Abstract
Methotrexate (1b), which remains the single most important antifol anticancer agent after 30 years of clinical use, owes its activity to its stoichiometric inhibition of the enzyme dihydrofolate reductase (EC 1. 5. 1. 3.). Methotrexate was introduced as an antileukaemic agent 10 years before dihydrofolate reductase was demonstrated to be its prime intracellular target, although it was designed to inhibit the utilisation of the vitamin folic acid (2). Its close structural relationship to folic acid, and the fact that it was found to be a competitive inhibitor of dihydrofolate reductase, led to the seemingly obvious conclusion that it binds to the active site of the reductase in the manner of folic acid. Only very recently has there appeared evidence that methotrexate actually binds to dihydrofolate reductase in a conformation substantially different from that of the vitamin.
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Footnote
The reader’s attention is drawn to recent amendments to the amino acid sequence for bovine liver DHFR. See Lai, P. -H., Pan, Y. -C. E., Gleisner, J. M., Peterson, D. L., Williams, K. R. and Blakley, R. L. (1982). Biochem., 21, 3284
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Roth, B., Bliss, E., Beddell, C.R. (1983). Inhibitors of Dihydrofolate Reductase. In: Neidle, S., Waring, M.J. (eds) Molecular Aspects of Anti-Cancer Drug Action. Topics in Molecular and Structural Biology. Palgrave, London. https://doi.org/10.1007/978-1-349-06010-8_11
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Publisher Name: Palgrave, London
Print ISBN: 978-1-349-06012-2
Online ISBN: 978-1-349-06010-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)