The 1.9 Å structure of α-N-acetylgalactosaminidase: molecular basis of glycosidase deficiency diseases

摘要: In the lysosome, glycosidases degrade glycolipids, glycoproteins, and oligosaccharides. Mutations in glycosidases cause disorders characterized by the deposition of undegraded carbohydrates. Schindler and Fabry diseases are caused by the incomplete degradation of carbohydrates with terminal α-N-acetylgalactosamine and α-galactose, respectively. Here we present the X-ray structure of α-N-acetylgalactosaminidase (α-NAGAL), the glycosidase that removes α-N-acetylgalactosamine, and the structure with bound ligand. The active site residues of α-NAGAL are conserved in the closely related enzyme α-galactosidase A (α-GAL). The structure demonstrates the catalytic mechanisms of both enzymes and reveals the structural basis of mutations causing Schindler and Fabry diseases. As α-NAGAL and α-GAL produce type O "universal donor" blood from type A and type B blood, the α-NAGAL structure will aid in …