Methotrexate is an antimetabolite and antifolate drug used in treatment of cancer, autoimmune diseases and abortion. It acts by inhibiting the metabolism of folic acid. Methotrexate began to replace the more powerful and toxic antifolate aminopterin starting in the 1950s, and the two should not be confused. The drug was developed by Yellapragada Subbarao. Methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about one thousand-fold that of folate for DHFR. Dihydrofolate reductase catalyses the conversion of dihydrofolate to the active tetrahydrofolate. Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis. Also, folate is needed for purine base synthesis, so all purine synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.
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