title: Precision medicine in rare disease: Mechanisms of disparate effects of N-carbamyl-l-glutamate on mutant CPS1 enzymes.
abstract: This study documents the disparate therapeutic effect of N-carbamyl-l-glutamate (NCG) in the activation of two different disease-causing mutants of carbamyl phosphate synthetase 1 (CPS1). We investigated the effects of NCG on purified recombinant wild-type (WT) mouse CPS1 and its human corresponding E1034G (increased ureagenesis on NCG) and M792I (decreased ureagenesis on NCG) mutants. NCG activates WT CPS1 sub-optimally compared to NAG. Similar to NAG, NCG, in combination with MgATP, stabilizes the enzyme, but competes with NAG binding to the enzyme. NCG supplementation activates available E1034G mutant CPS1 molecules not bound to NAG enhancing ureagenesis. Conversely, NCG competes with NAG binding to the scarce M792I mutant enzyme further decreasing residual ureagenesis. These results correlate with the respective patient's response to NCG. Particular caution should be taken in the administration of NCG to patients with hyperammonemia before their molecular bases of their urea cycle disorders is known.
authors.affiliation: Center for Genetic Medicine Research, Department of Integrative Systems Biology, Children's Research Institute, Children's National Health System, The George Washington University, Washington, DC 20010, USA. Electronic address: dshi@childrensnational.org.
authors.forename: Dashuang
authors.initials: D
authors.lastname: Shi
authors.affiliation: Center for Genetic Medicine Research, Department of Integrative Systems Biology, Children's Research Institute, Children's National Health System, The George Washington University, Washington, DC 20010, USA.
authors.forename: Gengxiang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Center for Genetic Medicine Research, Department of Integrative Systems Biology, Children's Research Institute, Children's National Health System, The George Washington University, Washington, DC 20010, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ah Mew
authors.affiliation: Center for Genetic Medicine Research, Department of Integrative Systems Biology, Children's Research Institute, Children's National Health System, The George Washington University, Washington, DC 20010, USA.
authors.forename: Mendel
authors.initials: M
authors.lastname: Tuchman
mesh_terms: D000255:Adenosine Triphosphate / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000737:chemistry* / Q000235:genetics*; D020165:Carbamoyl-Phosphate Synthase I Deficiency Disease / Q000188:drug therapy* / Q000201:enzymology; D004359:Drug Therapy, Combination; D005260:Female; D005971:Glutamates / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D057285:Precision Medicine; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D035583:Rare Diseases / Q000188:drug therapy / Q000201:enzymology
chemical_list: D005971:Glutamates; C006895:N-carbamylglutamate; D000255:Adenosine Triphosphate; D002222:Carbamoyl-Phosphate Synthase (Ammonia)
keywords: Carbamyl phosphate synthetase 1 deficiency; Hyperammonemia; N-acetyl-l-glutamate; Urea cycle disorder, mutations