O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis.

Life-threatening hyperammonemia occurs in both inherited and acquired liver diseases affecting ureagenesis, the main pathway for detoxification of neurotoxic ammonia in mammals. Protein O-GlcNAcylation is a reversible and nutrient-sensitive post-translational modification using as substrate UDP-GlcNAc, the end-product of hexosamine biosynthesis pathway. Here we show that increased liver UDP-GlcNAc during hyperammonemia increases protein O-GlcNAcylation and enhances ureagenesis. Mechanistically, O-GlcNAcylation on specific threonine residues increased the catalytic efficiency for ammonia of carbamoyl phosphate synthetase 1 (CPS1), the rate-limiting enzyme in ureagenesis. Pharmacological inhibition of O-GlcNAcase, the enzyme removing O-GlcNAc from proteins, resulted in clinically relevant reductions of systemic ammonia in both genetic (hypomorphic mouse model of propionic acidemia) and acquired (thioacetamide-induced acute liver failure) mouse models of liver diseases. In conclusion, by fine-tuned control of ammonia entry into ureagenesis, hepatic O-GlcNAcylation of CPS1 increases ammonia detoxification and is a novel target for therapy of hyperammonemia in both genetic and acquired diseases. © 2022. The Author(s).

Citation

Leandro R Soria, Georgios Makris, Alfonso M D'Alessio, Angela De Angelis, Iolanda Boffa, Veronica M Pravata, Véronique Rüfenacht, Sergio Attanasio, Edoardo Nusco, Paola Arena, Andrew T Ferenbach, Debora Paris, Paola Cuomo, Andrea Motta, Matthew Nitzahn, Gerald S Lipshutz, Ainhoa Martínez-Pizarro, Eva Richard, Lourdes R Desviat, Johannes Häberle, Daan M F van Aalten, Nicola Brunetti-Pierri. O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis. Nature communications. 2022 Sep 05;13(1):5212

Mesh Tags

Substances

PMID: 36064721

search → result