Biosynthesis and Degradation of Nucleotides:-Thymidylate Is Derived from dCDP and dUMP
DNA contains thymine rather than uracil, and the de novo pathway to thymine involves only deoxyribonucleotides. The immediate precursor of thymidylate (dTMP) is dUMP. In bacteria, the pathway to dUMP be gins with formation of dUTP, either by deamination of dCTP or by phosphorylation of dUDP (Fig. 1. The dUTP is converted to dUMP by a dUTPase. The latter reaction must be efficient to keep dUTP pools low and prevent incorporation of uridylate into DNA.
FIGURE 1 Biosynthesis of thymidylate (dTMP). The pathways are shown beginning with the reaction catalyzed by ribonucleotide reductase. Figure 2 gives details of the thymidylate synthase reaction.
Conversion of dUMP to dTMP is catalyzed by thymidylate synthase. A one-carbon unit at the hydroxy methyl (-CH2OH) oxidation level is transferred from N5, N10-methylenetetrahydrofolate to dUMP, then reduced to a methyl group (Fig. 2). The reduction occurs at the expense of oxidation of tetrahydrofolate to dihydrofolate, which is unusual in tetrahydrofolate-requiring reactions. The dihydrofolate is reduced to tetrahydrofolate by dihydrofolate reductase—a regeneration that is essential for the many processes that require tetrahydrofolate. In plants and at least one protist, thymidylate synthase and dihydrofolate reductase reside on a single bifunctional protein.
FIGURE 2 Conversion of dUMP to dTMP by thymidylate synthase and dihydrofolate reductase. Serine hydroxymethyltransferase is required for regeneration of the N5,N10-methylene form of tetrahydrofolate. In the synthesis of dTMP, all three hydrogens of the added methyl group are derived from N5,N10-methylenetetrahydrofolate (pink and gray).
