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Methylated metabolite of arsenite blocks glycerol production in yeast by inhibition of glycerol-3-phosphate dehydrogenase

The yeast high-osmolarity glycerol (HOG) stress-activated protein kinase Hog1 is activated in response to hyperosmotic stress, inducing the production and retention of glycerol to restore osmotic balance. Hog1 promotes retention of glycerol through closure of the plasma-membrane glycerol channel Fps...

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Autores principales: Lee, Jongmin, Levin, David E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743455/
https://www.ncbi.nlm.nih.gov/pubmed/31141459
http://dx.doi.org/10.1091/mbc.E19-04-0228
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author Lee, Jongmin
Levin, David E.
author_facet Lee, Jongmin
Levin, David E.
author_sort Lee, Jongmin
collection PubMed
description The yeast high-osmolarity glycerol (HOG) stress-activated protein kinase Hog1 is activated in response to hyperosmotic stress, inducing the production and retention of glycerol to restore osmotic balance. Hog1 promotes retention of glycerol through closure of the plasma-membrane glycerol channel Fps1. Treatment of yeast with the toxic trivalent metalloid arsenite (As(III)) also activates Hog1 as part of a protective response in which Hog1 closes Fps1, the main entry port for As(III). In this study, we investigated how cells treated with As(III) avoid creating a new stress caused by the accumulation of glycerol in the absence of hyperosmotic stress conditions. We found that As(III) treatment did not induce glycerol accumulation and, in fact, blocked the accumulation of glycerol induced by constitutive Hog1 activity. We demonstrated that As(III) blocks glycerol production indirectly after its metabolic activation to methylarsenite (MAs(III)), which is a potent inhibitor of glycerol-3-phosphate dehydrogenase. Finally, we used a biotinylated arsenic probe to establish that Cys306 of yeast Gpd1, a highly conserved residue within the active site, is the key target of MAs(III). Conservative mutations at this residue greatly diminished Gpd1 activity. This study offers insight into mechanisms by which SAPK outputs are tailored to specific stressors.
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spelling pubmed-67434552019-10-16 Methylated metabolite of arsenite blocks glycerol production in yeast by inhibition of glycerol-3-phosphate dehydrogenase Lee, Jongmin Levin, David E. Mol Biol Cell Brief Reports The yeast high-osmolarity glycerol (HOG) stress-activated protein kinase Hog1 is activated in response to hyperosmotic stress, inducing the production and retention of glycerol to restore osmotic balance. Hog1 promotes retention of glycerol through closure of the plasma-membrane glycerol channel Fps1. Treatment of yeast with the toxic trivalent metalloid arsenite (As(III)) also activates Hog1 as part of a protective response in which Hog1 closes Fps1, the main entry port for As(III). In this study, we investigated how cells treated with As(III) avoid creating a new stress caused by the accumulation of glycerol in the absence of hyperosmotic stress conditions. We found that As(III) treatment did not induce glycerol accumulation and, in fact, blocked the accumulation of glycerol induced by constitutive Hog1 activity. We demonstrated that As(III) blocks glycerol production indirectly after its metabolic activation to methylarsenite (MAs(III)), which is a potent inhibitor of glycerol-3-phosphate dehydrogenase. Finally, we used a biotinylated arsenic probe to establish that Cys306 of yeast Gpd1, a highly conserved residue within the active site, is the key target of MAs(III). Conservative mutations at this residue greatly diminished Gpd1 activity. This study offers insight into mechanisms by which SAPK outputs are tailored to specific stressors. The American Society for Cell Biology 2019-08-01 /pmc/articles/PMC6743455/ /pubmed/31141459 http://dx.doi.org/10.1091/mbc.E19-04-0228 Text en © 2019 Lee and Levin. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.
spellingShingle Brief Reports
Lee, Jongmin
Levin, David E.
Methylated metabolite of arsenite blocks glycerol production in yeast by inhibition of glycerol-3-phosphate dehydrogenase
title Methylated metabolite of arsenite blocks glycerol production in yeast by inhibition of glycerol-3-phosphate dehydrogenase
title_full Methylated metabolite of arsenite blocks glycerol production in yeast by inhibition of glycerol-3-phosphate dehydrogenase
title_fullStr Methylated metabolite of arsenite blocks glycerol production in yeast by inhibition of glycerol-3-phosphate dehydrogenase
title_full_unstemmed Methylated metabolite of arsenite blocks glycerol production in yeast by inhibition of glycerol-3-phosphate dehydrogenase
title_short Methylated metabolite of arsenite blocks glycerol production in yeast by inhibition of glycerol-3-phosphate dehydrogenase
title_sort methylated metabolite of arsenite blocks glycerol production in yeast by inhibition of glycerol-3-phosphate dehydrogenase
topic Brief Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743455/
https://www.ncbi.nlm.nih.gov/pubmed/31141459
http://dx.doi.org/10.1091/mbc.E19-04-0228
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