Diagram of folate and one-carbon metabolism in mammalian organisms. Intracellular one-carbon transfer reactions are essential for nucleotide (thymidylate and purine) synthesis and methylation of numerous compounds, including DNA, RNA, proteins, and phospholipids. These one-carbon transfer reactions are mainly supported by folate, a B vitamin that serves as a one-carbon carrier/donor. This diagram depicts absorption, transport, and metabolism of folate around the intracellular one-carbon metabolism as well as enzymes/proteins and other nutritional factors involved.1-5 Folates in food, mostly polyglutamates, are hydrolyzed to monoglutamates by GGH in the gut and are absorbed across the intestinal mucosa with folic acid from fortified foods and supplements mostly by a saturable pH-dependent process, via reduced folate carrier (encoded by SLC19A1), and by passive diffusion at high concentrations. Once absorbed into the portal circulation, folates are taken up by the liver, where they are metabolized to polyglutamates by FPGS and retained or released into blood or bile as 5-methylTHF. Folate released in bile is reabsorbed in the small intestine. About two thirds of 5-methylTHF, the predominant form of folate in circulation, is bound to low-affinity proteins, mostly albumin: low levels of high-affinity folate binders are also found in blood. Blood 5-methylTHF is transported into the cell by carrier-mediated or receptor-mediated mechanisms. Reduced folate carrier has a higher affinity for reduced folate than oxidized folic acid and accounts for the transport of most folate and methotrexate. Membrane-bound folate receptors, including folate receptor 1 encoded by FOLR1, with high affinity for folic acid are expressed in epithelial tissues, and its expression is elevated in malignant epithelial tumors.6 The predominant cytoplasmic folate, 5-methylTHF, donates its one-carbon moiety to methylate homocysteine to methionine, yielding THF. THF is a much preferred substrate to FPGS that lengthens the glutamate chain of the monoglutamate folate so folates can be retained in the cell. This polyglutamylation also enables folates to be used by one-carbon metabolizing enzymes that have much higher affinities for polyglutamates than monoglutamates. In deficiency of vitamin B12, which is a coenzyme for methionine synthase (MTR) that converts 5-methylTHF to THF, or with insufficient transcobalamins (TCN1, TCN2) for vitamin B12 absorption, deficiency of functional folate (THF) occurs despite sufficient folate in circulation (“methyl-trap”). MTR loses its activity when its vitamin B12–derived coenzyme, cobalamin, gets oxidized: MTRR reactivates MTR using the methyl supply from SAM. Homocysteine can be remethylated via an alternative mechanism of BHMT using betaine, supplied from dietary choline, in kidney and liver. Methionine, from homocysteine and also supplied from diet, is converted to SAM, a universal donor of one-carbon unit to numerous methylation reactions via MTs in part for DNA methylation. Resulting SAH is hydrolyzed to homocysteine, which then gets remethylated or catabolyzed via the transsulfuration pathway initiated by CBS. The active coenzyme THF obtains one-carbon moiety from amino acid serine via SHMT1 catalysis, yielding 5,10-methyleneTHF, which is an important common substrate to methylation pathway described (remethylation of homocysteine to methionine) via MTHFR or to nucleic acid synthesis pathways via TYMS (uridylate to thymidylate conversion; pyrimidine synthesis) or MTHFD1/FTHFD (purine synthesis). DHF, the remnant of TYMS reaction on THF, is also supplied from folic acid that is reported to be found in blood in higher proportion than usual when a large dose is consumed from fortified foods or supplements. 5,10-MethenylTHF can be interconverted with 5-formylTHF (also known as folinic acid or leucovorin; thought to be the storage form of folate) via SHMT1/MTHFS. Although less understood, mitochondrial one-carbon metabolism is proposed to be in equilibrium with cytoplasmic metabolism and contains glycine cleavage system. AHCY indicates S-adenosylhomocysteine hydrolase; AICART, phosphoribosylaminoimidazolecarboxamide formyltransferase; AMT, aminomethyltransferase; B2, vitamin B2; B6, vitamin B6; B12, vitamin B12; BHMT, betaine-homocysteine methyltransferase; CBS, cystathionine-beta-synthase; CTH, cystathionase; DHF, dihydrofolate; DHFR, dihydrofolate reductase; FPGS, folylpolyglutamate synthase; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; FOLR, folate receptor; FTHFD, 10-formyltetrahydrofolate dehydrogenase; FTHFS, 10-formyltetrahydrofolate synthase; FTHFSDC1, 10-formyltetrahydrofolate synthetase domain containing 1; GART, glycinamide ribonucleotide formyltransferase; GCPII, glutamate carboxypeptidase II; GCSH, glycine cleavage system protein H; GGH, gamma-glutamylhydrolase; MAT, methionine S-adenosyltransferase; MTs, a group of methyltransferases; MTHFD1, cytoplasmic 5,10-methylenetetrahydrofolate dehydrogenase; MTHFD2, mitochondrial 5,10-methylenetetrahydrofolate dehydrogenase; MTHFR, 5,10-methylenetetrahydrofolate reductase; MTHFS, 5,10-methenyltetrahydrofolate synthetase; MTR, methionine synthase; MTRR, methionine synthase reductase; PLP, pyridoxal 5′-phosphate; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; SHMT1, cytoplasmic serine hydroxymethyltransferase; SHMT2, mitochondrial serine hydroxymethyltransferase; SLC19A1, reduced folate carrier; TCN1, transcobalamin 1; TCN2, transcobalamin 2; THF, tetrahydrofolate; and TYMS, thymidylate synthetase.
