Journal Article

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

Motta, Andrea, Nitzahn, Matthew, Häberle, Johannes, Paris, Debora, Cuomo, Paola, Ferenbach, Andrew T., Richard, Eva, Desviat, Lourdes R., van Aalten, Daan M. F., Martínez-Pizarro, Ainhoa, Lipshutz, Gerald S., Brunetti-Pierri, Nicola, Pravata, Veronica M., Soria, Leandro R., De Angelis, Angela, Arena, Paola, Rüfenacht, Véronique, Nusco, Edoardo, D’Alessio, Alfonso M., Attanasio, Sergio, Boffa, Iolanda, Makris, Georgios

2022

Overview

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. Hyperammonemia occurs in liver diseases affecting ureagenesis, and is life-threatening. Here, the authors show that liver UDP-GlcNAc is increased during hyperammonemia, leading to O-GlcNAcylation of the rate-limiting ureagenesis enzyme CPS1, that enhanced ureagenesis and ammonia detoxification. They also showed that pharmacological increase of protein O-GlcNAcylation reduces hyperammonemia in mouse models of liver disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/44 / 13/89 / 64/110 / 64/60 / 692/308/2778 / 692/4020/4021/288/2032 / 82/1 / 82/58 / Acetylglucosamine / Ammonia / Ammonia - metabolism / Animal models / Animals / Biocatalysis / Biosynthesis / Carbamoyl phosphate / Carbamoyl-Phosphate Synthase (Ammonia) - genetics / Carbamoyl-Phosphate Synthase (Ammonia) - metabolism / Constraining / Detoxification / Disease Models, Animal / Enzymes / Glycosylation / Humanities and Social Sciences / Humans / Hyperammonemia / Hyperammonemia - genetics / Hyperammonemia - metabolism / Liver / Liver diseases / Liver failure / Mammals - metabolism / Mice / multidisciplinary / N-Acetylglucosaminyltransferases - genetics / N-Acetylglucosaminyltransferases - metabolism / Neurotoxicity / O-GlcNAcylation / Pharmacology / Post-translation / Propionic acidemia / Propionic Acidemia - genetics / Propionic Acidemia - metabolism / Protein Processing, Post-Translational - genetics / Proteins / Science / Science (multidisciplinary) / Substrates / Thioacetamide / Threonine / Urea - metabolism / Uridine Diphosphate - genetics / Uridine Diphosphate - metabolism