Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years

Figure 2 Methylentetrahydrofolate reductase plays an important role in the action of 5-fluorouracil, an inhibitor of thymidylate synthase. Methylentetrahydrofolate reductase (MTHFR) catalyses a unidirectional reaction that lowers the levels of 5,10-methylenetetrahydrofolate (CH₂THF) by increasing levels of 5-methyltetrahydrofolate (CH₃THF) which is used for biological methylation. Other factors, such as vitamin B12 and homocysteine, are involved in biological methylation processes. The addition of folinic acid (leucovorin) to 5-FU improves the response rates and survival of CRC patients. Thymidylate synthase (TS) catalyses the reductive methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) with the reduced folate, CH₂THF, as the methyl donor. This reaction provides the sole de novo source of thymidylate, which is necessary for DNA replication and repair. TS contains a nucleotide-binding site and a binding site for CH₂THF. The 5-FU metabolite, FdUMP, binds to the nucleotide-binding site of TS, forming a stable ternary complex with the enzyme and CH₂THF which blocks binding of the normal substrate dUMP, thereby inhibiting dTMP synthesis. Inhibition of thymidylate synthesis causes disruption of nucleotide levels that results in DNA damage[402].