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Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2016.175 Figure 5 Role of dyhydrofolate reductase (DHFR) in the generation of methyl donors Figure 5 | Role of dyhydrofolate reductase (DHFR) in the generation of methyl donors. S-Adenosylmethionine (SAM) is the main cellular methyl donor in humans. Synthesis of SAM is dependent on methionine, which is generated from homocysteine, with 5-methyl-tetrahydrofolate (5-CH3-THF) as a cofactor. 5-CH3-THF production is dependent on tetrahydrofolate (THF) production. Methotrexate acts to antagonize DHFR, and thereby reduces the availability of THF and metabolites for subsequent methyl-donor production. Some evidence also suggests that methotrexate polyglutamates directly antagonize synthesis by methionine synthetase (MS). DHF, dihydrofolate; MTHFR, methylenetetrahydrofolate reductase; SAH, S-adenosylhomocysteine. Brown, P. M. et al. (2016) Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2016.175