Figure 1.

MTHFR, a critical branch point of one-carbon metabolism. A, one-carbon metabolism encompasses the folate cycle, methionine cycle, and transsulfuration pathway. The folate cycle plays a crucial role in nucleotide biosynthesis (purines and thymidine) and redox balance (by utilization and production of NADPH at various steps). Folate metabolism is linked to the methionine cycle via 5-CH₃THF, a folate intermediate synthesized by the activity of the MTHFR enzyme. MS remethylates homocysteine to methionine by expending 5-CH₃THF, which enters the methionine cycle. The methionine cycle, in addition to providing methionine for protein translation, is the major source of SAM, the cellular methylation currency. SAM also yields polyamines via the methionine salvage pathway or enters the transsulfuration pathway via hydrolysis of SAH to homocysteine. The transsulfuration pathway synthesizes GSH via a series of steps. GSH is the major anti-oxidant moiety in the cell. SHMT, serine hydroxyl methyltransferase; TYMS, thymidine synthase; GART, glycinamide ribonucleotide transformylase; AICART, aminoimidazolecarboxamide ribonucleotide formyltransferase. B, schematic representation of eukaryotic MTHFR. Shown is the domain organization of the yeast MTHFR, Met13p, with ∼300-amino acid-long catalytic domain at the N terminus and an equally large regulatory domain at the C terminus.