Cell

Cystathionine beta synthase

Enzyme

Homocysteine

Methionine

Methylation

Nucleotide

Biology

Gene

Chemistry

Vitamin B12

Cobalamin

Extracellular

Cell growth

Metabolism

Cell division

Methionine Adenosyltransferase

Amino acid

Biosynthesis

Biochemistry

Methionine synthase

Methyltransferase

Nature Metabolism

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. Ghergurovich, Xu and Wang et al. show that methionine synthase is important for tumour cell survival through the generation of tetrahydrofolate rather than methionine.

Methionine synthase supports tumour tetrahydrofolate pools