Which nucleotide is directly affected by 5-FU's inhibition of thymidylate synthase?

Which nucleotide is directly affected by 5-FU's inhibition of thymidylate synthase?

• A. dGTP
• B. dCTP
• C. dATP
• D. dTMP

Answer: (D)

Thymidylate synthase is the enzyme that converts dUMP into dTMP, using 5,10-methylene-THF as a cofactor. 5-FU, once activated to FdUMP, binds thymidylate synthase and forms a stable complex that blocks this conversion. Because of this, production of dTMP drops, leading to a depletion of dTTP necessary for DNA synthesis. The direct consequence is a shortage of dTMP, which halts DNA replication in rapidly dividing cells. Other nucleotides (like dGTP, dCTP, or dATP) aren’t the immediate product of this enzyme, so their levels aren’t directly affected by the block; they may be influenced indirectly due to overall nucleotide imbalance, but the primary direct effect is on dTMP.

Thymidylate synthase is the enzyme that converts dUMP into dTMP, using 5,10-methylene-THF as a cofactor. 5-FU, once activated to FdUMP, binds thymidylate synthase and forms a stable complex that blocks this conversion. Because of this, production of dTMP drops, leading to a depletion of dTTP necessary for DNA synthesis. The direct consequence is a shortage of dTMP, which halts DNA replication in rapidly dividing cells. Other nucleotides (like dGTP, dCTP, or dATP) aren’t the immediate product of this enzyme, so their levels aren’t directly affected by the block; they may be influenced indirectly due to overall nucleotide imbalance, but the primary direct effect is on dTMP.