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Propionic acidemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The hyperammonemia observed in infants with propionic acidemia is a consequence of the inhibition of the urea cycle at the carbamylphosphate synthetase (CPS) step by propionyl CoA. This results from a competitive inhibition of N-acetylglutamate synthetase [72].
Metabolism of Glutamine and Glutamate in the Liver — Regulation and Physiological Significance
Published in Elling Kvamme, Glutamine and Glutamate in Mammals, 1988
Glutamate is a poor primary substrate for gluconeogenesis in the liver,” and has been assumed to penetrate the liver membrane relatively slowly (but see Section V). Glutamate is formed from the transamination of a number of amino acids with 2-oxoglutarate, and also by the metabolism of histidine, ornithine, and proline, as well as glutamine. Glutamate is also formed by the reductive amination of 2-oxoglutarate via glutamate dehydrogenase, and this reaction is of importance in urea synthesis from exogenous ammonia. Glutamate degradation proceeds either via the aminotransferase pathway as described above, or via the glutamate dehydrogenase reaction, producing ammonia and 2-oxoglutarate. A feature of glutamine and glutamate metabolism in the liver is the important role of mitochondrial enzymes in these pathways.6 Thus, glutaminase, glutamate dehydrogenase, 2-oxoglutarate dehydrogenase, glutamate-oxoaloacetate aminotransferase, ornithine transcarbamylase, proline dehydrogenase, and carbamoyl phosphate synthetase are all located in the mitochondrial matrix. A reaction of particular importance in liver mitochondria is the conversion of glutamate to N-acetylglutamate via the enzyme N-acetylglutamate synthetase. N-Acetylgluta-mate is the essential activator of carbamoyl phosphate synthetase, an enzyme which is important in the regulation of urea synthesis.
Birth weight related essential, non-essential and conditionally essential amino acid blood concentrations in 12,000 breastfed full-term infants perinatally
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2020
Penelope D. Manta-Vogli, Kleopatra H. Schulpis, Yannis L. Loukas, Yannis Dotsikas
CEAAs (Table 1) can be synthesized in adequate amounts by the organism, but in cases of preterm birth, LBW or perinatal nutritional problems that impose parenteral nutrition their quantities that can be synthesized could be quite limited [3]. Perinatally, Gln is one of the most important amino acids for energy production and gut maturity [38]. Additionally, Glu + Gln are the main precursors for intestinal Arg synthesis in neonates [30]. In this metabolic pathway, the enzymes phosphate-dependent glutaminase, OAT, arginosuccinate synthetase (ASS), arginosuccinate lyase (ASL) and aspartate aminotransferase, are widely distributed in animal tissues, whereas CPS I, OCT and N-acetyl glutamate synthase are restricted in the liver and intestinal mucosa. Proline oxidase is present mainly in the small intestine, liver and kidneys but P-5-C is located almost exclusively in the intestinal mucosa, with only trace amounts in other tissues [30].
Inherited hyperammonemias: a Contemporary view on pathogenesis and diagnosis
Published in Expert Opinion on Orphan Drugs, 2018
Evelina Maines, Giovanni Piccoli, Antonia Pascarella, Francesca Colucci, Alberto B. Burlina
The urea cycle represents the major pathway of nitrogen disposal from the body and is the unique pathway able to transform ammonia into a nontoxic product, the urea. Hosting both the mechanisms, the liver is the main player in ammonia detoxification. The urea cycle takes place exclusively in the liver, in particular in the periportal hepatocytes, and therefore is tightly related to the integrity and functionality of this organ [9]. It converts ammonia and carbon dioxide (under the form of bicarbonate) into urea and water through a five-enzymatic-step process (Figure 2). One activating enzyme (N-acetylglutamate synthase, NAGS) and two transport proteins on the mitochondrial membrane are also required: ornithine carrier (ORNT) allows ornithine (Orn) import and citrulline (Cit) export, and citrin allows export of Asp and Glu import. The urea cycle is mostly regulated by N-acetylglutamate (NAG) controlling the CPS1 activity and by the availability of Orn [5].
Recent advances towards gene therapy for propionic acidemia: translation to the clinic
Published in Expert Review of Precision Medicine and Drug Development, 2019
One of the most dangerous manifestations of the disease is hyperammonemia [4]. Hyperammonemia appears to be due to inhibition of the enzyme N-acetylglutamate synthase (NAGS) by propionyl-CoA (C3) [5,6]. Long-term outcomes on neurological development appear to be strongly determined by the peak levels and duration of hyperammonemia in PA patients [4].