Abstract
Superactivity of PRPP synthetase (PS) is associated with purine nucleotide and uric acid overproduction, usually manifested by early adult-onset gout. We studied fibroblasts and lymphoblasts from a male child (NB) with inherited uric acid overproduction, deafness, and retarded motor development, suspected to have a superactive PS (Simmonds et al. 1982. Lancet 2:68-70). Our studies confirm a defective enzyme altered in regulation of PS activity in response to noncompetitive inhibitors and to the activator, Pi.
Fibroblasts and lymphoblasts from NB show PRPP concentrations and generation and rates of all PRPP-requiring purine synthetic pathways, including purine synthesis de novo, which are increased at least 2-fold with respect to normal. In dialyzed fibroblast and lymphoblasts extracts, NB PS shows hyperbolic Pi activation due to increased maximal reaction velocity which is found only at <2 mM Pi. In chromatographed or partially purified enzyme preparations, Km's of normal and NB PS for substrates and Mg2+ are comparable, but the Pi concentration at which PS is half activated is 0.12 mM for NB PS and 0.45 to 0.60 mM for normal PS. In addition, inhibitory constants (I0.5) for the competitive inhibitors ADP and 2,3-DPG are comparable for normal and NB PS, while NB PS is, respectively, 5- and 6-fold less responsive than normal PS to the noncompetitive inhibitors GDP and MMPR monophosphate. The association of increased rates of intracellular PRPP and purine synthesis with specific defects in the regulation of PS activity suggest that these PS regulatory mechanisms are of physiological importance in the control of PRPP and purine production.
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Becker, M., Losman, M. & Simmonds, H. INHERITED PRPP SYNTHETASE SUPERACTIVITY DUE: TO ABERRANT INHIBITOR AND ACTIVATOR RESPONSIVENESS: 12. Pediatr Res 19, 745 (1985). https://doi.org/10.1203/00006450-198507000-00032
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DOI: https://doi.org/10.1203/00006450-198507000-00032