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

Nat Commun. 2022 Sep 5;13(1):5212. doi: 10.1038/s41467-022-32904-x.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

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


  • Uridine Diphosphate
  • Ammonia
  • Urea
  • N-Acetylglucosaminyltransferases
  • CPS1 protein, human
  • Carbamoyl-Phosphate Synthase (Ammonia)
  • Acetylglucosamine