Inhibitors Of The De Novo Purine Biosynthesis Pathway

In contrast to pyrimidine nucleotide biosynthesis, where a preformed heterocyclic moiety is attached to PRPP, in the case of purine nucleotides the purine ring is constructed gradually. The complete route comprises 10 steps, and is summarized in Fig. 2.31. This de novo pathway leads to the formation of inosine monophosphate (IMP), the precursor of ATP, GTP, dATP, and dGTP necessary for RNA and DNA formation. Only the steps most relevant to antitumor drug action will be treated in the discussion below.

6.1. Inhibitors of phosphoribosylpyrophosphate (PRPP) amidotransferase

The first irreversible step in the de novo purine biosynthesis involves the nucleo-philic displacement of the pyrophosphate group of phosphoribosylpyropho-sphate (PRPP) by a molecule of ammonia, generated by hydrolysis of glutamine to glutamic acid. Both reactions are catalyzed by PRPP amidotransferase, whose

Glutamic Glutamine acid

HO HOO-P-P PRPP aminotransferase HO HO

Glycine + ATP

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