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1.
Sci Rep ; 11(1): 3580, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33574402

RESUMEN

The urea cycle protects the central nervous system from ammonia toxicity by converting ammonia to urea. N-acetylglutamate synthase (NAGS) catalyzes formation of N-acetylglutamate, an essential allosteric activator of carbamylphosphate synthetase 1. Enzymatic activity of mammalian NAGS doubles in the presence of L-arginine, but the physiological significance of NAGS activation by L-arginine has been unknown. The NAGS knockout (Nags-/-) mouse is an animal model of inducible hyperammonemia, which develops hyperammonemia without N-carbamylglutamate and L-citrulline supplementation (NCG + Cit). We used adeno associated virus (AAV) based gene transfer to correct NAGS deficiency in the Nags-/- mice, established the dose of the vector needed to rescue Nags-/- mice from hyperammonemia and measured expression levels of Nags mRNA and NAGS protein in the livers of rescued animals. This methodology was used to investigate the effect of L-arginine on ureagenesis in vivo by treating Nags-/- mice with AAV vectors encoding either wild-type or E354A mutant mouse NAGS (mNAGS), which is not activated by L-arginine. The Nags-/- mice expressing E354A mNAGS were viable but had elevated plasma ammonia concentration despite similar levels of the E354A and wild-type mNAGS proteins. The corresponding mutation in human NAGS (NP_694551.1:p.E360D) that abolishes binding and activation by L-arginine was identified in a patient with NAGS deficiency. Our results show that NAGS deficiency can be rescued by gene therapy, and suggest that L-arginine binding to the NAGS enzyme is essential for normal ureagenesis.


Asunto(s)
N-Acetiltransferasa de Aminoácidos/genética , Técnicas de Transferencia de Gen , Hiperamonemia/genética , Trastornos Innatos del Ciclo de la Urea/genética , N-Acetiltransferasa de Aminoácidos/metabolismo , Animales , Arginina/metabolismo , Arginina/farmacología , Citrulina/metabolismo , Citrulina/farmacología , Dependovirus/genética , Modelos Animales de Enfermedad , Glutamatos/metabolismo , Glutamatos/farmacología , Humanos , Hiperamonemia/metabolismo , Hiperamonemia/patología , Hiperamonemia/terapia , Ratones , Ratones Noqueados , Proteínas Mutantes/genética , Urea/metabolismo , Trastornos Innatos del Ciclo de la Urea/metabolismo , Trastornos Innatos del Ciclo de la Urea/patología , Trastornos Innatos del Ciclo de la Urea/terapia
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