Synthesis and Utilization of 5Phosphoribosyl1Pyrophosphate
Page 516 + metabolic condition is favored when the concentration of NAD is low, it means that the concentration of NADH is correspondingly high. 12.10— Synthesis and Utilization of 5Phosphoribosyl1Pyrophosphate 5Phosphoribosyl1pyrophosphate (PRPP) is a key molecule in de novo synthesis of purine and pyrimidine nucleotides, salvage of purine and pyrimidine bases, and synthesis of NAD+. PRPP synthetase catalyzes the reaction presented in Figure 12.35. Ribose 5phosphate used in this reaction is generated from glucose 6 phosphate metabolism via the hexose monophosphate shunt or from ribose 1phosphate (generated by phosphorolysis of nucleotides) via a phosphoribomutase reaction. The enzyme has an absolute requirement for inorganic phosphate and is strongly regulated. The v versus [Pi] curve for PRPP synthetase activity is sigmoidal rather than hyperbolic, meaning that at the normal cellular concentration of Pi, the enzyme activity is depressed. The enzyme activity is further regulated by ADP, 2,3 bisphosphoglycerate, and other nucleotides. ADP serves as a competitive inhibitor of PRPP synthetase with respect to ATP; 2,3bisphosphoglycerate is a competitive inhibitor with respect to ribose 5phosphate; and nucleotides serve as noncompetitive inhibitors with respect to both substrates. 2,3Bisphosphoglycerate may be important in regulating PRPP synthetase activity in red cells. Levels of PRPP are low in "resting" or confluent cells but increase rapidly at the time of rapid cell division. Increased flux of glucose 6phosphate through the hexose monophosphate shunt can result in increased cellular levels of PRPP and increased production of purine and pyrimidine nucleotides. PRPP is important not only because it serves as a substrate in the glutamine PRPP amidotransferase reaction and the phosphoribosyltransferase reactions, but also because it serves as a positive effector of the major regulated steps in purine and pyrimidine nucleotide synthesis, namely, PRPP amidotransferase and carbamoyl phosphate synthetase II. Reactions and pathways in which PRPP is required are as follows: 1. De novo purine nucleotide synthesis 2. Salvage of purine bases 3. De novo pyrimidine nucleotide synthesis Figure 12.35 Synthesis of PRPP.