Function of Phosphoribosylpyrophosphate (PRPP) Synthetase
PRPP synthetase catalyzes the transfer of phosphate from ATP to D-ribose-5-phosphate to produce phosphoribosylpyrophosphate (PRPP), which serves as an essential precursor for all purine and pyrimidine nucleotide synthesis, as well as for tryptophan and histidine biosynthesis. 1, 2
Primary Biochemical Function
PRPP synthetase generates PRPP by transferring the pyrophosphate group from ATP to carbon-1 of ribose-5-phosphate, creating the activated sugar phosphate that is required for subsequent biosynthetic reactions 3
The enzyme functions as a hexamer, with the active site located between two domains and including residues from two different subunits, representing a unique structural arrangement among metabolic enzymes 3
Critical Metabolic Pathways Dependent on PRPP
Purine nucleotide synthesis: PRPP is the obligate substrate for both de novo purine synthesis (via phosphoribosylamine formation) and purine salvage pathways (via base phosphoribosylation reactions) 1, 4
Pyrimidine nucleotide synthesis: PRPP serves as the precursor for pyrimidine nucleotide formation, making it essential for DNA and RNA synthesis 1, 4
Amino acid biosynthesis: PRPP is required for the biosynthesis of tryptophan and histidine in organisms capable of synthesizing these amino acids 2
Activation of chemotherapeutic agents: PRPP is necessary for converting certain chemotherapeutic drugs into their active nucleotide forms 1
Regulatory Mechanisms
The enzyme is subject to complex allosteric regulation, with noncompetitive inhibition by GDP and competitive inhibition by ADP and 2,3-diphosphoglycerate, allowing fine-tuned control of nucleotide synthesis 5
Inorganic phosphate (Pi) acts as an activator of PRPP synthetase, with Pi binding to a regulatory site consisting of residues from three subunits of the hexamer 5, 3
The enzyme responds to cellular energy status and nucleotide pools, with feedback inhibition by purine and pyrimidine nucleotides preventing excessive nucleotide accumulation 1
Mitogenic Regulation and Cell Growth
Growth factors including EGF, insulin, bombesin, and FGF stimulate metabolic flux through PRPP synthetase by approximately 2-fold within 45-60 minutes in quiescent fibroblasts, representing an early mitogenic response 4
External magnesium is absolutely required for mitogen-induced stimulation of PRPP synthesis, with Mg²⁺ entry into cells playing a critical role in signal transduction, while calcium is dispensable 4
The divalent cation ionophore A23187 mimics growth factor effects, suggesting that divalent cation mobilization is the key intracellular signaling mechanism for increased PRPP synthesis 4
Clinical Significance
PRPP synthetase is essential for cell viability, as demonstrated by the inability to generate homozygous null mutants in Candida albicans, indicating that complete loss of enzyme function is lethal 2
Genetic mutations causing PRPP synthetase superactivity result in purine overproduction, hyperuricemia, and neurological deficits due to selective resistance to noncompetitive inhibitors (3-4 fold increased I₀.₅ for GDP) and increased responsiveness to Pi activation (3-4 fold reduced KD) 5
Testing for PRPP synthetase superactivity should be considered in patients with unexplained hyperuricemia and neurological symptoms, particularly when serum and urine uric acid are elevated 6, 5
The enzyme represents a potential therapeutic target in leukemia chemotherapy, as different types of leukemic cells show differential responses to compounds affecting PRPP synthetase activity 1