Folate metabolism cytotoxicity

B Fluorouracil is a prodrug that is metabolized to FdUMP and a triphosphate metabolite. FdUMP binds and interferes with thymidylate synthase, whereas the triphosphate metabolite interferes with RNA function. Leucovorin is a reduced form of folic acid. Leucovorin provides folate cofactors that stabilize the binding of FdUMP and thymidylate synthase, thus enhancing the cytotoxic effects of fluorouracil. 

Kim, J.-S., Lowe, K. E., and Shane, B. (1993). Regulation of folate and one carbon metabolism in mammalian cells. 4. Role of folylpolyglutamate synthetase in antifolate metabolism and cytotoxicity. J. Biol. Chem. 268, 21 0-21685. 

Vitamin B12 is an essential coenzyme for the methylation cycle by activating THF. An activated folate is not only a coenzyme for methionine synthase but also plays a pivotal role in one-carbon metabolism it promotes the generation of methionine from homocysteine, which is a cytotoxic sulfur-containing amino acid that can induce DNA strand breakage, oxidative stress and apoptosis. The methylation cycle is very important in the brain and depends on the SAM concentration. 

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