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N-carbamoylglutamate-responsive carbamoyl phosphate synthetase 1 (CPS1) deficiency: A patient with a novel CPS1 mutation and an experimental study on the mutation's effects.

ABSTRACT: N-carbamoyl-l-glutamate (NCG), the N-acetyl-l-glutamate analogue used to treat N-acetylglutamate synthase deficiency, has been proposed as potential therapy of carbamoyl phosphate synthetase 1 deficiency (CPS1D). Previous findings in five CPS1D patients suggest that NCG-responsiveness could be mutation-specific. We report on a patient with CPS1D, homozygous for the novel p.(Pro1211Arg) CPS1 mutation, who presented at 9 days of life with hyperammonemic coma which was successfully treated with emergency measures. He remained metabolically stable on merely oral NCG, arginine, and modest protein restriction. Ammonia scavengers were only added after poor dietary compliance following solid food intake at age 1 year. The patient received a liver transplantation at 3.9 years of age, having normal cognitive, motor, and quality of life scores despite repeated but successfully treated episodes of hyperammonemia. Studies using recombinantly produced mutant CPS1 confirmed the partial nature of the CPS1D triggered by the p.(Pro1211Arg) mutation. This mutation decreased the solubility and yield of CPS1 as expected for increased tendency to misfold, and reduced the thermal stability, maximum specific activity (V max; ~2-fold reduction), and apparent affinity (~5-fold reduction) for ATP of the purified enzyme. By increasing the saturation of the NAG site in vivo, NCG could stabilize CPS1 and minimize the decrease in the effective affinity of the enzyme for ATP. These observations, together with prior experience, support the ascertainment of clinical responsiveness to NCG in CPS1 deficient patients, particularly when decreased stability or lowered affinity for NAG of the mutant enzyme are suspected or proven.

SUBMITTER: Yap S

PROVIDER: S-EPMC6606979 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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N-carbamoylglutamate-responsive carbamoyl phosphate synthetase 1 (CPS1) deficiency: A patient with a novel CPS1 mutation and an experimental study on the mutation's effects.

Yap Sufin S Gougeard Nadine N Hart Anthony R AR Barcelona Belén B Rubio Vicente V

JIMD reports 20190502 1

N-carbamoyl-l-glutamate (NCG), the N-acetyl-l-glutamate analogue used to treat N-acetylglutamate synthase deficiency, has been proposed as potential therapy of carbamoyl phosphate synthetase 1 deficiency (CPS1D). Previous findings in five CPS1D patients suggest that NCG-responsiveness could be mutation-specific. We report on a patient with CPS1D, homozygous for the novel p.(Pro1211Arg) CPS1 mutation, who presented at 9 days of life with hyperammonemic coma which was successf ...[more]

PMID: 31392111

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Project description:The transfer of ammonia in carbamoyl phosphate synthetase (CPS) was investigated by molecular dynamics simulations and experimental characterization of mutations within the ammonia tunnel. In CPS, ammonia is derived from the hydrolysis of glutamine and this intermediate must travel approximately 45 A from the site of formation in the small subunit to the site of utilization in the large subunit. In this investigation, the migration of ammonia was analyzed from the exit of the small subunit through the large subunit where it ultimately reacts with the carboxy phosphate intermediate. Potential of mean force calculations along the transfer pathway for ammonia indicate a relatively low free-energy barrier for the translocation of ammonia. The highest barrier of 7.2 kcal/mol is found at a narrow turning gate surrounded by the side chains of Cys-232, Ala-251, and Ala-314 in the large subunit. The environment of the ammonia tunnel from the exit of the small subunit to the turning gate in the tunnel is filled with clusters of water molecules and the ammonia is able to travel through this area easily. After ammonia passes through the turning gate, it enters a hydrophobic passage. A hydrogen bond then forms between the ammonia and Thr-249, which facilitates the delivery to a more hydrophilic environment near the active site for the reaction with the carboxy phosphate intermediate. The transport process from the turning gate to the end of the tunnel is favored by an overall downhill free-energy potential and no free-energy barrier higher than 3 kcal/mol. A conformational change of the turning gate, caused by formation of the carboxy phosphate intermediate, is consistent with a mechanism in which the reaction between ATP and bicarbonate triggers the transport of ammonia and consequently accelerates the rate of glutamine hydrolysis in the small subunit. A blockage in the turning gate passageway was introduced by the triple mutant C232V/A251V/A314V. This mutant is unable to synthesize carbamoyl phosphate using glutamine as a nitrogen source.

Dataset Information

N-carbamoylglutamate-responsive carbamoyl phosphate synthetase 1 (CPS1) deficiency: A patient with a novel CPS1 mutation and an experimental study on the mutation's effects.

Publications

<i>N</i>-carbamoylglutamate-responsive carbamoyl phosphate synthetase 1 (CPS1) deficiency: A patient with a novel CPS1 mutation and an experimental study on the mutation's effects.

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