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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.

Project description:Sustained activity of mammalian methionine synthase (MS) requires MS reductase (MSR), but there have been few studies of the interactions between these two proteins. In this study, recombinant human MS (hMS) and MSR (hMSR) were expressed in baculovirus-infected insect cells and purified to homogeneity. hMSR maintained hMS activity at a 1:1 stoichiometric ratio with a K(act) value of 71 nM. Escherichia coli MS, however, was not activated by hMSR. Moreover, hMS was not significantly active in the presence of E. coli flavodoxin and flavodoxin reductase, which maintain the activity of E. coli MS. These results indicate that recognition of MS by their reductive partners is very strict, despite the high homology between MS from different species. The effects of hMSR on the formation of hMS holoenzyme also were examined by using crude extracts of baculovirus-infected insect cells containing hMS apoenzyme (apoMS). In the presence of MSR and NADPH, holoenzyme formation from apoMS and methylcobalamin was significantly enhanced. The observed stimulation is shown to be due to stabilization of human apoMS in the presence of MSR. Apoenzyme alone is quite unstable at 37 degrees C. MSR also is able to reduce aquacobalamin to cob(II)alamin in the presence of NADPH, and this reduction leads to stimulation of the conversion of apoMS and aquacobalamin to MS holoenzyme. Based on these findings, we propose that MSR serves as a special chaperone for hMS and as an aquacobalamin reductase, rather than acting solely in the reductive activation of MS.

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Formyltetrahydrofolate hydrolase, a regulatory enzyme that functions to balance pools of tetrahydrofolate and one-carbon tetrahydrofolate adducts in Escherichia coli.

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Project description:Polymorphisms in genes involved in folate metabolism may modulate the risk of colorectal cancer (CRC), but data from published studies are conflicting. The current meta-analysis was performed to address a more accurate estimation. A total of 41 (17,552 cases and 26,238 controls), 24(8,263 cases and 12,033 controls), 12(3,758 cases and 5,646 controls), and 13 (5,511 cases and 7,265 controls) studies were finally included for the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1289C, methione synthase reductase (MTRR) A66G, methionine synthase (MTR) A2756G polymorphisms and the risk of CRC, respectively. The data showed that the MTHFR 677T allele was significantly associated with reduced risk of CRC (OR = 0.93, 95%CI 0.90-0.96), while the MTRR 66G allele was significantly associated with increased risk of CRC (OR = 1.11, 95%CI 1.01-1.18). Sub-group analysis by ethnicity revealed that MTHFR C677T polymorphism was significantly associated with reduced risk of CRC in Asians (OR = 0.80, 95%CI 0.72-0.89) and Caucasians (OR = 0.84, 95%CI 0.76-0.93) in recessive genetic model, while the MTRR 66GG genotype was found to significantly increase the risk of CRC in Caucasians (GG vs. AA: OR = 1.18, 95%CI 1.03-1.36). No significant association was found between MTHFR A1298C and MTR A2756G polymorphisms and the risk of CRC. Cumulative meta-analysis showed no particular time trend existed in the summary estimate. Probability of publication bias was low across all comparisons illustrated by the funnel plots and Egger's test. Collectively, this meta-analysis suggested that MTHFR 677T allele might provide protection against CRC in worldwide populations, while MTRR 66G allele might increase the risk of CRC in Caucasians. Since potential confounders could not be ruled out completely, further studies were needed to confirm these results.

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| S-EPMC2903885 | biostudies-literature

Association of methionine synthase rs1801394 and methionine synthase reductase rs1805087 polymorphisms with meningioma in adults: A meta-analysis.

Project description:Several epidemiological studies suggested that methionine synthase (MTRR) rs1801394 and methionine synthase reductase (MTR) rs1805087 polymorphisms may be involved in the risk of meningioma in adults; however, the results from different case-control studies have been inconsistent. Therefore, we performed a meta-analysis to investigate the association of MTRR and MTR polymorphisms with meningioma. PubMed, Web of Knowledge, China National Knowledge Infrastructure and Wanfang databases were searched up to October 30, 2013 and 3 publications, involving 7 case-control studies, were finally included. Following data extraction, a meta-analysis was conducted using Stata 12.0 software. The pooled results based on the fixed effects model demonstrated that the MTRR rs1801394 polymorphism was associated with an increased risk of meningioma [odds ratio (OR)=1.18, 95% confidence interval (CI): 1.05-1.32 for G vs. A; OR=1.41, 95% CI: 1.12-1.77 for GG vs. AA; OR=1.08, 95% CI: 0.94-1.33 for AG vs. AA; OR=1.19, 95% CI: 1.01-1.40 for (AG+GG) vs. AA; and OR=1.32, 95% CI: 1.07-1.63 for GG vs. (AG+AA)]; however, an association between the MTR rs1805087 polymorphism and the risk of meningioma was not identified [OR=0.99, 95% CI: 0.88-1.12 for G vs. A; OR=1.09, 95% CI: 0.80-1.48 for GG vs. AA; OR=0.95, 95% CI: 0.82-1.11 for AG vs. AA; OR=0.97, 95% CI: 0.84-1.13 for (AG+GG) vs. AA; and OR=1.09, 95% CI: 0.80-1.48 for GG vs. (AG+AA)]. Therefore, the currently available evidence suggests that the MTRR rs1801394 polymorphism may increase the risk of meningioma, whereas the MTRR rs1801394 polymorphism is not associated with meningioma.

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Polymorphisms in methionine synthase, methionine synthase reductase and serine hydroxymethyltransferase, folate and alcohol intake, and colon cancer risk.

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.

| S-EPMC2758622 | biostudies-literature

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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 2 mutant

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. Includes 3 biological replicates and dye-swaps, with one additional replicate for ATCC PTA 6475 versus tetrahydrofolate synthase 1 mutant. Reference time point is L. reuteri ATCC PTA 6475.

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

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

Project description:Gene expression comparison of L. reuteri ATCC PTA 6475 and tetrahydrofolate synthase 2 mutant in MRS medium in anaerobic conditions at 37C. Includes 3 biological replicates and dye-swaps for ATCC PTA 6475 versus tetrahydrofolate synthase 2 mutant. Reference time point is L. reuteri ATCC PTA 6475.

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

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