Clinical Relevance of Tetrahydrofolate
- Tetrahydrofolate (THF) is regenerated from the dihydrofolate (DHF) product of the thymidylate synthase reaction by the action of dihydrofolate reductase (DHFR), an enzyme that requires NADPH.
- Cells that are unable to regenerate THF suffer defective DNA synthesis and eventual death. For this reason, as well as the fact that dTTP is utilized only in DNA, it is therapeutically possible to target rapidly proliferating cells over non-proliferating cells through the inhibition of thymidylate synthase.
- Many anti-cancer drugs act directly to inhibit thymidylate synthase, or indirectly, by inhibiting DHFR.
- The class of molecules used to inhibit thymidylate synthase is called the suicide substrates because they irreversibly inhibit the enzyme.
- Molecules of this class include 5-fluorouracil and 5-fluorodeoxyuridine. Both are converted within cells to 5-fluorodeoxyuridylate, FdUMP.
- It is this drug metabolite that inhibits thymidylate synthase. Many DHFR inhibitors have been synthesized, including methotrexate, aminopterin, and trimethoprim. Each of these is an analog of folic acid.