It and its active metabolites compete for the folate binding site of the enzyme dihydrofolate reductase. Folic acid must be reduced to tetrahydrofolic acid by this enzyme for DNA synthesis and cellular replication to occur. Competitive inhibition of the enzyme leads to blockage of tetrahydrofolate synthesis, depletion of nucleotide precursors, and inhibition of DNA, RNA and protein synthesis. Methotrexate is cell cycle phase-specific (S phase).
Leukovorin (Folinic Acid)