Which functional group of fluorouracil is responsible for preventing the elimination step in nucleic acid synthesis and therefore responsible for fluorouracil’s anticancer properties? Your answer: a. Alcohol b. Amide c. Fluoride d. Ester
The Correct Answer and Explanation is:
Correct Answer: c. Fluoride
Explanation:
Fluorouracil (5-fluorouracil or 5-FU) is a widely used chemotherapeutic agent, especially in the treatment of solid tumors like colorectal, breast, and head and neck cancers. Its anticancer activity is primarily attributed to the fluorine atom (fluoride) at the 5-position of the uracil ring, which plays a crucial role in inhibiting nucleic acid synthesis.
Once inside the cell, 5-FU is metabolized into several active metabolites. One of the key metabolites is 5-fluoro-2’-deoxyuridine monophosphate (FdUMP). This metabolite inhibits thymidylate synthase (TS), an essential enzyme in the synthesis of thymidine monophosphate (dTMP), a nucleotide required for DNA replication and repair.
Normally, thymidylate synthase catalyzes the methylation of deoxyuridine monophosphate (dUMP) to dTMP using a cofactor called 5,10-methylene tetrahydrofolate. During this process, a crucial elimination step occurs in which a hydrogen is abstracted from the C5 position of the uracil ring to complete the methylation. However, when FdUMP binds to TS, the fluorine atom at the C5 position prevents this elimination step from occurring due to the strong carbon-fluorine bond, which is much more stable and less reactive than a carbon-hydrogen bond.
This covalent and irreversible inhibition of TS by FdUMP results in a “thymineless death” — cells cannot produce the dTMP needed for DNA synthesis, leading to DNA damage and cell death. Since rapidly dividing cancer cells are especially dependent on efficient DNA replication, they are particularly sensitive to this disruption.
In summary, the fluoride (fluorine atom) in fluorouracil is the critical functional group responsible for its ability to block DNA synthesis and exert its anticancer effects by preventing the elimination step in thymidylate synthase-mediated nucleotide synthesis.
