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Pathway Description
Methotrexate Action Pathway
Homo sapiens
Drug Action Pathway
Methotrexate is an antifolate antimetabolite used in the treatment of rheumatoid arthritis and cancer. Methotrexate is taken up into the cell by human reduced folate carriers (SLC19A1). In the cytoplasm, methotrexate is polyglutamated by folylpolyglutamate synthase, which enhances its retention inside the cell. Both methotrexate and methotrexate-polyglutamate inhibit dihydrofolate reductase, an enzyme that catalyzes the conversion of dihydrofolate into tetrahydrofolate, which is the active form of folic acid. Tetrahydrofolate is involved in many single-carbon transfer reactions, including the synthesis of DNA and RNA nucleotides. Inhibition of dihydrofolate reductase causes depletion of intracellular tetrahydrofolate, which has a cytotoxic effect, especially on rapidly dividing cells. Methotrexate-polyglutamate further inhibits de novo purine synthesis and thymidylate synthase, which contribute to methotrexate’s cytotoxic effects.
References
Methotrexate Pathway References
Braun J, Rau R: An update on methotrexate. Curr Opin Rheumatol. 2009 May;21(3):216-23. doi: 10.1097/BOR.0b013e328329c79d.
Pubmed: 19373092
Fotoohi AK, Albertioni F: Mechanisms of antifolate resistance and methotrexate efficacy in leukemia cells. Leuk Lymphoma. 2008 Mar;49(3):410-26. doi: 10.1080/10428190701824569.
Pubmed: 18297517
Folate Metabolism References
Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.
Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.
Blom HJ, Smulders Y: Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis. 2011 Feb;34(1):75-81. doi: 10.1007/s10545-010-9177-4. Epub 2010 Sep 4.
Pubmed: 20814827
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