Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria. A possible explanation for hyperammonemia in propionic and methylmalonic acidemia.

Coudé, F. X.; Sweetman, Lawrence; Nyhan, William L.

doi:10.1172/jci109614

Cited by 199 publications

(99 citation statements)

References 36 publications

(28 reference statements)

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“…Notably, ureagenesis in methylmalonic and propionic aciduria is disturbed due to propionyl-CoA-induced inhibition of N-acetylglutamate synthetase, resulting in decreased N-acetylglutamate, the required allosteric activator of carbamoylphospate synthase I (46,47). In line with this, hyperammonemia is a frequent finding in methylmalonic aciduria (1).…”

Section: Discussionmentioning

confidence: 98%

Neurodegeneration in Methylmalonic Aciduria Involves Inhibition of Complex II and the Tricarboxylic Acid Cycle, and Synergistically Acting Excitotoxicity

Okun¹,

Hörster²,

Farkas³

et al. 2002

Journal of Biological Chemistry

162

151

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Methylmalonic acidurias are biochemically characterized by an accumulation of methylmalonate (MMA) and alternative metabolites. There is growing evidence for basal ganglia degeneration in these patients. The pathomechanisms involved are still unknown, a contribution of toxic organic acids, in particular MMA, has been suggested. Here we report that MMA induces neuronal damage in cultures of embryonic rat striatal cells at a concentration range encountered in affected patients. MMA-induced cell damage was reduced by ionotropic glutamate receptor antagonists, antioxidants, and succinate. These results suggest the involvement of secondary excitotoxic mechanisms in MMA-induced cell damage. MMA has been implicated in inhibition of respiratory chain complex II. However, MMA failed to inhibit complex II activity in submitochondrial particles from bovine heart. To unravel the mechanism underlying neuronal MMA toxicity, we investigated the formation of intracellular metabolites in MMA-loaded striatal neurons. There was a time-dependent intracellular increase in malonate, an inhibitor of complex II, and 2-methylcitrate, a compound with multiple inhibitory effects on the tricarboxylic acid cycle, suggesting their putative implication in MMA neurotoxicity. We propose that neuropathogenesis of methylmalonic aciduria may involve an inhibition of complex II and the tricarboxylic acid cycle by accumulating toxic organic acids, and synergistic secondary excitotoxic mechanisms.

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Section: Discussionmentioning

confidence: 98%

Neurodegeneration in Methylmalonic Aciduria Involves Inhibition of Complex II and the Tricarboxylic Acid Cycle, and Synergistically Acting Excitotoxicity

Okun¹,

Hörster²,

Farkas³

et al. 2002

Journal of Biological Chemistry

162

151

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“…Factors known to be involved in the control of acetylglutamate synthetase activity are the intracellular levels of glutamate and acetyl-CoA [3], substrates, the concentrations of competitive inhibitors, such as propionyl-CoA [20], the hepatic content of arginine [3], a specific activator of the synthetase and the changes in sensitivity of the synthetase to arginine activation [ 191. It was also found [19] that cycloheximide injection, which inhibited the total protein synthesis in the mouse liver by 90070, did not inhibit the postprandial increase in arginine activation of the synthetase, thus indicating that the protein synthesis is not required for the change; actually cycloheximide stimulated the increase to a significant extent.…”

Section: Discussionmentioning

confidence: 99%

Arginine activation of N‐acetylglutamate synthetase in mouse liver

Kawamoto

Tatibana

1983

FEBS Letters

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N‐Acetyl‐L‐glutamate sythetase catalyzes the synthesis of N‐acetyl‐L‐glutamate, an allosteric and esential activator of carbamoyl‐phosphate synthetase I in the liver of ureotelic animals. The enzyme is activated specifically by arginine. We report here that the sensitivity of the synthetase to activation by arginine increases markedly after intraperitoneal administration to mice of inhibitors of nucleic acid and protein synthesis, including actinomycin D, aurintricarboxylic acid, cycloheximide, emetine and puromycin. The effects of cycloheximide were investigated in detail and an amino acid analysis was made of the homogenate of freeze‐clamped livers of control or cycloheximide‐treated mice.

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“…For instance, in propionic acidemia (PA), or a congenital deficiency of propionyl-CoA carboxylase, a decrease in NAG synthesis may occur either from competitive inhibition of NAGS by propionyl-CoA [29][30][31][32] or a relative depletion of hepatic acetyl-CoA or free coenzyme A [32]. Individual case reports suggest that NCG is helpful in the treatment of PA [33][34][35][36][37], but these are uncontrolled studies performed during an acute illness in which the effect of NCG is difficult to differentiate from that of standard care.…”

Section: Evaluating the Efficacy Of Therapeuticsmentioning

confidence: 99%

Stable isotopes in the diagnosis and treatment of inherited hyperammonemia

Tuchman

Mew

2016

J Pediatr Biochem

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Stable isotopes have greatly contributed to our understanding of nitrogen metabolism and the urea cycle. The measurement of urea flux via isotopic methods has traditionally been utilized to determine total body protein synthesis in subjects with an intact urea cycle. However, isotopic studies of nitrogen metabolism are also a useful adjunct to conventional clinical investigations in the diagnosis and management of the inherited hyperammonemias. Such studies offer a safe noninvasive method of measuring the reduction of in vivo hepatic ureagenesis, and thus may provide a more accurate measure of phenotypic severity in affected patients. In addition, isotopic methods are ideally suited to evaluate the efficacy of novel therapies to augment urea production.

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Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria. A possible explanation for hyperammonemia in propionic and methylmalonic acidemia.

Cited by 199 publications

References 36 publications

Neurodegeneration in Methylmalonic Aciduria Involves Inhibition of Complex II and the Tricarboxylic Acid Cycle, and Synergistically Acting Excitotoxicity

Neurodegeneration in Methylmalonic Aciduria Involves Inhibition of Complex II and the Tricarboxylic Acid Cycle, and Synergistically Acting Excitotoxicity

Arginine activation of N‐acetylglutamate synthetase in mouse liver

Stable isotopes in the diagnosis and treatment of inherited hyperammonemia

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