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Lipophilic Cations Rescue the Growth of Yeast under the Conditions of Glycolysis Overflow

Chemicals inducing a mild decrease in the ATP/ADP ratio are considered as caloric restriction mimetics as well as treatments against obesity. Screening for such chemicals in animal model systems requires a lot of time and labor. Here, we present a system for the rapid screening of non-toxic substanc...

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Autores principales: Sokolov, Svyatoslav S., Smirnova, Ekaterina A., Markova, Olga V., Kireeva, Natalya A., Kirsanov, Roman S., Khailova, Liudmila S., Knorre, Dmitry A., Severin, Fedor F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563754/
https://www.ncbi.nlm.nih.gov/pubmed/32962296
http://dx.doi.org/10.3390/biom10091345
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author Sokolov, Svyatoslav S.
Smirnova, Ekaterina A.
Markova, Olga V.
Kireeva, Natalya A.
Kirsanov, Roman S.
Khailova, Liudmila S.
Knorre, Dmitry A.
Severin, Fedor F.
author_facet Sokolov, Svyatoslav S.
Smirnova, Ekaterina A.
Markova, Olga V.
Kireeva, Natalya A.
Kirsanov, Roman S.
Khailova, Liudmila S.
Knorre, Dmitry A.
Severin, Fedor F.
author_sort Sokolov, Svyatoslav S.
collection PubMed
description Chemicals inducing a mild decrease in the ATP/ADP ratio are considered as caloric restriction mimetics as well as treatments against obesity. Screening for such chemicals in animal model systems requires a lot of time and labor. Here, we present a system for the rapid screening of non-toxic substances causing such a de-energization of cells. We looked for chemicals allowing the growth of yeast lacking trehalose phosphate synthase on a non-fermentable carbon source in the presence of glucose. Under such conditions, the cells cannot grow because the cellular phosphate is mostly being used to phosphorylate the sugars in upper glycolysis, while the biosynthesis of bisphosphoglycerate is blocked. We reasoned that by decreasing the ATP/ADP ratio, one might prevent the phosphorylation of the sugars and also boost bisphosphoglycerate synthesis by providing the substrate, i.e., inorganic phosphate. We confirmed that a complete inhibition of oxidative phosphorylation alleviates the block. As our system includes a non-fermentable carbon source, only the chemicals that did not cause a complete block of mitochondrial ATP synthesis allowed the initial depletion of glucose followed by respiratory growth. Using this system, we found two novel compounds, dodecylmethyl diphenylamine (FS1) and diethyl (tetradecyl) phenyl ammonium bromide (Kor105), which possess a mild membrane-depolarizing activity.
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spelling pubmed-75637542020-10-27 Lipophilic Cations Rescue the Growth of Yeast under the Conditions of Glycolysis Overflow Sokolov, Svyatoslav S. Smirnova, Ekaterina A. Markova, Olga V. Kireeva, Natalya A. Kirsanov, Roman S. Khailova, Liudmila S. Knorre, Dmitry A. Severin, Fedor F. Biomolecules Article Chemicals inducing a mild decrease in the ATP/ADP ratio are considered as caloric restriction mimetics as well as treatments against obesity. Screening for such chemicals in animal model systems requires a lot of time and labor. Here, we present a system for the rapid screening of non-toxic substances causing such a de-energization of cells. We looked for chemicals allowing the growth of yeast lacking trehalose phosphate synthase on a non-fermentable carbon source in the presence of glucose. Under such conditions, the cells cannot grow because the cellular phosphate is mostly being used to phosphorylate the sugars in upper glycolysis, while the biosynthesis of bisphosphoglycerate is blocked. We reasoned that by decreasing the ATP/ADP ratio, one might prevent the phosphorylation of the sugars and also boost bisphosphoglycerate synthesis by providing the substrate, i.e., inorganic phosphate. We confirmed that a complete inhibition of oxidative phosphorylation alleviates the block. As our system includes a non-fermentable carbon source, only the chemicals that did not cause a complete block of mitochondrial ATP synthesis allowed the initial depletion of glucose followed by respiratory growth. Using this system, we found two novel compounds, dodecylmethyl diphenylamine (FS1) and diethyl (tetradecyl) phenyl ammonium bromide (Kor105), which possess a mild membrane-depolarizing activity. MDPI 2020-09-20 /pmc/articles/PMC7563754/ /pubmed/32962296 http://dx.doi.org/10.3390/biom10091345 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sokolov, Svyatoslav S.
Smirnova, Ekaterina A.
Markova, Olga V.
Kireeva, Natalya A.
Kirsanov, Roman S.
Khailova, Liudmila S.
Knorre, Dmitry A.
Severin, Fedor F.
Lipophilic Cations Rescue the Growth of Yeast under the Conditions of Glycolysis Overflow
title Lipophilic Cations Rescue the Growth of Yeast under the Conditions of Glycolysis Overflow
title_full Lipophilic Cations Rescue the Growth of Yeast under the Conditions of Glycolysis Overflow
title_fullStr Lipophilic Cations Rescue the Growth of Yeast under the Conditions of Glycolysis Overflow
title_full_unstemmed Lipophilic Cations Rescue the Growth of Yeast under the Conditions of Glycolysis Overflow
title_short Lipophilic Cations Rescue the Growth of Yeast under the Conditions of Glycolysis Overflow
title_sort lipophilic cations rescue the growth of yeast under the conditions of glycolysis overflow
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563754/
https://www.ncbi.nlm.nih.gov/pubmed/32962296
http://dx.doi.org/10.3390/biom10091345
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