Phosphoribosyltransferase Mechanisms and Roles in Nucleic Acid Metabolism

Purine and pyrimidine phosphoribosyltransferases govern the metabolic branchpoints between salvage and degradation for these nucleic acid precursors. Deficiency or inhibition leads to overproduction and increased degradation products in organisms with de novo synthetic pathways and to growth inhibition in auxotrophic organisms. Purine and pyrimidine phosphoribosyltransferases catalyze their reactions by activating the purine{plus 45 degree rule}pyrimidine, forming dissociative ribooxacarbenium-(S_N1-like) transition states with the assistance of neighboring group participation, followed by the migration of the ribosyl anomeric carbon region to immobilized and activated MgPPi. This class of enzymatic mechanism is called nucleophilic substitution by electrophile migration. The enzymes require substantial loop and flap motion to position reactive groups and close the catalytic site for catalysis. The enzymes use a surprisingly large number of carefully positioned and immobilized waters to hold the complex reactants in place during the chemical transformation. Despite our increased understanding of these enzymes and pathways, no drugs that target the phosphoribosyltransferases for inhibition have been approved. Transforming selected cells with increased activity of specific phosphoribosyltransferases sensitizes them to suicide purine substrates.