Thymidylate Is Formed from dUMP

Since DNA contains thymine (5-methyluracil) as a major base instead of uracil, the synthesis of thymidine monophosphate (dTMP, or thymidylate) is essential to provide dTTP (thymidine triphosphate), which is needed for DNA replication together with dATP, dGTP, and dCTP. 

Thymidylate is synthesized from dUMP, which may be formed by two pathways in cells. The major precursor of dUMP is dCMP, which is converted to dUMP by deoxycytidylate deaminase  

This enzyme is widely distributed in animal tissues, and the enzyme produced by yeast, by bacteriophage T2-infected E. coli, and by animal cells has been studied extensively. Deamination of 5-methyldeoxycytidylate and 5-hydroxy-methyldeoxycytidylate is also catalyzed by this enzyme. 

Another route to dUMP is the reduction of UDP to dUDP, followed by phosphorylation of dUDP to dUTP (or direct reduction of UTP to dUTP in some microorganisms). The dUTP is then hydrolyzed to dUMP. This circuitous route to dUMP is dictated by two considerations. First, the ribonucleotide reductase in most cells acts only on ribonu-cleoside diphosphates, probably because this permits better regulation of its activity. Second, cells contain a highly active deoxyuridine triphosphate diphosphohydrolase (dUT-Pase). It prevents the incorporation of dUTP into DNA by keeping intracellular levels of dUTP low by means of the reaction 

Methylation of dUMP to give thymidylate is catalyzed by thymidylate synthase and utilizes 5,10-methylenetetra-hydrofolate as the source of the methyl group. This reaction is unique in the metabolism of folate derivatives because the folate derivative acts both as a donor of the one-carbon group and as its reductant, using the reduced pteridine ring as the source of reducing potential. Consequently, in this reaction, unlike any other in folate metabolism, dihydrofolate is a product (fig. 23.16). Since folate derivatives are present in cells at very low concentrations, continued syn- 

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