistry, 2004Co-Authors: Jorge Ruiz Encinar, Dirk Schaumloffel, Yasumitsu Ogra, Ryszard LobinskiAbstract:A method for the accurate determination of selenoamino acids in human serum by HPLC−ICPMS was developed using the species-specific isotope dilution analysis principle. A serum sample was enzymatically digested with a mixture of lipase and protease after derivatization of the selenocysteine residues with iodoacetamide. The selenoamino acid fraction was isolated by size exclusion LC followed by the separation of Selenomethionine and the carboxymethylated selenocysteine by capillary HPLC. The isotope-specific determination of 77Se and 80Se was achieved on-line by ICP collision cell MS allowing the removal of polyatomic interferences. Quantification was carried out by isotope dilution using a 77Se-labeled Selenomethionine spike and the determination of the 77Se/80Se ratio in the cHPLC Selenomethionine peak. The accurately determined Selenomethionine was used as an internal standard for the selenocysteine determination from the same chromatogram. The modification of the previously developed cHPLC−ICPMS interfa...
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analysis of selenized yeast for selenium speciation by size exclusion chromatography and capillary zone electrophoresis with inductively coupled plasma mass spectrometric detection sec cze icp ms
Journal of Analytical Atomic Spectrometry, 2002Co-Authors: Sandra Mounicou, Joanna Szpunar, Shona Mcsheehy, Martine Potingautier, Ryszard LobinskiAbstract:A two-dimensional separation approach based on size-exclusion chromatography (SEC) followed by capillary zone electrophoresis (CZE) is proposed for the mapping of seleno-compounds in aqueous extracts of selenized yeast. The coupling of CZE with ICP-MS via a self-aspirating total consumption micronebulizer was optimized for the separation of Se species. Selenate, selenite, selenocystine, Selenomethionine and selenoethionine could be baseline separated at pH 10.5 using a 10 mM phosphate buffer containing 0.8 mM cetyltriammonium bromide. Detection limits were 7–18 ng mL−1 for a 20 nL injection. The CZE-ICP-MS analysis of a yeast extract demonstrated the presence of many Se species, which all migrated less rapidly than any of the standards. The following difficulties occurred during the CZE-ICP-MS analysis of the SEC fractions of the extract: the recovery of the high-molecular Se-species from the electrophoretic capillary, the presence of a large number of compounds in the medium-molecular weight fraction and the presence of a single intense peak for the low-molecular weight fraction. Proteolysis of the high- and medium-molecular weight fractions dramatically improved the recovery of Se species from the capillary, resulting in several peaks in the CZE-ICP-MS electropherograms.
Sylvain Blanquet - One of the best experts on this subject based on the ideXlab platform.
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Exposure to Selenomethionine causes selenocysteine misincorporation and protein aggregation in Saccharomyces cerevisiae.
Scientific Reports, 2017Co-Authors: Pierre Plateau, Marc Dauplais, Sylvain Blanquet, Cosmin Saveanu, Roxane Lestini, Laurence Decourty, Alain Jacquier, Myriam LazardAbstract:Selenomethionine, a dietary supplement with beneficial health effects, becomes toxic if taken in excess. To gain insight into the mechanisms of action of Selenomethionine, we screened a collection of ≈5900 Saccharomyces cerevisiae mutants for sensitivity or resistance to growth-limiting amounts of the compound. Genes involved in protein degradation and synthesis were enriched in the obtained datasets, suggesting that Selenomethionine causes a proteotoxic stress. We demonstrate that Selenomethionine induces an accumulation of protein aggregates by a mechanism that requires de novo protein synthesis. Reduction of translation rates was accompanied by a decrease of protein aggregation and of Selenomethionine toxicity. Protein aggregation was supressed in a ∆cys3 mutant unable to synthetize selenocysteine, suggesting that aggregation results from the metabolization of Selenomethionine to selenocysteine followed by translational incorporation in the place of cysteine. In support of this mechanism, we were able to detect random substitutions of cysteinyl residues by selenocysteine in a reporter protein. Our results reveal a novel mechanism of toxicity that may have implications in higher eukaryotes.
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Trans-sulfuration Pathway Seleno-amino Acids Are Mediators of Selenomethionine Toxicity in Saccharomyces cerevisiae.
Journal of Biological Chemistry, 2015Co-Authors: Myriam Lazard, Marc Dauplais, Sylvain Blanquet, Pierre PlateauAbstract:Toxicity of Selenomethionine, an organic derivative of selenium widely used as supplement in human diets, was studied in the model organism Saccharomyces cerevisiae. Several DNA repair-deficient strains hypersensitive to selenide displayed wild-type growth rate properties in the presence of Selenomethionine indicating that selenide and Selenomethionine exert their toxicity via distinct mechanisms. Cytotoxicity of Selenomethionine decreased when the extracellular concentration of methionine or S-adenosylmethionine was increased. This protection resulted from competition between the S- and Se-compounds along the downstream metabolic pathways inside the cell. By comparing the sensitivity to Selenomethionine of mutants impaired in the sulfur amino acid pathway, we excluded a toxic effect of Se-adenosylmethionine, Se-adenosylhomocysteine, or of any compound in the methionine salvage pathway. Instead, we found that Selenomethionine toxicity is mediated by the trans-sulfuration pathway amino acids selenohomocysteine and/or selenocysteine. Involvement of superoxide radicals in Selenomethionine toxicity in vivo is suggested by the hypersensitivity of a Δsod1 mutant strain, increased resistance afforded by the superoxide scavenger manganese, and inactivation of aconitase. In parallel, we showed that, in vitro, the complete oxidation of the selenol function of selenocysteine or selenohomocysteine by dioxygen is achieved within a few minutes at neutral pH and produces superoxide radicals. These results establish a link between superoxide production and trans-sulfuration pathway seleno-amino acids and emphasize the importance of the selenol function in the mechanism of organic selenium toxicity.
