Thymidylate synthase–FdUMP–5,10-methylenetetrahydrofolate ternary complex (TS–FdUMP–CH2THF complex)

The TS–FdUMP–reduced folate ternary complex is a stable, covalently bound molecular assembly that represents the pharmacologically inhibited state of the enzyme thymidylate synthase (TS). This complex is formed when 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), the active metabolite of the chemotherapy drug 5-fluorouracil (5-FU), binds to the active site of TS in the presence of the essential cofactor 5,10-methylenetetrahydrofolate (CH2THF) (StatPearls, https://www.ncbi.nlm.nih.gov/books/NBK532925/). Under normal conditions, TS catalyzes the reductive methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), which is a rate-limiting step in the synthesis of thymidine nucleotides required for DNA replication and repair (UniProt, https://www.uniprot.org/uniprotkb/P04818/entry). The formation of this ternary complex effectively traps the enzyme, preventing the synthesis of dTMP and leading to a state known as thymineless death in rapidly proliferating cancer cells (PubMed, https://pubmed.ncbi.nlm.nih.gov/11812451/). Clinically, the stability of this complex is often enhanced by the co-administration of leucovorin (folinic acid), which increases the intracellular pool of reduced folates to ensure maximal enzyme inhibition (Cancer.gov, https://www.cancer.gov/about-cancer/treatment/drugs/leucovorin-calcium). This mechanism remains a cornerstone of treatment regimens for various solid tumors, particularly gastrointestinal and colorectal malignancies.

Other names

TS-FdUMP-folate complexThymidylate synthase inhibitory complex5-FU-TS-folate ternary complexCovalent thymidylate synthase complex

Irreversible covalent inhibition of thymidylate synthase, preventing the conversion of dUMP to dTMP and leading to thymineless cell death.