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Methionine synthase supports tumour tetrahydrofolate pools.

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.

SUBMITTER: Ghergurovich JM

PROVIDER: S-EPMC9284419 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Human methionine synthase reductase is a molecular chaperone for human methionine synthase.

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Project description:We examined associations among folate and alcohol intake, single nucleotide polymorphisms (SNPs) in genes involved in one-carbon metabolism, and colon cancer risk.Colon cancer cases (294 African-Americans and 349 whites) were frequency matched to population controls (437 African-Americans and 611 whites) by age, race and sex from 33 North Carolina counties from 1996 to 2000. Folate and alcohol intakes were collected by dietary interview. Five SNPs were genotyped using DNA from whole blood: SHMT C1420T; MTRR A66G; MTR A2756G, and the previously-reported MTHFR C677T and MTHFR A1298C. Adjusted odds ratios (OR) and 95% CI were calculated using logistic regression.An inverse association was observed for SHMT TT genotype as compared to CC genotype in whites (OR = 0.6, 95% CI = 0.4, 1.0), but not in African Americans. Inverse associations were observed for high folate intake in individuals carrying 0 or 1 variant allele [OR 0.2 (95% CI 0.06-0.8) for African-Americans; OR 0.2 (95% CI 0.1-0.6) for whites] compared to low folate intake. Modest interactions between these SNPs and alcohol or folate intakes were observed.Our results are consistent with other findings and provide needed data on these associations among African-Americans.

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Project description:Gene expression comparison of L. reuteri ATCC PTA 6475 and tetrahydrofolate synthase 2 mutant in MRS medium in anaerobic conditions at 37C.

2012-06-11 | GSE32972 | GEO

Gene expression comparison of L. reuteri ATCC PTA 6475 and tetrahydrofolate synthase 1 mutant

Project description:Gene expression comparison of L. reuteri ATCC PTA 6475 and tetrahydrofolate synthase 1 in MRS medium in anaerobic conditions at 37C.

2012-06-11 | GSE32971 | GEO

Gene expression comparison of L. reuteri ATCC PTA 6475 and tetrahydrofolate synthase 1 mutant

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2012-06-10 | E-GEOD-32971 | biostudies-arrayexpress

Gene expression comparison of L. reuteri ATCC PTA 6475 and tetrahydrofolate synthase 2 mutant

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2012-06-10 | E-GEOD-32972 | biostudies-arrayexpress

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