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

Author

Listed:
  • 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
    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
    Federico II University
    University of Naples Federico II)

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.

Suggested Citation

  • Leandro R. Soria & Georgios Makris & Alfonso M. D’Alessio & Angela Angelis & Iolanda Boffa & Veronica M. Pravata & Véronique Rüfenacht & Sergio Attanasio & Edoardo Nusco & Paola Arena & Andrew T. Fere, 2022. "O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32904-x
    DOI: 10.1038/s41467-022-32904-x
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    References listed on IDEAS

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    Cited by:

    1. Jian-Hui Shi & Yu-Xia Chen & Yingying Feng & Xiaohang Yang & Jie Lin & Ting Wang & Chun-Chun Wei & Xian-Hua Ma & Rui Yang & Dongmei Cao & Hai Zhang & Xiangyang Xie & Zhifang Xie & Weiping J. Zhang, 2023. "Fructose overconsumption impairs hepatic manganese homeostasis and ammonia disposal," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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