Figure 1

Overview of the folate metabolic pathway. Folates require several transport systems to enter the cells, the best characterized being the reduced folate carrier (RFC1). Methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylenetetrahydrofolate (5,10-MTHF) to 5-methyltetrahydrofolate (5-MTHF). Subsequently, methionine synthase (MTR) transfers a methyl group from 5-MTHF to homocysteine (Hcy) forming methionine (Met) and tetrahydrofolate (THF). Methionine is then converted to S-adenosylmethionine (SAM) in a reaction catalyzed by methionine adenosyltransferase (MAT). Most of the SAM generated is used in transmethylation reactions, whereby SAM is converted to S-adenosylhomocysteine (SAH) by DNA methyltransferases (DNMTs) that transfer the methyl group to the DNA. Vitamin B12 (or cobalamin) is a cofactor of MTR, and methionine synthase reductase (MTRR) is required for the maintenance of MTR in its active state. If not converted into methionine, Hcy can be condensed with serine to form cystathionine in a reaction catalyzed by cystathionine β-synthase (CBS), which requires vitamin B6 as a cofactor. Cystathionine can be then utilized to form the antioxidant compound glutathione (GSH). Another important function of tetrahydrofolate derivatives is in the de novo synthesis of DNA and RNA precursors, where they are used by thymidylate synthase (TYMS) and methylenetetrahydrofolate dehydrogenase (MTHFD) for the synthesis of nucleic acid precursors. MTHFD is a trifunctional enzyme that interconverts tetrahydrofolate derivatives for purine, methionine and thymidylate synthesis. TYMS requires 5,10-MTHF and deoxyuridine monophosphate (dUMP) for the production of to deoxythymine monophospate (dTMP) and dihydrofolate (DHF) in the de novo synthesis of pyrimidines. Other enzymes participate in folate metabolism, among them phosphoribosylglycinamide transformylase (GART) which is a protein required for purine synthesis.