PMID: 24737316

 

    Legend: Sugar

Title : Structural basis of pharmacological chaperoning for human β -galactosidase

Abstract :

1. GM1 gangliosidosis and Morquio B disease are autosomal recessive diseases caused by the defect in the lysosomal β -galactosidase (β-Gal), frequently related to misfolding and subsequent endoplasmic reticulum-associated degradation
2. Pharmacological chaperone (PC) therapy is a newly developed molecular therapeutic approach by using small molecule ligands of the mutant enzyme that are able to promote the correct folding and prevent endoplasmic reticulum-associated degradation and promote trafficking to the lysosome
3. In this report, we describe the enzymological properties of purified recombinant human β-Gal(WT) and two representative mutations in GM1 gangliosidosis Japanese patients, β-Gal(R201C) and β-Gal(I51T).
4. We have also evaluated the PC effect of two competitive inhibitors of β-Gal.
5. Moreover, we provide a detailed atomic view of the recognition mechanism of these compounds in comparison with two structurally related analogues
6. All compounds bind to the active site of β-Gal with the sugar-mimicking moiety making hydrogen bonds to active site residues
7. Moreover, the binding affinity, the enzyme selectivity, and the PC potential are strongly affected by the mono- or bicyclic structure of the core as well as the orientation, nature, and length of the exocyclic substituent
8. These results provide understanding on the mechanism of action of β-Gal selective chaperoning by newly developed PC compounds.