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Methionine coordinates a hierarchically organized anabolic program enabling proliferation
Methionine availability during overall amino acid limitation metabolically reprograms cells to support proliferation, the underlying basis for which remains unclear. Here we construct the organization of this methionine-mediated anabolic program using yeast. Combining comparative transcriptome analy...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340205/ https://www.ncbi.nlm.nih.gov/pubmed/30354837 http://dx.doi.org/10.1091/mbc.E18-08-0515 |
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author | Walvekar, Adhish S. Srinivasan, Rajalakshmi Gupta, Ritu Laxman, Sunil |
author_facet | Walvekar, Adhish S. Srinivasan, Rajalakshmi Gupta, Ritu Laxman, Sunil |
author_sort | Walvekar, Adhish S. |
collection | PubMed |
description | Methionine availability during overall amino acid limitation metabolically reprograms cells to support proliferation, the underlying basis for which remains unclear. Here we construct the organization of this methionine-mediated anabolic program using yeast. Combining comparative transcriptome analysis and biochemical and metabolic flux-based approaches, we discover that methionine rewires overall metabolic outputs by increasing the activity of a key regulatory node. This comprises the pentose phosphate pathway (PPP) coupled with reductive biosynthesis, the glutamate dehydrogenase (GDH)-dependent synthesis of glutamate/glutamine, and pyridoxal-5-phosphate (PLP)-dependent transamination capacity. This PPP-GDH-PLP node provides the required cofactors and/or substrates for subsequent rate-limiting reactions in the synthesis of amino acids and therefore nucleotides. These rate-limiting steps in amino acid biosynthesis are also induced in a methionine-dependent manner. This thereby results in a biochemical cascade establishing a hierarchically organized anabolic program. For this methionine-mediated anabolic program to be sustained, cells co-opt a “starvation stress response” regulator, Gcn4p. Collectively, our data suggest a hierarchical metabolic framework explaining how methionine mediates an anabolic switch. |
format | Online Article Text |
id | pubmed-6340205 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-63402052019-03-02 Methionine coordinates a hierarchically organized anabolic program enabling proliferation Walvekar, Adhish S. Srinivasan, Rajalakshmi Gupta, Ritu Laxman, Sunil Mol Biol Cell Articles Methionine availability during overall amino acid limitation metabolically reprograms cells to support proliferation, the underlying basis for which remains unclear. Here we construct the organization of this methionine-mediated anabolic program using yeast. Combining comparative transcriptome analysis and biochemical and metabolic flux-based approaches, we discover that methionine rewires overall metabolic outputs by increasing the activity of a key regulatory node. This comprises the pentose phosphate pathway (PPP) coupled with reductive biosynthesis, the glutamate dehydrogenase (GDH)-dependent synthesis of glutamate/glutamine, and pyridoxal-5-phosphate (PLP)-dependent transamination capacity. This PPP-GDH-PLP node provides the required cofactors and/or substrates for subsequent rate-limiting reactions in the synthesis of amino acids and therefore nucleotides. These rate-limiting steps in amino acid biosynthesis are also induced in a methionine-dependent manner. This thereby results in a biochemical cascade establishing a hierarchically organized anabolic program. For this methionine-mediated anabolic program to be sustained, cells co-opt a “starvation stress response” regulator, Gcn4p. Collectively, our data suggest a hierarchical metabolic framework explaining how methionine mediates an anabolic switch. The American Society for Cell Biology 2018-12-15 /pmc/articles/PMC6340205/ /pubmed/30354837 http://dx.doi.org/10.1091/mbc.E18-08-0515 Text en © 2018 Walvekar et al. “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 | Articles Walvekar, Adhish S. Srinivasan, Rajalakshmi Gupta, Ritu Laxman, Sunil Methionine coordinates a hierarchically organized anabolic program enabling proliferation |
title | Methionine coordinates a hierarchically organized anabolic program enabling proliferation |
title_full | Methionine coordinates a hierarchically organized anabolic program enabling proliferation |
title_fullStr | Methionine coordinates a hierarchically organized anabolic program enabling proliferation |
title_full_unstemmed | Methionine coordinates a hierarchically organized anabolic program enabling proliferation |
title_short | Methionine coordinates a hierarchically organized anabolic program enabling proliferation |
title_sort | methionine coordinates a hierarchically organized anabolic program enabling proliferation |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340205/ https://www.ncbi.nlm.nih.gov/pubmed/30354837 http://dx.doi.org/10.1091/mbc.E18-08-0515 |
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