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Methionine synthase supports tumor tetrahydrofolate pools
Mammalian cells require activated folates to generate nucleotides for growth and division. The most abundant circulating folate species is 5-methyl tetrahydrofolate (5-methyl-THF), which is used to synthesize methionine from homocysteine via the cobalamin-dependent enzyme methionine synthase (MTR)....
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9284419/ https://www.ncbi.nlm.nih.gov/pubmed/34799699 http://dx.doi.org/10.1038/s42255-021-00465-w |
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author | Ghergurovich, Jonathan M. Xu, Xincheng Wang, Joshua Z. Yang, Lifeng Ryseck, Rolf-Peter Wang, Lin Rabinowitz, Joshua D. |
author_facet | Ghergurovich, Jonathan M. Xu, Xincheng Wang, Joshua Z. Yang, Lifeng Ryseck, Rolf-Peter Wang, Lin Rabinowitz, Joshua D. |
author_sort | Ghergurovich, Jonathan M. |
collection | PubMed |
description | Mammalian cells require activated folates to generate nucleotides for growth and division. The most abundant circulating folate species is 5-methyl tetrahydrofolate (5-methyl-THF), which is used to synthesize methionine from homocysteine via the cobalamin-dependent enzyme methionine synthase (MTR). Cobalamin deficiency traps folates as 5-methyl-THF. Here, we show using isotope tracing that methionine synthase is only a minor source of methionine in cell culture, tissues, or xenografted tumors. Instead, methionine synthase is required for cells to avoid folate trapping and assimilate 5-methyl-THF into other folate species. Under conditions of physiological extracellular folates, genetic MTR knockout in tumor cells leads to folate trapping, purine synthesis stalling, nucleotide depletion, and impaired growth in cell culture and as xenografts. These defects are rescued by free folate but not one-carbon unit supplementation. Thus, MTR plays a crucial role in liberating tetrahydrofolate for use in one-carbon metabolism. |
format | Online Article Text |
id | pubmed-9284419 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
spelling | pubmed-92844192022-07-15 Methionine synthase supports tumor tetrahydrofolate pools Ghergurovich, Jonathan M. Xu, Xincheng Wang, Joshua Z. Yang, Lifeng Ryseck, Rolf-Peter Wang, Lin Rabinowitz, Joshua D. Nat Metab Article Mammalian cells require activated folates to generate nucleotides for growth and division. The most abundant circulating folate species is 5-methyl tetrahydrofolate (5-methyl-THF), which is used to synthesize methionine from homocysteine via the cobalamin-dependent enzyme methionine synthase (MTR). Cobalamin deficiency traps folates as 5-methyl-THF. Here, we show using isotope tracing that methionine synthase is only a minor source of methionine in cell culture, tissues, or xenografted tumors. Instead, methionine synthase is required for cells to avoid folate trapping and assimilate 5-methyl-THF into other folate species. Under conditions of physiological extracellular folates, genetic MTR knockout in tumor cells leads to folate trapping, purine synthesis stalling, nucleotide depletion, and impaired growth in cell culture and as xenografts. These defects are rescued by free folate but not one-carbon unit supplementation. Thus, MTR plays a crucial role in liberating tetrahydrofolate for use in one-carbon metabolism. 2021-11 2021-11-18 /pmc/articles/PMC9284419/ /pubmed/34799699 http://dx.doi.org/10.1038/s42255-021-00465-w Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Ghergurovich, Jonathan M. Xu, Xincheng Wang, Joshua Z. Yang, Lifeng Ryseck, Rolf-Peter Wang, Lin Rabinowitz, Joshua D. Methionine synthase supports tumor tetrahydrofolate pools |
title | Methionine synthase supports tumor tetrahydrofolate pools |
title_full | Methionine synthase supports tumor tetrahydrofolate pools |
title_fullStr | Methionine synthase supports tumor tetrahydrofolate pools |
title_full_unstemmed | Methionine synthase supports tumor tetrahydrofolate pools |
title_short | Methionine synthase supports tumor tetrahydrofolate pools |
title_sort | methionine synthase supports tumor tetrahydrofolate pools |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9284419/ https://www.ncbi.nlm.nih.gov/pubmed/34799699 http://dx.doi.org/10.1038/s42255-021-00465-w |
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