title: Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria. A possible explanation for hyperammonemia in propionic and methylmalonic acidemia.
abstract: In the search for the mechanism by which hyperammonemia complicates propionic and methylmalonic acidemia the effects of a series of acyl-coenzyme A (CoA) derivatives were studied on the activity of N-acetylglutamate synthetase in rat liver mitochondria using acetyl-CoA as substrate. Propionyl-CoA was found to be a competitive inhibitor. The inhibition constant of 0.71 mM is in the range of concentrations of propionate found in the serum of patients with propionic and methylmalonic acidemia. Propionyl-CoA was also found to be a substrate for N-acetylglutamate synthetase, forming N-propionylglutamate. This compound was a weak activator of rat liver carbamoylphosphate synthetase; the activation constant was 1.1 mM as compared with 0.12 mM for N-acetylglutamate. A decreased level of N-acetylglutamate in liver mitochondria that would follow inhibition of N-acetylglutamate synthetase by propionyl-CoA would be expected to lead to hyperammonemia. Methylmalonyl-CoA, tiglyl-CoA, and isovaleryl-CoA at a concentration of 3 mM caused 30-70% inhibition of N-acetylglutamate synthetase. 3the latter two compounds are readily detoxified by the formation of N-acylglycine conjugates in liver, which may prevent large accumulations and could explain why hyperammonemia is not characteristic of patients with beta-ketothiolase deficiency or isovaleric acidemia in whom these compounds would be expected to be elevated.
mesh_terms: D000105:Acetyl Coenzyme A; D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000138:Acidosis / Q000378:metabolism*; D000214:Acyl Coenzyme A / Q000494:pharmacology*; D000641:Ammonia / Q000097:blood; D000818:Animals; D005971:Glutamates; D007700:Kinetics; D008314:Malonates / Q000097:blood*; D008764:Methylmalonic Acid / Q000097:blood*; D008930:Mitochondria, Liver / Q000201:enzymology*; D011422:Propionates / Q000097:blood*; D051381:Rats; D013379:Substrate Specificity
chemical_list: D000214:Acyl Coenzyme A; D005971:Glutamates; D008314:Malonates; D011422:Propionates; D000105:Acetyl Coenzyme A; D000641:Ammonia; D008764:Methylmalonic Acid; D000123:Acetyltransferases