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

• 成果类型: Article
• 署名作者: Jacobs, Jean; Lyubenova, Hristiana; Potelle, Sven; Kopp, Johannes; Gerin, Isabelle; Chan, Wing Lee; Rodriguez de los Santos, Miguel; Hulsemann, Wiebke; Mensah, Martin A.; Cormier-Daire, Valerie; Joosten, Marieke; Bruggenwirth, Hennie T.; Stuurman, Kyra E.; Miranda, Valancy; Campeau, Philippe M.; Wittler, Lars; Graff, Julie; Mundlos, Stefan; Ibrahim, Daniel M.; Van Schaftingen, Emile; Fischer-Zirnsak, Bjorn; Kornak, Uwe; Ehmke, Nadja; Bommer, Guido T.
• 署名单位: Universite Catholique Louvain; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; Max Planck Society; Free University of Berlin; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Icahn School of Medicine at Mount Sinai; University of Hamburg; University Medical Center Hamburg-Eppendorf; Helios Kliniken; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Necker-Enfants Malades - APHP; Erasmus University Rotterdam; Erasmus MC; Universite de Montreal; Centre Hospitalier Universitaire Sainte-Justine; University of Gottingen; University of Gottingen Hospital; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09397-x
• 发表日期: 2025-10-02
• 关键词: catel-manzke syndrome; 11-beta-hydroxysteroid dehydrogenase type-1; d-xylose synthase; hexose-6-phosphate dehydrogenase; liquid-chromatography; escherichia-coli; mass spectrometry; mutations; nucleotide; variants

摘要

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.