Abidi Iram, Kocev Alexander N, Babulic Jonathan L, Capicciotti Chantelle J, Walia Jagdeep, Brockhausen Inka
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
Department of Chemistry, Queen's University, Kingston, ON K7L 3N6, Canada.
Molecules. 2025 Sep 4;30(17):3615. doi: 10.3390/molecules30173615.
Gangliosides are essential for membrane functions, cell recognition, and maintenance of the nervous system. GM2 gangliosidosis is a group of rare genetic lysosomal storage diseases that includes Tay-Sachs disease (TSD), Sandhoff disease (SD), and AB variant. TSD and SD are characterized by deficient β-N-acetyl-hexosaminidase activity. This leads to decreased catabolism of β-N-acetyl-hexosamine-containing ganglioside GM2 in the lysosomes, damage to cells and tissues, and severe neurological symptoms. GM2 is a major ganglioside accumulating in TSD and SD, and is synthesized from GM3 by β1,4-N-acetylgalactosaminyltransferase 1 (B4GALNT1, GM2 synthase). Therapies under development for GM2 gangliosidosis include adeno-associated virus gene therapy, enzyme replacement, and substrate reduction therapy (SRT). The goal of this work was to express and purify human B4GALNT1, characterize its activity, and explore its structural features by protein modeling and substrate docking. We used a panel of synthetic compounds to study their potential inhibition of B4GALNT1 activity. This work can serve to develop SRT for GM2 gangliosidosis.
神经节苷脂对于膜功能、细胞识别及神经系统维持至关重要。GM2神经节苷脂沉积症是一组罕见的遗传性溶酶体贮积病，包括泰-萨克斯病（TSD）、桑德霍夫病（SD）及AB变异型。TSD和SD的特征是β-N-乙酰己糖胺酶活性缺乏。这导致溶酶体中含β-N-乙酰己糖胺的神经节苷脂GM2分解代谢减少，细胞和组织受损，以及严重的神经症状。GM2是TSD和SD中蓄积的主要神经节苷脂，由β1,4-N-乙酰半乳糖胺基转移酶1（B4GALNT1，GM2合酶）从GM3合成。正在研发的GM2神经节苷脂沉积症治疗方法包括腺相关病毒基因治疗、酶替代疗法及底物减少疗法（SRT）。本研究的目的是表达并纯化人B4GALNT1，表征其活性，并通过蛋白质建模和底物对接探索其结构特征。我们使用一组合成化合物研究它们对B4GALNT1活性的潜在抑制作用。这项工作有助于开发针对GM2神经节苷脂沉积症的SRT。
