Structural basis of pharmacological chaperoning for human beta-galactosidase.
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Suzuki H, Ohto U, Higaki K, Mena-Barragan T, Aguilar-Moncayo M, Ortiz Mellet C, Nanba E, Garcia Fernandez JM, Suzuki Y, Shimizu T
Structural basis of pharmacological chaperoning for human beta-galactosidase.
J Biol Chem. 2014 May 23;289(21):14560-8. doi: 10.1074/jbc.M113.529529. Epub 2014 Apr 15.
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- 24737316 [ View in PubMed]
- Abstract
GM1 gangliosidosis and Morquio B disease are autosomal recessive diseases caused by the defect in the lysosomal beta-galactosidase (beta-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 beta-Gal(WT) and two representative mutations in GM1 gangliosidosis Japanese patients, beta-Gal(R201C) and beta-Gal(I51T). We have also evaluated the PC effect of two competitive inhibitors of beta-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 beta-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 beta-Gal selective chaperoning by newly developed PC compounds.