Thymidylate

Thymidylate, commonly referred to as deoxythymidine monophosphate (dTMP), is a deoxyribonucleotide that serves as a building block of DNA. It consists of the thymine base linked to a deoxyribose sugar and a single phosphate group at the 5' position.

Biosynthesis of thymidylate occurs primarily from deoxyuridine monophosphate (dUMP) via the enzyme thymidylate synthase. This reaction uses 5,10-methylene-tetrahydrofolate as a one-carbon donor to install a methyl group on the pyrimidine ring, producing dihydrofolate as a byproduct. Dihydrofolate is then reduced back to tetrahydrofolate by dihydrofolate reductase, enabling continued thymidylate production. Thymidylate can also be formed through salvage pathways by phosphorylation of thymidine by thymidine kinase.

Role in the cell is as a substrate for further phosphorylation to dTDP and dTTP, the active forms used by DNA polymerases during replication and repair. Proper balance of dTMP and its phosphorylated derivatives is essential for maintaining appropriate deoxynucleotide pools and genomic stability.

Medical relevance arises from its central role in DNA synthesis. Inhibitors of thymidylate synthase, such as 5-fluorouracil and raltitrexed, disrupt dTMP production and are used in cancer chemotherapy. Antifolate drugs like methotrexate limit dihydrofolate reductase activity, indirectly reducing thymidylate synthesis. Disruption of thymidylate metabolism preferentially affects rapidly dividing cells and can contribute to therapeutic efficacy and toxicity.

See also: thymidylate synthase, thymidine kinase, nucleotide metabolism.