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

Leandro R Soria (Lead / Corresponding author), 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 HäberleDaan M. F. van Aalten, Nicola Brunetti-Pierri (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

2 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article number5212
Number of pages14
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - 5 Sep 2022

Keywords

  • Acetylglucosamine
  • Ammonia/metabolism
  • Animals
  • Carbamoyl-Phosphate Synthase (Ammonia)/genetics
  • Disease Models, Animal
  • Hyperammonemia/genetics
  • Mammals/metabolism
  • Mice
  • N-Acetylglucosaminyltransferases/genetics
  • Propionic Acidemia
  • Protein Processing, Post-Translational
  • Urea/metabolism
  • Uridine Diphosphate/metabolism

Fingerprint

Dive into the research topics of 'O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis'. Together they form a unique fingerprint.

Cite this