Effects of methionine synthase and methylenetetrahydrofolate reductase gene polymorphisms on markers of one-carbon metabolism

Abstract

Genetic and nutritional factors play a role in determining the functionality of the one-carbon (1C) metabolism cycle, a network of biochemical reactions critical to intracellular processes. Genes encoding enzymes for methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) may determine biomarkers of the cycle including homocysteine (HCY), S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH). MTHFR C677T is an established genetic determinant of HCY but less is known of its effect on SAM and SAH. Conversely, the relationship between MTR A2756G and HCY remains inconclusive, and its effect on SAM and SAH has only been previously investigated in a female-specific population. Folate and vitamin B12 are essential substrate and cofactor of 1C metabolism; thus, consideration of gene-nutrient interactions may clarify the role of genetic determinants of HCY, SAM and SAH. This cross-sectional study included 570 healthy volunteers from Kingston, Ontario, Ottawa, Ontario and Halifax, Nova Scotia, Canada. Least squares regression was used to examine the effects of MTR and MTHFR polymorphisms on plasma HCY, SAM and SAH concentrations; gene-gene and gene-nutrient interactions were considered with the inclusion of cross-products in the model. Main effects of MTR and MTHFR polymorphisms on HCY concentrations were observed; however, no gene-gene or gene-nutrient interactions were found. No association was observed for SAM. For SAH, interactions between MTR and MTHFR polymorphisms, and MTHFR polymorphism and serum folate were found. The findings of this research provide evidence that HCY and SAH, biomarkers of 1C metabolism, are influenced by genetic and nutritional factors and their interactions.

Dietary folate levels alter the kinetics and molecular mechanism of prostate cancer recurrence in the CWR22 model

“…One way to balance this would be to allow more one-carbon units to flow through MTHFR from folate metabolism to the methionine cycle (Figure 1 ). Although we did not find a significant increase in MTHFR expression levels ( Supplementary Figure 4C ), SAM is an allosteric inhibitor of MTHFR activity [ 31 ] and so it would follow that increased consumption of SAM by AMD1 would lead to increased activity of MTHFR, and therefore flow of one-carbon units. Consistent with this interpretation, we found decreased expression of TYMS and accumulation of dUMP in the recurrent tumors on the folate depleted diet.…”

Interplay between 3′-UTR polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and the risk of ischemic stroke

“…The MTHFR gene is critical for Hcy and folate metabolism, and polymorphic variants of the enzymes involved in Hcy and folate metabolism also play an important role in determining the susceptibility of an individual to disease 16 . Lower MTHFR enzyme activity, which can increase total plasma homocysteine (tHcy) levels and decrease plasma folate levels, contributes to stroke development 16 – 18 . Folate concentrations inversely correlate with tHcy levels 19 .…”

Introductory Chapter: General Aspects Regarding Homocysteine

“…The functionality of methionine synthase is maintained by methionine synthase reductase, which catalyzes the reductive reactivation of inactive MS bound to oxidized cobalamin to maintain its active form using S-adenosylmethionine (SAM). Polymorphisms in MS and MTHFR were suggested to act independently to elevate Hcy concentrations by compromising different parts of the pathway that might not interact directly with one another [3].…”