Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Work is continuing in the attempt to increase knowledge of the regulation of the rate of purine synthesis in man by means of an analysis of biochemical alterations leading to purine overproduction among patients with gout. The authors are now assessing the frequency of kinetic mutations in enzymes whose alterations already have been associated with increased purine synthesis. Efforts in this regard have been rewarded by the identification of a new form of alteration leading to partial deficiency of HGPRT and a kinetic variant of PRPP synthetase with increased affinity for ribose-5-phosphate. In order to identify new forms of enzyme abnormalities associated with excessive purine synthesis, the value of a proposed classification scheme requiring measurement of PRPP and ribose-5-phosphate concentration and generation is being assessed in cultured fibroblasts. It is hoped that the results of these measurements will lead to the identification of additional kinetic variants of presently known enzyme abnormalities and will help to identify new classes of mutants in the regulation of human purine metabolism. The excessive purine synthesis that underlies the hyperuricemia of a substantial number of patients with gouty arthritis reflects alterations in the normal mechanism regulating the rate of purine nucleotide synthesis. The study of such purine "overproducers" has provided insight into the nature of this regulatory mechanism and has underscored the diversity of specific genetic and biochemical aberrations affecting it. Despite these advances, however, less than 10% of all patients with gout and excessive purine production can presently be accounted for by known enzyme abnormalities (1). Recognition that current knowledge of the regulation of the rate of purine nucleotide synthesis in man is incomplete has provided the authors impetus leading to the studies described here, which are preceded by a brief review of background.
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PMID:Recent advances in the identification of enzyme abnormalities underlying excessive purine synthesis in man. 17 46

Some physicochemical properties of HGPRTase were studied in hemolysates and fibroblasts of a gout patient with partial deficiency of this enzyme. In comparison to normal HGPRTase the mutant enzyme from erythrocytes was found to have an elevated apparent Km-value for hypoxanthine and guanine and a lower Km-value for PRPP. The patient's enzyme from erythrocytes is more stable at +4 degrees C and +80 degrees C, the enzyme from fibroblasts more labile than that of controls. The inhibition of the mutant enzyme by some purine nucleosides and -nucleotides differed from that found in controls. No evidence was shown for an inhibitor of the patient's HGPRTase from erythrocytes. Ultracentrifugation of hemolysate in a saccharose gradient revealed no difference in the sedimentation coefficient.
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PMID:[Properties of hypoxanthineguanine-phosphoribosyltransferase (HGPRTase) in a gout patient with partial deficiency of this enzyme (author's transl)]. 76 46

Deficiencies of HPRT are usually associated with increased concentrations of PRPP and increased levels of APRT activity in erythrocytes. We report the case of a male with a partial deficiency of HPRT in whom these two parameters were normal. The clinical features of this patient were those associated with severe hyperuricaemia and gout. Studies of intact erythrocytes showed rates of incorporation of [14C]hypoxanthine and of [14C]adenine into purine nucleotides which were almost indistinguishable from normal. However, HPRT activity in erythrocyte lysates was only 9% of normal. In cell extracts of cultured lymphoblasts, the HPRT activity was 20% of control values and the APRT activity was normal. The PRPP concentration and the rate of de novo purine synthesis in cultured lymphoblasts were both intermediate between controls and lymphoblasts from patients with the Lesch-Nyhan syndrome.
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PMID:HPRT-deficiency associated with normal PRPP concentration and APRT activity. 243 88

We have studied families C and A in which superactivity of PRPP synthetase (E.C. 2.7.6.1) is associated with gout and uric acid overproduction in affected hemizygous males. PRPP synthetase catalyzes synthesis of PRPP, a regulatory substrate in purine synthesis de novo. Activities of the enzyme in erythrocyte and fibroblast extracts from the male index cases, T.C. and R.A., were nearly threefold greater than normal at each Pi concentration tested. PRPP synthetase superactivity was accompanied by increased intracellular PRPP concentration and generation in erythrocytes and fibroblasts from these patients, and enhanced rates of PRPP-dependent purine synthesis reactions, including purine synthesis de novo, were demonstrable in their fibroblasts. These findings suggested that increased intracellular synthesis dut to enzyme superactivity underlay purine nucleotide and uric acid overproduction in these patients. Similar studies in cells from the sister of T.C. and the mother of R.A. showed increased values that were, however, intermediate between normal values and those of the affected males, indicating that these women are heterozygous carriers of the traits for enzyme superactivity. The enzymatic basis for increased PRPP synthetase activity in both families was investigated. Immunochemical studies in dialyzed erythrocyte lysates and highly purified erythrocyte enzyme preparations provided evidence for increased enzyme activity per molecule of immunoreactive enzyme. In addition, purified T.C. and R.A. PRPP synthetases showed 3.1- and 2.8-fold greater enzyme specific activities, respectively, than comparably purified normal enzymes. Kinetic constants of purified T.C. and R.A. PRPP synthetases for substrates, activators, and inhibitors were indistinguishable from normal, and increased maximal reaction velocity alone appeared to account for enzyme superactivity. Despite an apparently similar kinetic mechanism for superactivity, the diminished electrophoretic mobility of T.C. PRPP synthetase and increased thermal lability of R.A. PRPP synthetase suggested distinct structural alterations leading to enzyme superactivity in families C and A.
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PMID:Gout with superactive phosphoribosylpyrophosphate synthetase due to increased enzyme catalytic rate. 617 58

PRPP synthetase catalyzes the synthesis of PRPP, a regulatory substrate in the pathway of purine nucleotide synthesis de novo. We have developed a specific assay for quantitative determination of PRPP synthetase immunologically cross-reactive material in human erythrocyte and fibroblast extracts. The sensitivity of the radioimmunoassay (0.3% and 0.08% of normal mean cross-reactive material in erythrocytes and fibroblasts, respectively) was equivalent to that of the enzymatic activity assay, but enzyme protein initially present in relatively inactive monomeric and smaller aggregated forms was radioimmunochemically measurable. The radioimmunoassay was utilized in conjunction with the enzymatic assay to study normal PRPP synthetase and PRPP synthetases from five affected male patients (in four families) in whom inherited enzyme superactivity was associated with increased rates of PRPP and purine nucleotide synthesis and gout with excessive uric acid excretion. Despite increased enzymatic activities in patients' cell extracts, values for cross-reactive material were within the ranges measured in the respective normal cell extracts. Thus, calculated absolute specific activities (nmol/hr/mg cross-reactive material) of patients' PRPP synthetases were substantially greater than those of normal PRPP synthetase. Moreover, absolute specific activities in hemolysates from both patients and normal individuals were in close agreement with the enzyme-specific activities measured in preparations of erythrocyte PRPP synthetase purified to homogeneity from the corresponding patient or normal source. These findings provided evidence for the accuracy and specificity of the radioimmunoassay and supported previous evidence for increased maximal reaction velocity as the basis of superactivity of the patients' enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human phosphoribosylpyrophosphate synthetase: radioimmunochemical quantitation in erythrocytes and fibroblasts. 633 Feb 52

PRPP(phosphoribosyl pyrophosphate) synthetase catalyzes the formation of PRPP from ATP and ribose 5-phosphate. Human PRPP synthetase exists as heterogeneous aggregates composed of the 34kDa catalytic subunits (PRSI and PRSII) and other 39kDa and 41kDa components designated PRPP synthetase-associated protein (PAP39 and PAP41). A syndrome of increased activity of PRPP synthetase, an X-linked dominant-inherited disorder, is one of the models of gout caused by increased production of uric acid. By now, around twenty cases have been reported over the world. Two different molecular mechanisms underlie this syndrome: (1) point mutation in the gene coding the primary structure of PRPP synthetase causes the substitution of an amino acid residue and, consequently, the regulatory defects, those are resistant traits to allosteric nucleotide feedback inhibition; (2) increased transcription of PRPP synthetase mRNA causes overproduction of this enzyme protein. The mechanism producing increased mRNA is, however, not elucidated. The Japanese case has been found to be caused by the second mechanism.
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PMID:[Increased activity of PRPP synthetase]. 1840 17

Mutation of hypoxanthine guanine phosphoribosyltransferase (HPRT) gives rise to Lesch-Nyhan syndrome, which is characterized by hyperuricemia, severe motor disability, and self-injurious behavior, or HPRT-related gout with hyperuricemia. Four mutations were detected in two Lesch-Nyhan families and two families with partial deficiency since our last report. A new mutation of G to TT (c.456delGinsTT) resulting in a frameshift (p.Q152Hfs*3) in exon 3 has been identified in one Lesch-Nyhan family. In the other Lesch-Nyhan family, a new point mutation in intron 7 (c.532+5G>T) causing splicing error (exon 7 excluded, p.L163Cfs*4) was detected. In the two partial deficiency cases with hyperuricemia, two missense mutations of p.D20V (c.59A>T) and p.H60R (c.179A>G) were found. An increase of erythrocyte PRPP concentration was observed in the respective phenotypes and seems to be correlated with disease severity.
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PMID:Hypoxanthine guanine phosphoribosyltransferase (HPRT) deficiencies: HPRT1 mutations in new Japanese families and PRPP concentration. 2494 Jun 72