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Overview of folate-homocysteine metabolism

Humans can obtain folate from food or food supplements (folic acid [FA] and 5-methyltetrahydrofolate [5-Me-THF]). Folates from food are polyglutamates, which must be hydrolyzed to monoglutamates by the enzyme glutamate carboxypeptidase II (GCPII) in the intestine so they can be absorbed. In contrast, folic acid and 5-Me-THF from supplements are absorbed directly without modification.

Dietary folate and folic acid also need enzymatic activation. After entry through receptors in the cell membrane, folates are polyglutamated by folylpolyglutamate synthetase (FPGS) and reduced to dihydrofolate (DHF) and tetrahydrofolate (THF) by dihydrofolate reductase (DHFR). The latter enters the folate cycle (violet), which is shown here somewhat simplified. The folate cycle includes numerous other enzymes: methylenetetrahydrofolate dehydrogenase (MTHFD1), methylenetetrahydrofolate reductase (MTHFR), methionine synthase (5-methyltetrahydrofolate-homocysteine methyltransferase or MTR), and methionine synthase reductase (MTRR or 5-methyltetrahydrofolate-homocysteine methyltransferase reductase). The folate cycle is tightly connected to the methionine cycle (green), where homocysteine is re-methylated back to methionine.

Legend: B12: vitamin B12; DHF: dihydrofolate ; DHFR: dihydrofolate reductase; DNMT3B: DNA methyltransferase 3 beta; FA: folic acid; FGPS: folylpolyglutamate synthase; FOL-MG: folate monoglutamate; FOL-PG: folate polyglutamate; GCPII: glutamate carboxypeptidase II; GNMT: glycine N-methyltransferase; Hcy: homocysteine; MAT: methionine adenosyl transferase; Met: methionine; MTHFD1: methylenetetrahydrofolate dehydrogenase 1; MTHFR: methylenetetrahydrofolate reductase; MTR: methionine synthase; MTRR: methionine synthase reductase; RBC: red blood cell; SAH: S-adenosylhomocysteine; SAHH: S-adenosylhomocysteine hydrolase; SAM: S-adenosylmethionine; SLC19A1: reduced folate carrier protein; THF: tetrahydrofolate. (Source: Golja VM, Smid A, Kuzelicki KN, et al. Folate insufficiency due to MTHFR deficiency is bypassed by 5-methyltetrahydrofolate. J Clin Med 2020;9(9):2836. Creative Commons Attribution 4.0 [CC BY] license.)