Methionine synthase supports tumour tetrahydrofolate pools.

TitleMethionine synthase supports tumour tetrahydrofolate pools.
Publication TypeJournal Article
Year of Publication2021
AuthorsGhergurovich, JM, Xu, X, Wang, JZ, Yang, L, Ryseck, R-P, Wang, L, Rabinowitz, JD
JournalNat Metab
Date Published2021 Nov
Keywords5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase, Cell Line, Tumor, Cell Proliferation, Folic Acid, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Metabolic Networks and Pathways, Methionine, Methylation, Mutation, Neoplasms, Purines, Tetrahydrofolates, Vitamin B 12 Deficiency

<p>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 MTR is only a minor source of methionine in cell culture, tissues or xenografted tumours. Instead, MTR 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 tumour 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 THF for use in one-carbon metabolism.</p>

Alternate JournalNat Metab
PubMed ID34799699
PubMed Central IDPMC9284419
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States