比利时德杜夫生物化学研究所Guido T. Bommer小组取得一项新突破。他们研究出一种罕见的骨骼发育不良的原因是缺少一种酶援救代谢物。相关论文于2025年8月20日发表在《自然》杂志上。

在这里，该课题组研究人员报告了一种在不利环境中保持酶功能的基于代谢物的机制。该团队发现TGDS酶产生 UDP-4-酮-6-脱氧葡萄糖，这是UXS1酶的一种模拟反应中间体，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产生的“酶救援代谢物”代表了一种在缺乏NAD⁺的亚细胞区室中维持酶活性的机制。通过体外和体内研究的结合，该团队证明无法产生足够数量的这种酶救援代谢物导致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缺乏个体的遗传性骨骼疾病Catel-Manzke综合征的发展提供了解释。类似保护层的缺陷可能导致其他疾病的代谢变化，而这些疾病无法用代谢生物化学的常见概念来解释。

据介绍，活细胞依赖于一个由酶催化的复杂的化学反应网络，酶有时会犯错误，导致细胞失活。

附：英文原文

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

Author: Jacobs, Jean, Lyubenova, Hristiana, Potelle, Sven, Kopp, Johannes, Gerin, Isabelle, Chan, Wing Lee, Rodriguez de los Santos, Miguel, Hlsemann, Wiebke, Mensah, Martin A., Cormier-Daire, Valrie, 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, Bjrn, Kornak, Uwe, Ehmke, Nadja, Bommer, Guido T.

Issue&Volume: 2025-08-20

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.

DOI: 10.1038/s41586-025-09397-x

Source: https://www.nature.com/articles/s41586-025-09397-x