Inhibitors Of The Biosynthesis Of Thymidilic Acid

4.1. Thymidylate synthase

Thymidylate synthase (TS) catalyzes the conversion of deoxyuridine monophosphate (dUMP) to thymidylate (TMP), in a reductive methylation that involves the transfer of a carbon atom from the cofactor 5,10-methylenetetrahydrofolate to the

FIGURE 2.12 Feedback inhibition of ribonucleotide reductase.

5 position of the pyrimidine ring. This transformation, that is the only de novo source of thymidylate, is part of the so-called thymidylate cycle (Fig. 2.14), where two other enzymes take part, namely serine hydroxymethyl transferase (SHMT) and dihydrofolate reductase (DHFR). SHMT catalyzes the formation of 5,10-methylenetetrahydrofolate from tetrahydrofolate (THF), coupled with the conversion of serine into glycine, with pyridoxal phosphate (PLP) as a cofactor. In the reaction catalyzed by TS, the 5,10-methylene-THF thus formed donates its methylene group to dUMP, being transformed into dihydrofolate (DHF) by a mechanism that will be discussed below (see Fig. 2.15). DHFR finally closes the cycle by reducing DHF to THF. Although methylation of uracil is apparently a small structural change, the extra lipophilicity and bulk associated with the methyl group is essential for the proper discrimination of thymine from the other three bases present in DNA chains by transcription factors, repressors, enhancers, and other DNA-binding proteins.

HO OH Inosine

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