Disease relevance of pyrophosphate

• These results indicate that: (a) there is marked variation in HPRT, PRPP, and alkaline phosphatase in patients with acute lymphoblastic leukemia and b) following MP-containing maintenance chemotherapy, some patients develop biochemical changes that may result in decreased sensitivity to MP [1].
• The enzyme 5-phosphoribosyl-alpha-1-pyrophosphate (PRPP) synthetase from Escherichia coli was irreversibly inactivated on exposure to the affinity analog 2',3'-dialdehyde ATP (oATP) [2].
• Sulfhydryl-specific reagents were used to study the reactivities and function of the four cysteinyl residues per subunit present in Salmonella typhimurium 5-phosphoribosyl-alpha-1-pyrophosphate (PRPP) synthetase [3].

High impact information on pyrophosphate

• Eight molecules of the feedback inhibitor adenosine monophosphate (AMP) are bound to the tetrameric enzyme in two types of binding sites: the PRPP catalytic site of each subunit and an unusual regulatory site that is immediately adjacent to each active site but is between subunits [4].
• Activation of normal enzyme in transformed lymphocytes was also unlikely because absolute specific activities of lymphoblast PRPP synthetases corresponded to those of normal fibroblast and erythrocyte enzymes [5].
• Two of four patients demonstrated changes in all three parameters at relapse in the directions that could have resulted in decreased MP sensitivity (i.e., decreased HPRT, decreased PRPP, and increased alkaline phosphatase) [1].
• Protection studies demonstrated that Lys-26, and to a lesser extent Lys-100 and Lys-103, were protected against modification by OMP, whereas PRPP protected Lys-26, Lys-100 and Lys-103 [6].
• Exposure to 2 microM 6MP resulted in a rapid inhibition of purine de novo synthesis (PDNS) by increased levels of Me-tIMP, resulting in increased PRPP levels and decreased purine ribonucleotides, affecting cell growth and clonal growth, and less cell death [7].

Biological context of pyrophosphate

• However, the fact that disruption of this gene causes the most dramatic decrease in cell growth rate and enzyme activity suggests that Prs1p may have a key structural or regulatory role in the production of PRPP in the cell [8].
• The results are compatible with greater initial bioavailability of PRPP in the diabetic renal cortex than in controls but with a rate of maximal PRPP generation that is the same in both tissues [9].

Anatomical context of pyrophosphate

• Thus, lymphoblast PRPP synthetases from patients with catalytic superactivity appeared to differ structurally and functionally from their fibroblast counterparts [5].
• Nevertheless, when the possibility of direct mitogenic activation of PRPP synthase was studied, no differences were found in activities of this enzyme in extracts from stimulated and unstimulated 3T3 cells and mouse embryo fibroblasts [10].
• Although 3-N-ribosyluric acid (3-RUA) was not detected in the red cells of bovine fetuses, 3-N-ribosyluric acid 5'-monophosphate, the immediate precursor of 3-RUA, was synthesized from uric acid and 5-phosphoribosyl-1-pyrophosphate (PRPP) by hemolysates of fetal red cells [11].

Associations of pyrophosphate with other chemical compounds

• In Saccharomyces cerevisiae the metabolite phosphoribosyl-pyrophosphate (PRPP) is required for purine, pyrimidine, tryptophan and histidine biosynthesis [8].
• The tissue bioavailability of PRPP determines the effects of orotate or adenine administration on UTP, ATP, and GTP content and on the incorporation of labeled precursors into UTP and ATP [9].

Gene context of pyrophosphate

• IMP and GMP inhibited competitively with PRPP and promoted cooperativity in the binding of this substrate; there was no cooperativity in the binding of IMP to the enzyme [12].
• The optimum activity of the purified OPRTase was observed at 150 mM KCl, pH 9.0, 75-80 degrees C, and in the presence of 100 microM PRPP [13].
• Dibutyryl cyclic AMP (Bt2 cAMP) partially mimicked this effect of glucagon in that it did not increase the rate of de novo purine synthesis in spite of increased concentrations of PRPP [14].

Analytical, diagnostic and therapeutic context of pyrophosphate

• In addition, we replaced the corresponding residues (aspartic acid310, lysine333, and alanine417) that have been described to be important for PRPP amidotransferase feedback inhibition in other organisms by site-directed mutagenesis [15].
• PYP or GLUC was injected 45min before end of reperfusion [16].

References