Insights into mucopolysaccharidosis I from the structure and action of α- L -iduronidase

摘要: Mucopolysaccharidosis type I (MPS I), caused by mutations in the gene encoding α-L-iduronidase (IDUA), is one of approximately 70 genetic disorders collectively known as lysosomal storage diseases. To gain insight into basis for MPS I, we crystallized human IDUA produced an Arabidopsis thaliana cgl mutant. consists a TIM barrel domain containing catalytic site, β-sandwich and fibronectin-like domain. Structures bound to iduronate analogs illustrate Michaelis complex reveal (2,5)B conformation glycosyl-enzyme intermediate, which suggest retaining double displacement reaction involving nucleophilic Glu299 general acid/base Glu182. Unexpectedly, N-glycan attached Asn372 interacts with active site required enzymatic activity. Finally, these structures biochemical analysis disease-relevant P533R mutation have enabled us correlate effects clinical phenotypes.