Biochemistry: The Chemical Reactions of Living Cells, Volume 2 - D. Metzler 1980

Coenzymes: Specialized Natural Reagents
Tetrahydrofolic Acid and Other Pterin Coenzymes
Dihydrofolate Reductase

Folic acid and its polyglutamate derivatives can be reduced to H4Fоl Coenzymes in two stages: The First stage involves slow NADPH-dependent reduction to 7,8-dihydrofolate. This reaction is apparently catalyzed by the same enzyme that subsequently rapidly reduces dihydrofolates to tetrahydrofolates. Here again, NADPH serves as the reductant, and the enzyme is known as dihydrofolate reductase. This enzyme attracts intense interest not only for its pivotal role in supplying Cells with reduced forms of folate coenzymes, but also because it apparently serves as the target for two important anticancer drugs, aminopterin and amethopterin (methotrexate).

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These compounds inhibit dihydrofolate reductase at very low concentrations: 10-8–10-9 M. Because folate coenzymes are essential for The Biosynthesis of both Purines and thymine, rapidly proliferating Cancer cells require high activity of this enzyme. A vast number of synthetic derivatives have been synthesized in the hope of finding even more effective inhibitors. Unfortunately, dihydrofolate reductase is required by all cells; consequently, compounds that inhibit it are toxic and cannot be used for long-term therapy. Nevertheless, Treatment with such drugs has in many cases restored leukemia patients to normal life for many months1). Complete cures of relatively rare Choriocarcinoma have been documented, and novel Chemotherapy regimens utilizing antifolates in combination with other agents inspire hope for the future.

1) Some patients survived for 5 years or more, whereas prior to 1960, individuals with acute leukemia rarely lived longer than 3–6 months.



Last update: 06/08/2026

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