Structural comparison of differently glycosylated forms of acid-β-glucosidase, the defective enzyme in Gaucher disease
Structural comparison of differently glycosylated forms of acid-β-glucosidase, the defective enzyme in Gaucher disease
复制标题
DOI：
10.1107/s0907444906038303
复制
发表时间：
2006-12-01
影响因子：
2.2
通讯作者：
Sussman, Joel L.
中科院分区：
文献类型：
--
作者：
Brumshtein, Boris;Wormald, Mark R.;Sussman, Joel L.
戈谢病是由编码酸性β-葡萄糖苷酶的基因突变引起的。这种酶的一种重组形式，思而赞，被用于通过“酶替代疗法”治疗戈谢病患者。较早获得了部分去糖基化后的Cerezyme（R）晶体，并将结构解析至2.0埃分辨率[Dvir等（2003），EMBO Rep.4，704 - 709]。现在报道了未修饰的Cerezyme 1的晶体结构，其中可以看到大量的糖残基通过N-糖基化与三个天冬酰胺结合。完整的完全糖基化Cerezyme（（R））的结构与部分去糖基化酶的结构几乎相同。然而，在活性位点的入口处的三个环，这是以前观察到的替代构象，显示其结构的额外的可变性。酸性-β-葡糖苷酶与木聚糖酶（一种来自密切相关的蛋白质家族的细菌酶）的结构的比较证明了两种酶的活性位点残基之间的密切对应。
Gaucher disease is caused by mutations in the gene encoding acid-beta-glucosidase. A recombinant form of this enzyme, Cerezyme((R)), is used to treat Gaucher disease patients by 'enzyme- replacement therapy'. Crystals of Cerezyme((R)) after its partial deglycosylation were obtained earlier and the structure was solved to 2.0 angstrom resolution [Dvir et al. (2003), EMBO Rep. 4, 704 - 709]. The crystal structure of unmodified Cerezyme1 is now reported, in which a substantial number of sugar residues bound to three asparagines via N-glycosylation could be visualized. The structure of intact fully glycosylated Cerezyme((R)) is virtually identical to that of the partially deglycosylated enzyme. However, the three loops at the entrance to the active site, which were previously observed in alternative conformations, display additional variability in their structures. Comparison of the structure of acid-beta-glucosidase with that of xylanase, a bacterial enzyme from a closely related protein family, demonstrates a close correspondence between the active-site residues of the two enzymes.