Garman Scott C, Garboczi David N
Structural Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Twinbrook II, 12441 Parklawn Drive, Rockville, MD 20852,
Mol Genet Metab. 2002 Sep-Oct;77(1-2):3-11. doi: 10.1016/s1096-7192(02)00151-8.
Fabry disease is a lysosomal storage disease caused by deficiency in the enzyme alpha-galactosidase (alpha-GAL). To understand the molecular defects responsible for Fabry disease, we have collected more than 190 reported point and stop mutations and mapped them onto a model of human alpha-GAL based on the X-ray structure of the closely related enzyme alpha-N-acetylgalactosaminidase (alpha-NAGAL). The locations of the human alpha-GAL point mutations reveal two major classes of Fabry disease protein defects: active site mutations and folding mutations. Active site mutations reduce enzymatic activity by perturbing the active site without necessarily affecting the overall alpha-GAL structure. Folding mutations reduce the stability of alpha-GAL by disrupting its hydrophobic core. Examining the frequency of mutation around each alpha-GAL residue identifies the active site as a hotspot for mutations leading to Fabry disease. This study furthers our understanding of the structural basis for mutations leading to Fabry disease, from which new avenues for the treatment of lysosomal storage diseases may be developed.
法布里病是一种溶酶体贮积病，由α - 半乳糖苷酶（α - GAL）缺乏引起。为了解法布里病的分子缺陷，我们收集了190多个已报道的点突变和终止突变，并将它们映射到基于密切相关的酶α - N - 乙酰半乳糖胺酶（α - NAGAL）的X射线结构构建的人类α - GAL模型上。人类α - GAL点突变的位置揭示了法布里病蛋白质缺陷的两大主要类型：活性位点突变和折叠突变。活性位点突变通过扰乱活性位点来降低酶活性，而不一定影响α - GAL的整体结构。折叠突变通过破坏α - GAL的疏水核心来降低其稳定性。检查每个α - GAL残基周围的突变频率发现活性位点是导致法布里病的突变热点。这项研究加深了我们对导致法布里病的突变结构基础的理解，从中可能开发出治疗溶酶体贮积病的新途径。
