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Thymidylate synthetase is the enzyme used to generate thymidine monophosphate (dTMP), which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis and repair.

Function

The following reaction is catalyzed by thymidylate synthetase:

5,10-methylenetetrahydrofolate + dUMP dihydrofolate + dTMP

By means of reductive methylation, deoxyuridine monophosphate (dUMP) and N5,N10-methylene tetrahydrofolate are together used to form dTMP, yielding dihydrofolate as a secondary product.

 

This provides the sole de novo pathway for production of dTMP and is the only enzyme in folate metabolism in which the 5,10-methylenetetrahydrofolate is oxidised during one-carbon transfer. The enzyme is essential for regulating the balanced supply of the 4 DNA precursors in normal DNA replication: defects in the enzyme activity affecting the regulation process cause various biological and genetic abnormalities, such as thymineless death.

The enzyme is an important target for certain chemotherapeutic drugs. It is considered to be the primary site of action for 5-fluorouracil, 5-fluoro-2-prime-deoxyuridine, and some folate analogs. Low expression levels of TYMS have been related to a better response and survival benefit from 5 FU/capecitabine/pemetrexed based chemotherapy.

 

 

 

 

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