Isolation and Characterization of a Naturally Occurring Stimulator of Citrulline Biosynthesis

Hall, Leo M.; Metzenberg, Robert L.; Cohen, Philip P.

doi:10.1038/1781468a0

Cited by 38 publications

(40 citation statements)

References 5 publications

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“…NAG is an essential allosteric activator of carbamylphosphate synthetase I (CPSI), the first and rate limiting enzyme of the urea cycle [Hall et al, 1958;Waterlow, 1999]. NAGS deficiency is an autosomal recessive disorder that appeared to be the least prevalent of all urea cycle disorders [Brusilow and Horwich, 2001].…”

mentioning

confidence: 99%

Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene

2007

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confidence: 99%

Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene

2007

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“…This naturally occumng compound was isolated and identified as NAG, which is the cofactor of mitochondria1 CPS I, the first enzyme of the urea cycle in ureotelic animals (2). NAG is an allosteric activator of this enzyme (3) altering its conformation (4).…”

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confidence: 99%

N-Acetylglutamate Content in Liver and Gut of Normal and Fasted Mice, Normal Human Livers, and Livers of Individuals with Carbamyl Phosphate Synthetase or Ornithine Transcarbamylase Deficiency

Tuchman

Holzknecht

1990

Pediatr Res

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ABSTRACT. N-acetylglutamate (NAG) content was measured in homogenates of liver and small intestine obtained from normal and 24-h starved syngeneic mice. Subsequently, NAG was determined in normal, and in carbamyl phosphate synthetase I and ornithine transcarbamylase enzyme-deficient human liver tissue homogenates. The method used in this study, which is direct and highly specific, used anion exchange extraction, gas chromatographic separation, and mass spectrometric detection and quantitation. Hepatic NAG content in the fed animals was In three patients with apparently complete carbamyl phosphate synthetase I or ornithine transcarbamylase deficiency, hepatic NAG levels were lower than controls (2.2-12.8 nmoljg tissue 42.3-140.7 nmol/g protein), two patients with ornithine transcarbamylase deficiency had levels similar to the controls and one patient with carbamyl phosphate synthetase I deficiency had elevated levels (98.4 nmoljg tissue, 1185.5 nmoljg protein). The livers of two patients with cirrhosis and hyperammonemia contained amounts of NAG within the range of normal livers. The marked variability in tissue NAG concentrations in various nutritional and metabolic conditions favors the hypothesis that NAG plays a role in the regulation of urea synthesis. Hepatic NAG levels are markedly reduced in some but not all patients with defects in urea cycle enzymes. (Pediatr Res 27: 408-412,1990) Abbreviations NAG, N-acetylglutamate NAGS, N-acetylglutamate synthase

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“…Previous reports have suggested a role for NCG in the treatment of hyperammonemia in PA (Filippi et al 2010;Gebhardt et al 2003Gebhardt et al , 2005Jones et al 2008;Levrat et al 2008;Schwahn et al 2010). Since inhibition of N-acetylglutamate synthase may be a contributing factor to the hyperammonemia in PA, the use of NCG, a compound analogous to N-acetylglutamate, could stimulate CPSI in lieu of N-acetylglutamate (Hall et al 1958;Rubio and Grisolía 1981). Recently, other investigators provided support for this idea by showing increased ureagenesis and decreased ammonia levels following NCG administration in PA patients (Ah Mew et al 2010;Tuchman et al 2008).…”

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confidence: 59%

Short-Term Outcome of Propionic Aciduria Treated at Presentation with N-Carbamylglutamate: A Retrospective Review of Four Patients

et al. 2011

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N-carbamylglutamate (NCG) has been reported to decrease ammonia levels in patients with propionic aciduria (PA) and methylmalonic aciduria (MMA), but reports on clinical outcomes remain scant. Here, we report a retrospective series of four patients with neonatal PA treated with NCG at presentation. Patients presented between 2 and 9 days of age and peak plasma ammonia ranged from 524 to 1,572 mM. Patients received bolus (30-200 mg/kg) and sustaining (115-300 mg/kg per day) doses of NCG in addition to a standard treatment regimen that included ammonia scavenger drugs. Ammonia levels decreased significantly in three of the four cases within 2 h after administration of NCG and fell below 100 mM in all within 12-29 h. Two patients received NCG (bolus 200 mg/kg) while ammonia was above 500 mM (740 and 1,572) and their levels fell below 500 mM by 4 and 8 h post-treatment, respectively. Outcomes of these NGC-treated patients were not improved over previously reported PA patients who did not receive NCG: two died during the initial episode and one after his third metabolic decompensation at 46 days. The survivor is now 3 years old and has a well-controlled seizure disorder and a mild developmental delay mostly in language. We conclude that despite a trial of NCG and a rapid fall in plasma ammonia, the short-term outcome of these patients was not improved.

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Isolation and Characterization of a Naturally Occurring Stimulator of Citrulline Biosynthesis

Cited by 38 publications

References 5 publications

Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene

Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene

N-Acetylglutamate Content in Liver and Gut of Normal and Fasted Mice, Normal Human Livers, and Livers of Individuals with Carbamyl Phosphate Synthetase or Ornithine Transcarbamylase Deficiency

Short-Term Outcome of Propionic Aciduria Treated at Presentation with N-Carbamylglutamate: A Retrospective Review of Four Patients

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