Figure 3.

Pathways of folate metabolism and the interrelationships of folate-dependent reactions. Dihydrofolate (DHF) from nutritional sources and the gut microflora is enzymatically reduced engaging dihydrofolate reductase (DHFR) to biologically active tetrahydrofolate (THF), a process that is competitively blocked by the folate analogue methotrexate (Mtx). This has implications for cell proliferation, division, and survival. Folate metabolism branches out into anabolic pathways including synthesis of amino acids (AA) and amines (=NH) as well as purines and thymidylate for DNA production. Importantly, folate in the form of 5-methyl tetrahydrofolate (5-metTHF) serves as a methyl-group (CH₃) donor in the detoxification of proatherogenic homocysteine to the AA methionine. SAM is the universal CH₃ donor in histone- and DNA-methylation. This function gives folate powerful mediating properties at an epigenetic level with a potential role in thymic CD4⁺ nT_reg expansion. Abbreviations: MTR: methionine synthase requiring the co-factor vitamin B12 (cobalamin) as a methyl transfer vehicle (methyl cobalamin, CH₃-B12); MTHFR: 5,10-methylenetetrahydrofolate reductase (requiring the co-factor NADPH, not shown); THF: tetrahydrofolate. Methionine cycle metabolites: SAH: S-adenosylhomocysteine; SAM: S-adenosylmethionine; =NH: amines.