Arginine activation of <i>N</i>‐acetylglutamate synthetase in mouse liver

Kawamoto, Susumu; Tatibana, Masamiti

doi:10.1016/0014-5793(83)80355-x

Cited by 6 publications

(1 citation statement)

References 18 publications

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“…We reported that the sensitivity of acetylglutamate synthetase in mouse liver to arginine activation undergoes marked changes after ingestion offood (Kawamoto et al, 1982) and injection of inhibitors of nucleic acid and protein synthesis (Kawamoto & Tatibana, 1983). Correlations between the extent of arginine activation of acetylglutamate synthesis in isolated mitochondria and the sensitivity to arginine activation of acetylglutamate synthetase, extracted from the mitochondria, were also examined (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Stimulatory effect of arginine on acetylglutamate synthesis in isolated mitochondria of mouse and rat liver

Kawamoto¹,

Sonoda²,

Ohtake³

et al. 1985

Biochemical Journal

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N-Acetyl-L-glutamate synthetase (EC 2.3.1.1) catalyses the synthesis of N-acetyl-L-glutamate, an allosteric activator of carbamoyl-phosphate synthetase I in the liver of ureotelic animals, and the first enzyme is activated specifically by arginine. We have proposed that arginine can stimulate acetylglutamine synthetase in vivo and thereby increase the mitochondrial content of acetylglutamate. The effects of arginine on acetylglutamate synthesis in isolated mitochondria were investigated in detail in the present work. When rat liver mitochondria were isolated and incubated with [14C]glutamate and unlabelled acetate as substrates, acetyl[14C]glutamate synthesis in the mitochondria was more extensive in the presence than in the absence of L-arginine. There was no significant difference between the specific radioactivities of intramitochondrial [14C]glutamate in the presence and absence of arginine. When rat liver mitochondria were incubated with [14C]acetate and unlabelled glutamate as substrates, arginine also stimulated acetyl[14C]glutamate synthesis in the isolated mitochondria. L-Lysine or L-homoarginine, which does not activate acetylglutamate synthetase, had no effect on acetylglutamate synthesis, in the isolated mitochondria. The arginine concentration giving half-maximal synthesis of acetylglutamate in isolated mitochondria was about 50 microM, which is in the range of physiological concentrations of arginine in the liver. As we previously reported [Kawamoto, Ishida, Mori & Tatibana (1982) Eur. J. Biochem. 123, 637-641], the sensitivity of acetylglutamate synthetase to arginine activation undergoes marked changes after food ingestion. The extent of arginine activation of acetylglutamate synthesis in isolated mitochondria correlated well with the sensitivity of acetylglutamate synthetase extracted from the mitochondria to arginine activation. These data lend further support to the idea that arginine itself activates the mitochondrial synthesis of acetylglutamate.

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Section: Resultsmentioning

confidence: 99%

Stimulatory effect of arginine on acetylglutamate synthesis in isolated mitochondria of mouse and rat liver

Kawamoto¹,

Sonoda²,

Ohtake³

et al. 1985

Biochemical Journal

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Use of pure recombinant human enzymes to assess the disease‐causing potential of missense mutations in urea cycle disorders, applied to N‐acetylglutamate synthase deficiency

Gougeard,

Sancho‐Vaello,

Fernández‐Murga

et al. 2024

J of Inher Metab Disea

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N‐acetylglutamate synthase (NAGS) makes acetylglutamate, the essential activator of the first, regulatory enzyme of the urea cycle, carbamoyl phosphate synthetase 1 (CPS1). NAGS deficiency (NAGSD) and CPS1 deficiency (CPS1D) present identical phenotypes. However, they must be distinguished, because NAGSD is cured by substitutive therapy with the N‐acetyl‐L‐glutamate analogue N‐carbamyl‐L‐glutamate, while curative therapy of CPS1D requires liver transplantation. Since their differentiation is done genetically, it is important to ascertain the disease‐causing potential of CPS1 and NAGS genetic variants. With this goal, we previously carried out site‐directed mutagenesis studies with pure recombinant human CPS1. We could not do the same with human NAGS (HuNAGS) because of enzyme instability, leading to our prior utilization of a bacterial NAGS as an imperfect surrogate of HuNAGS. We now use genuine HuNAGS, stabilized as a chimera of its conserved domain (cHuNAGS) with the maltose binding protein (MBP), and produced in Escherichia coli. MBP‐cHuNAGS linker cleavage allowed assessment of the enzymatic properties and thermal stability of cHuNAGS, either wild‐type or hosting each one of 23 nonsynonymous single‐base changes found in NAGSD patients. For all but one change, disease causation was accounted by the enzymatic alterations identified, including, depending on the variant, loss of arginine activation, increased KmGlutamate, active site inactivation, decreased thermal stability, and protein misfolding. Our present approach outperforms experimental in vitro use of bacterial NAGS or in silico utilization of prediction servers (including AlphaMissense), illustrating with HuNAGS the value for UCDs of using recombinant enzymes for assessing disease‐causation and molecular pathogenesis, and for therapeutic guidance.

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The mechanism of the arginine dependent function in adenovirus type-2 infected cells: Late viral polypeptides are under-acetylated

Auborn

Rouse

1984

Virus Research

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Arginine activation of N‐acetylglutamate synthetase in mouse liver

Cited by 6 publications

References 18 publications

Stimulatory effect of arginine on acetylglutamate synthesis in isolated mitochondria of mouse and rat liver

Stimulatory effect of arginine on acetylglutamate synthesis in isolated mitochondria of mouse and rat liver

Use of pure recombinant human enzymes to assess the disease‐causing potential of missense mutations in urea cycle disorders, applied to N‐acetylglutamate synthase deficiency

The mechanism of the arginine dependent function in adenovirus type-2 infected cells: Late viral polypeptides are under-acetylated

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