Folate and folate-mediated one-carbon metabolism.

(A) Folate is comprised of a pteridine ring, p-aminobenzoic acid and glutamyl moieties with 5 to 8 glutamate residues attached in γ-linkage. The one-carbon units are attached to the N5- and/or N10-position of the pteridine ring at the oxidation levels of formate, formaldehyde and methanol. (B) The one-carbon units carried by reduced folate are involved in cytosolic, mitochondrial and nuclear folate pools and used for the biosynthesis of purines, thymidylate, amino acids and S-adenosylmethionine (SAM). Over-expressed γ-glutamylhydrolase (γGH) facilitates intracellular folate exportation by converting polyglutamylfolates (folate-Glun) to monoglutamylfolates (folate-Glu1), leading to intracellular folate deficiency (thickened circle and arrows in shadowed box). Enzyme abbreviations: DHFR, dihydrofolate reductase; MTHFD, methylenetetrahydrofolate dehydrogenase; FDH, 10-formyltetrahydrofolate dehydrogenase; GART, glycinamide ribonucleotide transformylase; AICART, aminoimidazolecarboxamide ribonucleotide transformylase; MTHFS, 5,10-methenyltetrahydrofolate synthetase; SHMT, Serine hydroxymethyltransferase; MTHFR, methylenetetrahydrofolate reductase; TS, thymidylate synthase; MTR, 5-methyltetrahydrofolate-homocysteine methyltransferase; MAT, methionine adenosyl transferase; MT, methyltransferase; SAHH, S-adenosylhomocysteine hydrolase.