Enzymes of fluoronucleotide biosynthesis

The enzymes of fluoronucleotide biosynthesis comprise a group of intracellular proteins responsible for the metabolic conversion of fluoropyrimidine prodrugs into their active, cytotoxic nucleotide forms (Longley et al., 2003). This pathway is central to the pharmacology of widely used chemotherapeutic agents like 5-fluorouracil (5-FU) and capecitabine. Key enzymes in this process include orotate phosphoribosyltransferase (OPRT), which converts 5-FU to 5-FUMP, and thymidine phosphorylase, which facilitates the formation of 5-fluorodeoxyuridine (Zhang et al., 2022). These active metabolites, such as 5-fluorodeoxyuridine monophosphate (5-FdUMP), act by inhibiting thymidylate synthase (TS), thereby depleting the deoxythymidine triphosphate (dTTP) pools necessary for DNA replication and repair (Noordhuis et al., 2004). Additionally, fluoronucleotides like 5-fluorouridine triphosphate (5-FUTP) are incorporated into RNA, disrupting normal processing and translation. The clinical efficacy and toxicity of fluoropyrimidine therapy are heavily dependent on the expression levels and genetic polymorphisms of these enzymes, as well as the activity of the catabolic enzyme dihydropyrimidine dehydrogenase (DPD). Understanding this enzymatic network is vital for predicting patient response and managing the severe side effects associated with antimetabolite chemotherapy.

Other names

Fluoropyrimidine metabolic pathway5-FU activation pathwayFluoronucleotide metabolic enzymes

Metabolic activation of fluoropyrimidine antimetabolites into active fluoronucleotides that inhibit thymidylate synthase and disrupt nucleic acid synthesis (Longley et al., 2003).