Jacobs Jean, Lyubenova Hristiana, Potelle Sven, Kopp Johannes, Gerin Isabelle, Chan Wing Lee, Rodriguez de Los Santos Miguel, Hülsemann Wiebke, Mensah Martin A, Cormier-Daire Valérie, 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 Björn, Kornak Uwe, Ehmke Nadja, Bommer Guido T
de Duve Institute-Biochemistry, UCLouvain, Brussels, Belgium.
Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Nature. 2025 Aug 20. doi: 10.1038/s41586-025-09397-x.
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.
活细胞依赖于由酶催化的复杂化学反应网络，而酶有时会出错导致自身失活。在此，我们报告一种基于代谢物的机制，用于在不利环境中维持酶的功能。我们发现，TGDS酶产生UDP-4-酮-6-脱氧葡萄糖，它是UXS1酶反应中间体的类似物，通过完成其催化循环在UXS1的催化口袋内再生必需的辅因子NAD。因此，TGDS产生“酶拯救代谢物”代表了一种在NAD稀缺的亚细胞区室中维持酶活性的机制。通过体外和体内研究相结合，我们证明无法产生足够量的这种酶拯救代谢物会导致UXS1失活，损害对骨骼发育至关重要的特定聚糖的合成。这为TGDS缺乏个体中遗传性骨骼疾病卡特-曼兹克综合征的发生提供了解释。类似保护层的缺陷可能导致其他疾病中无法用代谢生物化学的常见概念解释的代谢变化。
