Genetic Variation in Folate Metabolism

Abstract

Folate derivatives are utilized in single-carbon transfer reactions for many critical pathways, including methionine and DNA synthesis (see Fig. 1). For example, 5,10-methylene tetrahydrofolate (5,10-methylene THF) is required for conversion of dUMP to dTMP. It can also be converted to 10formyltetrahydrofolate for the synthesis of the purine ring, or reduced to 5-methyltetrahydrofolate (5-methylTHF) for the remethylation of homocysteine to methionine. Methionine is the precursor for S-adenosymethionine (SAM), the methyl donor in numerous methylation reactions. The enzyme 5,10-methylene tetrahydrofolate reductase (MTHFR) converts 5,10-methylene THF to 5-methylTHF, thereby regulating a balance between folate required for DNA synthesis and folate required for methionine/SAM synthesis and methylation reactions. The importance of MTHFR to SAM supply is highlighted by the fact that SAM is a MTHFR inhibitor.