O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis
Leandro R. Soria (l.soria@tigem.it),
Georgios Makris,
Alfonso M. D’Alessio,
Angela 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. Aalten and
Nicola Brunetti-Pierri (brunetti@tigem.it)
Additional contact information
Leandro R. Soria: Telethon Institute of Genetics and Medicine
Georgios Makris: University Children’s Hospital
Alfonso M. D’Alessio: Telethon Institute of Genetics and Medicine
Angela Angelis: Telethon Institute of Genetics and Medicine
Iolanda Boffa: Telethon Institute of Genetics and Medicine
Veronica M. Pravata: University of Dundee
Véronique Rüfenacht: University Children’s Hospital
Sergio Attanasio: Telethon Institute of Genetics and Medicine
Edoardo Nusco: Telethon Institute of Genetics and Medicine
Paola Arena: Telethon Institute of Genetics and Medicine
Andrew T. Ferenbach: University of Dundee
Debora Paris: National Research Council
Paola Cuomo: National Research Council
Andrea Motta: National Research Council
Matthew Nitzahn: David Geffen School of Medicine at UCLA
Gerald S. Lipshutz: David Geffen School of Medicine at UCLA
Ainhoa Martínez-Pizarro: Universidad Autónoma
Eva Richard: Universidad Autónoma
Lourdes R. Desviat: Universidad Autónoma
Johannes Häberle: University Children’s Hospital
Daan M. F. Aalten: University of Dundee
Nicola Brunetti-Pierri: Telethon Institute of Genetics and Medicine
Nature Communications, 2022, vol. 13, issue 1, 1-14
Abstract:
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.
Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32904-x
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DOI: 10.1038/s41467-022-32904-x
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