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