N

Fumaric acid main inhibitors are thiopurines (e.g., 6-mercaptopurine, MP), acting through feedback mechanisms. These antitumor drugs have a complex mechanism of action, involving the inhibition of several enzymes related to purine biosynthesis and misincorporation into nucleic acids, and will be studied in Section 6.5.

6.2. Inhibitors of glycinamide ribonucleotide formyltransferase (GARFT)

The third reaction in the de novo purine biosynthesis is the transformation of glycinamide ribonucleotide (GAR) into its formylderivative (FGAR) using 10-formyl-THF as the formyl donor (Fig. 2.32). The enzyme that catalyzes this step is known as glycinamide ribonucleotide formyltransferase (GARFT). In mammals, this enzyme is multifunctional and it also catalyzes the second and fifth steps of the pathway.

The first selective and sufficiently potent GARFT inhibitor was lometrexol, designed as a folate analog lacking the 5 and 10 nitrogen atoms and therefore unable to participate in the transfer of single carbon units.44 On the contrary, lometrexol has a 2-aminopyrimidin-4-one subunit identical to that found in the THF cofactor, and therefore different from the 2,4-diaminopyrimidine pattern o co2h

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