Abstract
Extract: The specific activity of argininosuccinate synthetase (micromoles of 14CO2 per milligram of protein per hour) was 0.00104 and 0.00087 in fibroblasts derived from two patients with citrullinemia, and was undetectable in both fibroblasts and cultured lymphocytes from a third patient. In five obligate heterozygotes the specific activity in fibroblasts was 0.012 0.029 and in nine control subjects was 0.058 ± 0.014 (0.030–0.076). In both control and patient cells, the maximum activity was obtained at pH 8.5 and there was no inhibition of normal argininosuccinate synthetase by any of the mutant cells.
Kinetic studies were consistent with decreased binding of citrulline and/or aspartate in fibroblasts from all three patients. The Km for citrulline was 4.2 × 10−3 and >2.0 × 10−2 M for the enzyme from patients 1 and 2, respectively (normal 1.1 × 10−4 M). Corresponding Km values for aspartate were 1.8 × 10−2 and >6.5 × 10−3 M, respectively (normal 3.4 × 10−5 M). Hill constants derived from the citrulline substrate curves from patients 1 and 2 were 1.01 and 1.50 (normal 0.91). Corresponding constants obtained from aspartate binding curves were 1.06 and 1.35, respectively (normal 0.97).
The activity of homoargininosuccinate synthetase was undetectable in fibroblasts from all three patients and a control subject.
Speculation: Heterogeneity of the primary enzyme defect will become a frequent observation in many inborn errors of metabolism. In disorders of the urea cycle, alternative and as yet unknown pathways of urea formation may be discovered.
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Kennaway, N., Harwood, P., Ramberg, D. et al. Citrullinemia: Enzymatic Evidence for Genetic Heterogeneity. Pediatr Res 9, 554–558 (1975). https://doi.org/10.1203/00006450-197506000-00008
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DOI: https://doi.org/10.1203/00006450-197506000-00008
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