Structural basis of pharmacological chaperoning for human ?-galactosidase.

ABSTRACT: GM1 gangliosidosis and Morquio B disease are autosomal recessive diseases caused by the defect in the lysosomal ?-galactosidase (?-Gal), frequently related to misfolding and subsequent endoplasmic reticulum-associated degradation. 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. In this report, we describe the enzymological properties of purified recombinant human ?-Gal(WT) and two representative mutations in GM1 gangliosidosis Japanese patients, ?-Gal(R201C) and ?-Gal(I51T). We have also evaluated the PC effect of two competitive inhibitors of ?-Gal. Moreover, we provide a detailed atomic view of the recognition mechanism of these compounds in comparison with two structurally related analogues. All compounds bind to the active site of ?-Gal with the sugar-mimicking moiety making hydrogen bonds to active site residues. 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. These results provide understanding on the mechanism of action of ?-Gal selective chaperoning by newly developed PC compounds.

SUBMITTER: Suzuki H 

PROVIDER: S-EPMC4031513 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature