Thermodynamic and structural study on the interaction of an enzyme and a substrate analogue for development of new therapy for lysosomal diseases

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To obtain basic information useful for development of chaperone therapy for Fabry disease and Pompe disease, we examined the molecular interactions between α-galactosidase A /acid α-glucosidase and their substrate analogues by means of isothermal titration calorimetry and surface plasmon resonance biosensor assays, and first determined the thermodynamic and binding-kinetics parameters. Furthermore, the structural analysis in silico revealed that the chemicals fit into the active site pocket of the enzyme molecule and undergo hydrogen bonding with residues comprising the pocket. The side chain of the chemicals is thought to be oriented towards the entrance of the pocket. On the basis of the results, we designed a new chemical that strongly stabilizes a mutant enzyme. Thermodynamic and structural studies should provide us with a lot of information for improving chaperone therapy for Fabry disease and Pompe disease.