FIGURE 1.

Folate-mediated one-carbon metabolism occurs in the mitochondria, nucleus, and cytoplasm. Mitochondrial-derived formate traverses to the cytoplasm where it is incorporated into the folate-activated one-carbon pool through the activity of FTHFS and utilized in the synthesis of purines, thymidylate, and the methylation of homocysteine to methionine. Methionine can be converted to a methyl donor through its adenosylation to AdoMet. Thymidylate biosynthesis occurs in the cytoplasm and nucleus. The one-carbon unit is labeled in bold. GCS, glycine cleavage system; mSHMT, mitochondrial serine hydroxymethyltransferase; mMTHFD, mitochondrial methylenetetrahydrofolate dehydrogenase; mMTHFC, mitochondrial methenyltetrahydrofolate cyclohydrolase; mFTHFS, mitochondrial formyltetrahydrofolate synthetase; MTHFD, methylenetetrahydrofolate dehydrogenase; MTHFC, methenyltetrahydrofolate cyclohydrolase; FTHFS, formyltetrahydrofolate synthetase; MTHFR, methylenetetrahydrofolate reductase; TS, thymidylate synthase; DHFR, dihydrofolate reductase; and cSHMT, cytoplasmic serine hydroxymethyltransferase.