Fluorouracil metabolic pathway (5-FU pathway)

The Fluorouracil metabolic pathway (5-FU pathway) is a complex biochemical network responsible for the activation and catabolism of the antimetabolite 5-fluorouracil (5-FU) (StatPearls, 2023). The pathway's primary therapeutic target is thymidylate synthase (TYMS), which is inhibited by the metabolite 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), leading to the depletion of thymidine triphosphate and subsequent inhibition of DNA synthesis (PharmGKB, 2021). Additionally, the pathway facilitates the incorporation of fluorinated ribonucleotides into RNA, disrupting RNA processing and protein synthesis (PubMed, 2002). The rate-limiting step in the catabolism of 5-FU is governed by dihydropyrimidine dehydrogenase (DPD), an enzyme that converts 5-FU into inactive metabolites (NIH, 2022). Genetic polymorphisms in the DPYD gene, which encodes DPD, are significant biomarkers as they can lead to severe systemic toxicity due to impaired drug clearance (CPIC, 2020). This pathway is central to the treatment of various solid tumors, including colorectal, breast, and gastric cancers, where it serves as a framework for both drug efficacy and the management of adverse effects (Journal of Clinical Oncology, 2019).

Other names

5-Fluorouracil metabolismPyrimidine metabolic pathway5-FU metabolic networkFluorouracil catabolic and anabolic pathways

The pathway facilitates the conversion of 5-fluorouracil into active metabolites that inhibit thymidylate synthase and incorporate into nucleic acids, while also managing the catabolic breakdown of the drug via dihydropyrimidine dehydrogenase.