Nutritional Manipulation of One-Carbon Metabolism: Effects on Arsenic Methylation and Toxicity

Figure 2

One-carbon metabolism. (1) Folic acid, arising from fortified foods or nutritional supplements, is reduced to dihydrofolate (DHF) and tetrahydrofolate (THF) by dihydrofolate reductase. (2) Serine hydroxymethyl-transferase transfers 1-carbon units from serine to THF, with PLP as a coenzyme, forming 5,10-methylene-THF and glycine. (3) 5,10-methyl THF reductase can reduce 5,10-methylene-THF to 5-methyl-THF. 5,10-methylene-THF can also generate DHF during the synthesis of thymidylate. After absorption from the GI tract, dietary folates can also enter the one-carbon metabolic pathway as 5 methyl THF. (4) In a reaction catalyzed by methionine synthetase and utilizing vitamin B12 as a cofactor, the methyl group of 5-methyl-THF is transferred to homocysteine (Hcys), generating methionine and THF. Alternatively, betaine can donate a methyl group for the remethylation of homocysteine to methionine in a reaction catalyzed by betaine homocysteine methyltransferase (BHMT). (5) Methionine adenosyltransferase activates methionine to form S-adenosylmethionine (SAM). (6) SAM is a methyl donor for a variety of acceptors, including guanidinoacetate (GAA—precursor to creatine), DNA, and As, in reactions that involve a number of methyltransferases. (7) The byproduct of these methylation reactions, s-adenosylhomocysteine (SAH), is hydrolyzed to generate Hcys. (8) Hcys is either used to regenerate methionine or is directed to the transsulfuration pathway.