Methionine synthase supports tumour tetrahydrofolate pools

Jonathan M. Ghergurovich, Xincheng Xu, Joshua Z. Wang, Lifeng Yang, Rolf Peter Ryseck, Lin Wang, Joshua D. Rabinowitz

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1512-1520
Number of pages9
JournalNature Metabolism
Volume3
Issue number11
DOIs
StatePublished - Nov 2021

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology
  • Physiology (medical)

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