A missing enzyme-rescue metabolite as cause of a rare skeletal dysplasia

Jean Jacobs, Hristiana Lyubenova, Sven Potelle, Johannes Kopp, Isabelle Gerin, Wing Lee Chan, Miguel Rodriguez de los Santos, Wiebke Hülsemann, Martin A. Mensah, Valérie Cormier-Daire, Marieke Joosten, Hennie T. Bruggenwirth, Kyra E. Stuurman, Valancy Miranda, Philippe M. Campeau, Lars Wittler, Julie Graff, Stefan Mundlos, Daniel M. Ibrahim, Emile Van Schaftingen, Björn Fischer-Zirnsak, Uwe Kornak, Nadja Ehmke () and Guido T. Bommer ()
Additional contact information
Jean Jacobs: UCLouvain
Hristiana Lyubenova: corporate member of Freie Universität Berlin and Humboldt–Universität zu Berlin
Sven Potelle: UCLouvain
Johannes Kopp: corporate member of Freie Universität Berlin and Humboldt–Universität zu Berlin
Isabelle Gerin: UCLouvain
Wing Lee Chan: Charité Universitätsmedizin Berlin
Miguel Rodriguez de los Santos: corporate member of Freie Universität Berlin and Humboldt–Universität zu Berlin
Wiebke Hülsemann: Children’s Hospital Wilhelmstift
Martin A. Mensah: corporate member of Freie Universität Berlin and Humboldt–Universität zu Berlin
Valérie Cormier-Daire: Imagine Institute
Marieke Joosten: Erasmus University Medical Center
Hennie T. Bruggenwirth: Erasmus University Medical Center
Kyra E. Stuurman: Erasmus University Medical Center
Valancy Miranda: CHU Sainte-Justine
Philippe M. Campeau: CHU Sainte-Justine
Lars Wittler: Max Planck Institute for Molecular Genetics
Julie Graff: UCLouvain
Stefan Mundlos: corporate member of Freie Universität Berlin and Humboldt–Universität zu Berlin
Daniel M. Ibrahim: Max Planck Institute for Molecular Genetics
Emile Van Schaftingen: UCLouvain
Björn Fischer-Zirnsak: corporate member of Freie Universität Berlin and Humboldt–Universität zu Berlin
Uwe Kornak: University Medical Center Göttingen
Nadja Ehmke: corporate member of Freie Universität Berlin and Humboldt–Universität zu Berlin
Guido T. Bommer: UCLouvain

Nature, 2025, vol. 646, issue 8083, 218-226

Abstract: Abstract Living cells depend on an intricate network of chemical reactions catalysed by enzymes, which sometimes make mistakes that lead to their inactivation. Here we report a metabolite-based mechanism for preserving enzyme function in an unfavourable environment. We found that the enzyme TGDS produces UDP-4-keto-6-deoxyglucose, a mimic of the reaction intermediate of the enzyme UXS1, which regenerates the essential cofactor NAD+ within the catalytic pocket of UXS1 by completing its catalytic cycle. Thus, the production of an ‘enzyme-rescue metabolite’ by TGDS represents a mechanism for maintaining the activity of an enzyme in a subcellular compartment where NAD+ is scarce. Using a combination of in vitro and in vivo studies, we demonstrate that the inability to produce sufficient amounts of this enzyme-rescue metabolite leads to the inactivation of UXS1, impairing the synthesis of specific glycans that are crucial for skeletal development. This provides an explanation for the development of the hereditary skeletal disorder Catel–Manzke syndrome in individuals with TGDS deficiency. Defects in similar protective layers might contribute to metabolic changes in other diseases that cannot be explained with common concepts in metabolic biochemistry.

Date: 2025
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DOI: 10.1038/s41586-025-09397-x

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