Purine Biosynthesis Is Regulated at Two Levels

Many lines of evidence indicate that the first committed step in de novo purine nucleotide biosynthesis, production of 5-phosphoribosylamine by glutamine PRPP amidotransfer-ase, is rate-limiting for the entire sequence. Consequently, regulation of this enzyme is probably the most important factor in control of purine synthesis de novo (fig. 23.24). The enzyme is inhibited by purine-5 -nucleotides, but the most inhibitory nucleotides vary with the source of the enzyme. Inhibition constants (A, ) are usually in the range 10-3-10-5 M. The maximum effect of this end-product inhibition is produced by certain combinations of nucleotides (e.g., AMP and GMP) in optimum concentrations and ratios, indicating two kinds of inhibitor binding sites. This is an example of a concerted feedback inhibition. 

The rate of the amidotransferase reaction is also governed by intracellular concentrations of the substrates l-glutamine and PRPP. Competing metabolic reactions or drugs that alter the supply of these substrates also affect the rate of IMP synthesis. 

The second important level of regulation of purine nu-cleotide synthesis is in the branch pathways from IMP to AMP and to GMP (see figs. 23.11 and 23.24). The first of the two reactions leading from IMP to AMP is the irreversible synthesis of adenylosuccinate. This requires GTP as a source of energy and is inhibited by AMP. Of the two reactions required to convert IMP to GMP, the first is irreversible and is inhibited by GMP, and the second requires ATP as a source of energy. Thus, two types of regulation occur at this level of purine nucleotide synthesis (1) a forward  

Degradation of pyrimidine bases. Parts of this pathway are widely distributed in nature. The entire pathway is found in mammalian liver. As in purine nucleotide catabolism, no ATP results from catabolism, and the ribose-1-phosphate is released during catabolism before destruction of the base. 

Regulation of purine biosynthesis. Red arrows show points of inhibition 0 or activation . In addition to the feedback inhibition, GTP stimulates ATP synthesis, and ATP stimulates GTP synthesis, thus helping to ensure a balance between the pools of the two nucleoside triphosphates. The full biosynthetic pathways are shown in figures 23.10 and 23.11. 

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Purine Biosynthesis Is Regulated at Two Levels Pyrimidine Biosynthesis Is Regulated at the Level of Carbamoyl Aspartate Formation Deoxyribonucleotide Synthesis Is Regulated by Both Activators and Inhibitors... 

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