1. Methylselenol Produced In Vivo from Methylseleninic Acid or Dimethyl Diselenide Induces Toxic Protein Aggregation in Saccharomyces cerevisiae
- Author
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Ryszard Lobinski, Marc Dauplais, Myriam Lazard, Katarzyna Bierla, Coralie Maizeray, Pierre Plateau, Roxane Lestini, Joanna Szpunar, Institut des sciences analytiques et de physico-chimie pour l'environnement et les materiaux (IPREM), Université de Pau et des Pays de l'Adour (UPPA)-Centre National de la Recherche Scientifique (CNRS), Lazard, Myriam, Laboratoire de Biochimie de l'Ecole polytechnique (BIOC), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Université de Pau et des Pays de l'Adour (UPPA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Optique et Biosciences (LOB), École polytechnique (X)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Laboratoire de Biologie Structurale de la Cellule (BIOC)
- Subjects
0301 basic medicine ,Metabolite ,Thioredoxin reductase ,Glutathione reductase ,methylseleninic acid ,thiol/disulfide exchange ,Saccharomyces cerevisiae metabolism ,01 natural sciences ,lcsh:Chemistry ,chemistry.chemical_compound ,Organoselenium Compounds ,M methylselenol ,Cytotoxicity ,lcsh:QH301-705.5 ,diselenide ,Spectroscopy ,chemistry.chemical_classification ,General Medicine ,[CHIM.MATE]Chemical Sciences/Material chemistry ,methylselenol ,Computer Science Applications ,[SDV.TOX] Life Sciences [q-bio]/Toxicology ,[CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry ,Biochemistry ,[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,[SDV.TOX]Life Sciences [q-bio]/Toxicology ,Thioredoxin ,[CHIM.POLY] Chemical Sciences/Polymers ,Saccharomyces cerevisiae Proteins ,[CHIM.ANAL] Chemical Sciences/Analytical chemistry ,chemistry.chemical_element ,Saccharomyces cerevisiae ,Protein Aggregation, Pathological ,Catalysis ,Article ,protein aggregation ,Inorganic Chemistry ,03 medical and health sciences ,[CHIM.ANAL]Chemical Sciences/Analytical chemistry ,redox equilibrium ,Physical and Theoretical Chemistry ,Molecular Biology ,[CHIM.MATE] Chemical Sciences/Material chemistry ,Methanol ,010401 analytical chemistry ,Organic Chemistry ,toxicity ,Glutathione ,0104 chemical sciences ,[CHIM.THEO] Chemical Sciences/Theoretical and/or physical chemistry ,030104 developmental biology ,Enzyme ,[CHIM.POLY]Chemical Sciences/Polymers ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Selenium - Abstract
Methylselenol (MeSeH) has been suggested to be a critical metabolite for anticancer activity of selenium, although the mechanisms underlying its activity remain to be fully established. The aim of this study was to identify metabolic pathways of MeSeH in Saccharomyces cerevisiae to decipher the mechanism of its toxicity. We first investigated in vitro the formation of MeSeH from methylseleninic acid (MSeA) or dimethyldiselenide. Determination of the equilibrium and rate constants of the reactions between glutathione (GSH) and these MeSeH precursors indicates that in the conditions that prevail in vivo, GSH can reduce the major part of MSeA or dimethyldiselenide into MeSeH. MeSeH can also be enzymatically produced by glutathione reductase or thioredoxin/thioredoxin reductase. Studies on the toxicity of MeSeH precursors (MSeA, dimethyldiselenide or a mixture of MSeA and GSH) in S. cerevisiae revealed that cytotoxicity and selenomethionine content were severely reduced in a met17 mutant devoid of O-acetylhomoserine sulfhydrylase. This suggests conversion of MeSeH into selenomethionine by this enzyme. Protein aggregation was observed in wild-type but not in met17 cells. Altogether, our findings support the view that MeSeH is toxic in S. cerevisiae because it is metabolized into selenomethionine which, in turn, induces toxic protein aggregation.
- Published
- 2021