Metabolic cooperation between human fibroblasts with normal and with mutant superactive phosphoribosylpyrophosphate synthetase.

Nature (Impact Factor: 42.35). 05/1976; 260(5554):787-8. DOI: 10.1038/260786a0
Source: PubMed

ABSTRACT METABOLIC cooperation is a form of intercellular communication by which cells in contact exchange molecules, a process providing multicellular organisms with an important mechanism for control of metabolic activity1. Subak-Sharpe et al.2 observed contact-dependent transfer of purine nucleotides from normal cells to cells mutationally incapable of producing inosinic acid due to deficiency in hypoxanthine-guanine phosphoribosyl-transferase3. Metabolic cooperation of this type was later also demonstrated with other enzymic markers, such as adenine phosphoribosyltransferase and thymidine kinase4,5. Such transfers are characterised, by the normal cell being the donor and the mutant cell being the recipient, the former transferring to the latter a mutationally lacking metabolite. We report here on a new form of contact-dependent metabolic cooperation, unique in that the transfer of a metabolite occurs from a mutant donor cell to a normal recipient cell.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The metabolic consequence of hypoxanthine-guanine phosphoribosyltransferase deficiency, the accelerated rate of purine synthesis de novo, was utilized as a marker for the detection in cultured fibroblasts of heterozygosity for the Lesch-Nyhan syndrome. This marker was found to be very sensitive allowing the detection of mutant cells in nonselected mixed mutant: normal cell cultures even at a low proportion of 1 to 10. Exposure of the mixed cultures to selection for the mutant cell with azaguanine increased the sensitivity of the test. Cultures from different biopsies, obtained from heterozygote females, were found to contain different proportions of the mutant cell, ranging from 10 to 84%.Copyright © 1979 S. Karger AG, Basel
    Human Heredity 01/1979; 29(1):64-68. DOI:10.1159/000153018 · 1.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Skin fibroblast cultures were utilized to study the mode of inheritance of a mutant feedback-resistant phosphoribosylpyrophosphate synthetase in a gouty family with purine overproduction. Selective conditions were applied to allow the survival in culture of mutant cells only. Whereas in the male gouty propositus the cell culture was homogeneous for the mutant enzyme, in the cell culture from his nongouty mother two cell populations were demonstrated, one normal and the other mutant. The mosaicism in the mother is compatible with X-linkage of the enzyme. From this finding, together with the clinical and biochemical data available, it is concluded that in this family the enzyme mutation is transmitted in a X-linked recessive pattern.Copyright © 1977 S. Karger AG, Basel
    Human Heredity 01/1977; 27(1):73-80. DOI:10.1159/000152853 · 1.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Superactive phosphoribosylpyrophosphate (PRPP) synthetases were characterized in fibroblasts and erythrocytes from 5 unrelated men with gout and/or hyperuricemia and uric acid overproduction. The kinetic basis of enzyme superactivity in all patients was increased maximal reaction velocity. Affinities of the enzymes for substrates and activators and responsiveness to inhibitors were normal, and levels of immunoreactive enzyme in patient and control fibroblast and erythrocyte extracts were comparable. Enzymes purified to homogeneity from 2 patients confirmed the presence of isolated catalytic defects. Altered physical properties of certain of the superactive enzymes suggested the presence of several distinctive structural defects among the aberrant forms. Fibroblasts from each affected patient showed increased PRPP concentration and generation, as well as accelerated rates of all PRPP-requiring purine nucleotide synthetic pathways. These findings support the concept that enzyme superactivity results in uric acid overproduction as a consequence of increased rates of PRPP and purine nucleotide synthesis. Cultured cells from female relatives of 2 patients showed evidence for the heterozygous carrier state, as measured both by enzyme activities and by rates of PRPP and purine synthesis. The clinical phenotype in 4 patients was limited to early adult-onset gout and its consequences, whereas the fifth patient expressed a familial constellation of hyperuricemia, sensorineural deafness, ataxia, and renal insufficiency. The severity of the derangements in PRPP synthetase and in PRPP and purine synthesis in cells from the 5 patients, however, was comparable. The neurologic accompaniments of enzyme superactivity found in 1 family described here, and in 2 others described previously, thus may not necessarily be consequences of primary defects in PRPP synthetase.
    Arthritis & Rheumatology 07/1986; 29(7):880 - 888. DOI:10.1002/art.1780290710 · 7.48 Impact Factor