Folate Metabolism

FOLATE METABOLISM AND THE INHIBITION OF DNA SYNTHESIS

The figure below provides an overview of the folate metabolism and the biochemical pathways leading to inhibition of DNA synthesis and cell growth in the presence of fluoropyrimidines such as 5-fluororuracil (5-FU).

Folic acid is converted by the human body into a pool of at least six interconvertible forms of reduced folates. MTHF, plays the most critical role as the last folate in the process acting as the essential one-carbon donor and substrate for the enzyme thymidylate synthase (TS). TS, in turn, plays an important role for DNA synthesis as it catalyses the methylation of deoxyuridine-5′-monophosphate (dUMP) to deoxythymidine-5′-monophosphate (dTMP). This enzymatic pathway is critical as it provides one of the four necessary nucleotide substrates for DNA synthesis. Without it, cell replication stops. For this reason, TS is used as an important target for cancer chemotherapy to kill tumour cells.

Active metabolite concentrations in tumor tissue

Mean (GGH-t) vs. Treatment