Glutamine phosphoribosyl

This enzyme [EC 2.4.2.14], also known as glutamine phosphoribosyl-pyrophosphate amidotransferase, catalyzes the reaction of glutamine with S-phospho-a-D-ri-bose 1-diphosphate and water to produce 5-phospho-)3-D-ribosylamine, diphosphate (or, pyrophosphate), and glutamate. 

Synthesis of 5 phosphoribosylamine from PRPP and glutamine is catalized by glutamine phosphoribosyl pyrophosphate amidotransferase. This enzyme is inhibited by the purine 5 -nucleotides, AMP, GMP, and IMP—the end-products of the pathway. This is the committed step in purine nucleotide biosynthesis. 

The committed step in purine nucleotide biosynthesis is the conversion of PRPP into phosphoribosylamine by glutamine phosphoribosyl amidotransferase. This important enzyme is feedback-inhibited by many purine ribonucleotides. It is noteworthy that AMP and GMP, the final products of the pathway, are synergistic in inhibiting the amidotransferase. 

Glutamine + phosphoribosyl pyrophosphate - phosphoribosyl amine + glutamate + PPj... 

In the first committed step of the purine biosynthetic pathway, PRPP reacts with glutamine to form phosphoribosylamine (Fig. 41.4). This reaction, which produces nitrogen 9 of the purine ring, is catalyzed by glutamine phosphoribosyl amido-transferase, a highly regulated enzyme. 

Cellular concentrations of PRPP and glutamine are usually below their for glutamine phosphoribosyl amidotransferase. Thus, any situation which leads to an increase in their concentration can lead to an increase in de novo purine biosynthesis. 

The committed step of purine synthesis is the formation of 5-phosphoribosyl 1-amine by glutamine phosphoribosyl amidotransferase. This enzyme is strongly inhibited by GMP and AMP (the end products of the purine biosynthetic pathway). The enzyme is also inhibited by the corresponding nucleoside di- and triphosphates, but under cellular conditions, these compounds probably do not play a central role in regulation. The active enzyme is a monomer of 133,000 daltons but is converted to an inactive dimer (270,000 daltons) by binding of the end products. 

Fig. 41.9. The regulation of purine synthesis. PRPP synthetase has two distinct allosteric sites, one for ADP, the other for GDP. Glutamine phosphoribosyl amidotransferase contains adenine nucleotide and guanine nucleotide binding sites the monophosphates are the most important, although the di- and tri-phosphates will also bind to and inhibit the enzyme. Adenylosuccinate synthetase is inhibited by AMP IMP dehydrogenase is inhibited by GMP.

Hyperuricemia in Lotta Topa ne s case arose as a consequence of over-j production of uric acid. Treatment with allopurinol not only inhibits xan-thine oxidase, lowering the formation of uric acid with an increase in the excretion of hypoxanthine and xanthine, but also decreases the overall synthesis of purine nucleotides. Hypoxanthine and xanthine produced by purine degradation are salvaged (i.e., converted to nucleotides) by a process that requires the consumption of PRPP. PRPP is a substrate for the glutamine phosphoribosyl amidotransferase reaction that initiates purine biosynthesis. Because the normal cellular levels of PRPP and glutamine are below the of the enzyme, changes in the level of either substrate can accelerate or reduce the rate of the reaction. Therefore, decreased levels of PRPP cause decreased synthesis of purine nucleotides. 

The reaction that catalyzes the conversion of ribosyl pyrophosphate to 5 -phosphoribosylamine is likely to be the rate-limiting step in purine biosynthesis. Of course, it is difficult to pinpoint a rate-limiting step in an intact mammal, but in vitro experiments have established a feedback inhibition of glutamine phosphoribosyl pyrophosphate amino transferase by adenylic and guanylic nucleotides (ATP, ADP, GMP, GDP, and IMP). 

Caskey, C. T., D. M. Ashton, and J. B. Wyngaarden. 1964. The enzymology of feedback inhibition of glutamine phosphoribosyl-pyrophosphate amidotransferase by purine ribonucleotides. J. Biol. Chem. 239 2570. 

J. H. Kim, D. Wolle, K. Haridas, R. J. Parry, J. L. Smith, and H. Zalkin, A stable carbocyclic analog of 5-phosphoribosyl-l-pyrophosphate to probe the mechanism of catalysis and regulation of glutamine phosphoribosyl-pyrophosphate amidotransferase, J. Biol Chem. 1995, 270. 17394-17399. 

Rowe, P.B. and Wyngaarden, J.B. 1968. Glutamine phosphoribosyl-pyrophosphate amidotransferase. Purification, substructure aminoacid composition and absorption spectra. J. Biol. Chem. 245 6373-6383. 

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