I was reading in my pharmacology textbook about fluorouracil, and my book mentioned that fluorouracil is an antimetabolite whose function is to inhibit pyrimidine synthesis. However, I was curious to know how exactly does fluorouracil accomplish this. Is this drug involved in a specific mechanism that enables it to prevent pyrimidine synthesis? If so, how?


Your cells produce thymidine by converting uridine using an enzyme called Thymidylate Synthase. 5-Fluorouracil irreversibly inhibits this enzyme.

Here is the structure of 5-Fluorouracil: enter image description here

Here is the mechanism the enzyme uses to make thymidine: enter image description here

It looks like the enzyme forms a bond to the uridine ring through a sulfur. 5-Fluorouracil probably inhibits the reaction at the next step because fluorine is much more electronegative than the proton it replaced. This makes it harder for the electrons on the double bond in step 2 to attack the folate. Might also inhibit step 3 because the fluorine won't want to give up its electrons to reform the double bond. Because 5-fluorouracil is stuck to the enzyme's active site, the enzyme can't perform its given duty of converting uridine to thymidine. Because you can't use uridine in your DNA, your cells don't have enough thymidine to copy the DNA and replication is slowed. If thymidine supplies are low enough, cells might die.


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