For the past month my son-in-law has been undergoing treatment for colorectal cancer. The procedure involves an 8-week regimen of chemo and radiation therapy prior to surgery. Capecitabine, a prodrug of 5-fluorouracil, (5-FU), is the
chemotherapeutic agent of choice in this case. The conversion of capecitabine into 5-FU entails 3 enzyme-catalyzed steps. The first step involves hydrolysis of the amide linkage. The product of this reaction is 5′-deoxy-5-fluorocytidine. This intermediate is converted into 5′-deoxy-5-fluorouridine, hydrolysis of which generates 5-FU. Pop quiz-What is the functional group involved in this reaction? The advantage that capecitabine offers is that it is taken orally rather than by injection, as is the case for 5-FU.
To understand how 5-FU works, you need to appreciate a bit of biochemistry, namely that the enzyme thymidylate synthase (TS) is the only enzyme that catalyses the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Both dUMP and dTMP are required for DNA synthesis. So, if you inhibit TS, you inhibit DNA synthesis and, as you might suspect, this poses an existential threat to cancer cells. That’s where 5-FU comes in. It is metabolized to 5-fluorodeoxyuridine monophosphate (FdUMP):
When FdUMP binds to the nucleotide bonding site of TS, it inhibits the conversion of dUMP into dTMP. I was going to joke that taking 5-FU prevents you from taking a dUMP, but, unfortunately, one of the side effects of 5-FU therapy is diarrhea, so I won’t say that. Suffice it to say that inhibition of TS prevents DNA synthesis. I believe that inhibition of the enzyme is, in part, a reflection of the fact that FdUMP binds more strongly to the active site of TS than dUMP does. Specifically, I suspect that there is a hydrogen bond between the carbonyl group of an arginine in TS and the N-H group of N3 of FdUMP and that this H-bond is stronger than the corresponding H-bond between TS and dUMP. The action page for this post illustrates why this might be the case.