Disease relevance of phosphoribosylpyrophosphate

• Multi-wavelength anomalous diffraction (MAD) has been used to determine the structure of the regulatory enzyme of de novo synthesis of purine nucleotides, glutamine 5-phosphoribosyl-1-pyrophosphate (PRPP) amidotransferase, from Bacillus subtilis [1].
• Phosphoribosylpyrophosphate overproduction, a new metabolic abnormality in the Lesch Nyhan syndrome [2].
• Impaired erythrocyte phosphoribosylpyrophosphate formation in hemolytic anemia due to pyruvate kinase deficiency [3].
• Increased 5-phospho-alpha-D-ribose-1-diphosphate synthetase (ribosephosphate pyrophosphokinase, EC 2.7.6.1) activity in rat hepatomas [4].
• Altered 5-phosphoribosyl 1-pyrophosphate amidotransferase activity in 6-thioguanine-resistant HL-60 human acute promyelocytic leukemia cells [5].

High impact information on phosphoribosylpyrophosphate

• Metabolic cooperation between human fibroblasts with normal and with mutant superactive phosphoribosylpyrophosphate synthetase [6].
• Regional localization of the gene for human phosphoribosylpyrophosphate synthetase on the X chromosome [7].
• Phosphoribosylpyrophosphate (PRPP) concentrations and PRPP synthetase activity were studied in cultured human fibroblasts with control and mutant hypoxanthine-guanine phosphoribosylpyrophosphate (HPRT) activity [8].
• In subconfluent cultures of fibroblasts from patients with complete or partial deficiencies of hypoxanthine-guanine phosphoribosyltransferase, phosphoribosylpyrophosphate synthetase activity is elevated [9].
• Phosphoribosylpyrophosphate synthetase is elevated in fibroblasts from patients with the Lesch-Nyhan syndrome [9].

Chemical compound and disease context of phosphoribosylpyrophosphate

• The liver and hepatoma enzyme exhibited apparent Km's for: glutamine, 1.7 and 2.3 mM; MgC12, 0.7 and 1.1 mM, and phosphoribosylpyrophosphate [10].
• Effect of methotrexate on 5-phosphoribosyl 1-pyrophosphate levels in L1210 leukemia cells in vitro [11].
• Glutamine phosphoribosylpyrophosphate amidotransferase, the first enzyme of purine nucleotide biosynthesis, is inactivated and degraded in Bacillus subtilis during carbon, nitrogen, or amino acid starvation [12].
• Binding of the substrates and the allosteric inhibitor adenosine 5'-diphosphate to phosphoribosylpyrophosphate synthetase from Salmonella typhimurium [13].
• Chemical modification of Salmonella typhimurium phosphoribosylpyrophosphate synthetase with 5'-(p-fluorosulfonylbenzoyl)adenosine. Identification of an active site histidine [14].

Biological context of phosphoribosylpyrophosphate

• Hyperbolic kinetics with increasing phosphoribosylpyrophosphate were converted to sigmoid kinetics by 0.2 mM GMP with the mutant enzyme but not with the normal enzyme [15].
• PPS1 was isolated and shown to be a previously undescribed gene coding for a protein similar in amino acid sequence to phosphoribosylpyrophosphate synthase, a rate-limiting enzyme in the biosynthesis of nucleotides, histidine, and tryptophan [16].
• Structure of the divalent cation.nucleotide complex at the active site of phosphoribosylpyrophosphate synthetase [17].
• The rat liver phosphoribosylpyrophosphate (PRPP) synthetase exists as complex aggregates composed of the 34-kDa catalytic subunits (PRS I and II) and other 39- and 41-kDa proteins (Kita, K., Otsuki, T., Ishizuka, T., and Tatibana, M. (1989) J. Biochem. (Tokyo) 105, 736-741), which are termed here PRPP synthetase-associated proteins (PAPs) [18].
• The nucleotide sequence of over 13 kilobase pairs indicates that this region contains a cluster of 12 genes, 11 of which encode enzymes that catalyze the 10 reactions for de novo purine nucleotide synthesis from 5-phosphoribosyl 1-pyrophosphate to IMP [19].

Anatomical context of phosphoribosylpyrophosphate

• Initial velocity studies of the normal enzyme and the mutant enzyme from erythrocytes with the substrates hypoxanthine, guanine, or phosphoribosylpyrophosphate showed that the Michaelis constants were similar [15].
• Serial biopsies and blood samples were obtained in selected patients to evaluate the effect of MTX on tissue and lymphocyte phosphoribosylpyrophosphate (PRPP) and PRPP synthetase levels [20].
• Effect of intracellular folate concentration on the modulation of 5-fluorouracil cytotoxicity by the elevation of phosphoribosylpyrophosphate in cultured human KB cells [21].
• In contrast, other enzymes of nucleotide metabolism, such as adenosine kinase, deoxycytidine kinase, and 5-phosphoribosyl-1-pyrophosphate synthetase, showed no significant change in the two cell lines [22].
• Added 5-phosphoribosyl 1-pyrophosphate is not taken up by liver cells [23].

Associations of phosphoribosylpyrophosphate with other chemical compounds

• Mutant feedback-resistant phosphoribosylpyrophosphate synthetase associated with purine overproduction and gout. Phosphoribosylpyrophosphate and purine metabolism in cultured fibroblasts [24].
• The addition of ATP, 5-phosphoribosyl-1-pyrophosphate, Mg++, or inorganic phosphate to the dossociated complex results in the appearance of a peak of aspartate transcarbamoylase activity with an apparent molecular weight of 110,000 +/- 10,000 [25].
• Because phosphoribosylpyrophosphate (PRPP) is a precursor of both adenine and pyridine nucleotides, we investigated the ability of intact PK-deficient RBCs to accumulate PRPP [3].
• Adenosine, 50 micron, in combination with the adenosine deaminase inhibitors reduced 14CO2 generation from [1-14C]glucose by 38%, depleted 5-phosphoribosyl-1-pyrophosphate by more than 90%, and reduced pyrimidine ribonucleotide concentrations [26].
• Glutamine nucleotide sequence of Saccharomyces cerevisiae ADE4 encoding phosphoribosylpyrophosphate amidotransferase [27].

Gene context of phosphoribosylpyrophosphate

• Accelerated transcription of PRPS1 in X-linked overactivity of normal human phosphoribosylpyrophosphate synthetase [28].
• Linkage of phosphoribosylpyrophosphate synthetases 1 and 2, Prps1 and Prps2, on the mouse X chromosome [29].
• PRS1 is a key member of the gene family encoding phosphoribosylpyrophosphate synthetase in Saccharomyces cerevisiae [30].
• Complementary DNA clones for phosphoribosylpyrophosphate synthetase subunits I and II (PRS I and PRS II) were used to determine the chromosomal localization of the corresponding human genes [31].
• PRS3 is one of a family of five genes encoding phosphoribosylpyrophosphate synthetase, an enzyme which catalyses the first step in a variety of biosynthetic pathways, including purine and pyrimidine biosynthesis [32].

Analytical, diagnostic and therapeutic context of phosphoribosylpyrophosphate

• The role of Mg ions in the hypoxanthine guanine phosphoribosyltransferase-catalyzed reaction have been studied using accurate values of proton and Mg stability constants of phosphoribosylpyrophosphate (P-Rib-PP) determined from pH titration data [33].
• On the basis of our in vitro results, we suggest that massive ATP degradation, as it occurs in brain during ischemia, might lead to an increase of the intracellular 5-phosphoribosyl-1-pyrophosphate and ribose-1-phosphate pools, to be utilized for nucleotide resynthesis during reperfusion [34].
• Glutamine amidotransferase function. Replacement of the active-site cysteine in glutamine phosphoribosylpyrophosphate amidotransferase by site-directed mutagenesis [35].
• The structure of TrpD from M.tuberculosis was solved by X-ray crystallography, at 1.9 A resolution for the native enzyme (R = 0.191, Rfree = 0.230) and at 2.3 A resolution for the complex with its substrate phosphoribosylpyrophosphate (PRPP) and Mg2+ (R = 0.194, Rfree = 0.255) [36].
• Overexpression of Bacillus subtilis phosphoribosylpyrophosphate synthetase and crystallization and preliminary X-ray characterization of the free enzyme and its substrate-effector complexes [37].

References