5-Phosphoribosyl-1 -pyrophosphate regulation

Lipstein, B., Boer, P. Sperling, O. (1978). Regulation of de novo purine synthesis in chick liver role of phosphoribosyl-pyrophosphate availability and of salvage purine nucleotide biosynthesis. Biochim Biophys. Acta, 521, 45—54. 

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. 

Figure 10-2. Regulation of purine synthesis by the nucleotides and the intermediate, 5 -phosphoribosyl-1 -pyrophosphate (PRPP). Both feedback and feed-forward mechanisms are utilized in this intricate scheme. IMP, inosine monophosphate.

The answer is c, (Murray, pp 375-801. Scriver, pp 2513-2570. Sack, pp 121-138. Wilson, pp 287-320.) 5 -phosphoribosyl-l-pyrophosphate (PRPP) donates the ribose phosphate unit of nucleotides and is absolutely required for the beginning of the synthesis of purines. In fact, the enzymes regulating the synthesis of PRPP and the subsequent synthesis of phospho-ribosylamine from PRPP are all end product-inhibited by inosine... 

As purines are built on a ribose base (see Fig. 41.2), an activated form of ribose is used to initiate the purine biosynthetic pathway. 5-Phosphoribosyl-l-pyrophosphate (PRPP) is the activated source of the ribose moiety. It is synthesized from ATP and ribose 5 -phosphate (Fig. 41.3), which is produced from glucose through the pentose phosphate pathway (see Chapter 29). The enzyme that catalyzes this reaction, PRPP synthetase, is a regulated enzyme (see section 1I.A.5) however, this step is not the committed step of purine biosynthesis. PRPP has many other uses, which are described as the chapter progresses. 

Glucagon increases DNA synthesis in regenerating rat liver or even in nonoperated rat liver and an elevated level of plasma glucagon has been documented after hepatectomy. Other investigations have demonstrated that the concentration of 5-phosphoribosyl 1-pyrophosphate(PP-ribose-P), which is an important regulator of purine biosynthesis de novo, and the rate of purine biosynthesis de novo itself are increased by glucagon administered in mice and in isolated rat hepatocytes,... 

It has been established in earlier investigations >2 that the synthesis of purine nucleotides in mammalian red blood cells (RBC) is governed by the extent of endogenous supply of 5-phosphoribosyl-1-pyrophosphate (PRPP), as an essential intermediary. Consequently, the elucidation of the mechanisms controlling the formation of PRPP within the cell appears to be of crucial importance for the understanding of the overall metabolic regulation of purine nucleotide biosynthesis. 

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