Abstract：
Lysosomal acid sphingomyelinase (ASM), a critical enzyme in lipid metabolism encoded by the SMPD1 gene, plays a crucial role in sphingomyelin hydrolysis in lysosomes. ASM deficiency leads to acid sphingomyelinase deficiency, a rare genetic disorder with diverse clinical manifestations, and the protein can be found mutated in other diseases. We employed a structure-based framework to comprehensively understand the functional implications of ASM variants, integrating pathogenicity predictions with molecular insights derived from a molecular dynamics simulation in a lysosomal membrane environment. Our analysis, encompassing over 400 variants, establishes a structural atlas of missense variants of lysosomal ASM, associating mechanistic indicators with pathogenic potential. Our study highlights variants that influence structural stability or exert local and long-range effects at functional sites. To validate our predictions, we compared them to available experimental data on residual catalytic activity in 135 ASM variants. Notably, our findings also suggest applications of the resulting data for identifying cases suited for enzyme replacement therapy. This comprehensive approach enhances the understanding of ASM variants and provides valuable insights for potential therapeutic interventions.
摘要：
溶酶体酸性鞘磷脂酶(ASM),由SMPD1基因编码的脂质代谢中的关键酶，在溶酶体鞘磷脂水解中起着至关重要的作用。ASM缺乏导致酸性鞘磷脂酶缺乏，一种罕见的遗传性疾病，临床表现多样，这种蛋白质可以在其他疾病中发现突变。我们采用了基于结构的框架来全面理解ASM变体的功能含义，将致病性预测与来自溶酶体膜环境中分子动力学模拟的分子见解相结合。我们的分析,包含400多种变体，建立了溶酶体ASM错义变体的结构图谱，将机理指标与致病潜力相关联。我们的研究强调了影响结构稳定性或在功能部位施加局部和长期影响的变体。为了验证我们的预测，我们将它们与135种ASM变体中残留催化活性的可用实验数据进行了比较。值得注意的是,我们的研究结果还建议将所得数据应用于鉴定适合酶替代疗法的病例.这种全面的方法增强了对ASM变体的理解，并为潜在的治疗干预措施提供了有价值的见解。
