Artículo
Structural basis of pharmacological chaperoning for human β-galactosidase
Autor/es | Suzuki, Hironori
Ohto, Umeharu Higaki, Katsumi Mena Barragán, Teresa Aguilar Moncayo, Matilde Ortiz Mellet, Carmen Nanba, Eiji García Fernández, José Manuel Suzuki, Yoshiyuki Shimizu, Toshiyuki |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2014 |
Fecha de depósito | 2022-02-07 |
Publicado en |
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Resumen | 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 ... 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. 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 β-GalWT and two representative mutations in GM1 gangliosidosis Japanese patients, β-GalR201C and β-GalI51T. We have also evaluated the PC effect of two competitive inhibitors of β-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 β-Gal with the sugar-mimicking moiety making hydrogen bonds to active site residues. Moreover, the binding affinity, the enzyme selectivity, and thePCpotential 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 β-Gal selective chaperoning by newly developed PC compounds. |
Identificador del proyecto | 13680918
14207106 H20-Kokoro-022 H22-Nanji-Ippan-002 AS232Z00009G SAF2010-15670 CTQ2010-15848 |
Cita | Suzuki, H., Ohto, U., Higaki, K., Mena Barragán, T., Aguilar Moncayo, M., Ortiz Mellet, C.,...,Shimizu, T. (2014). Structural basis of pharmacological chaperoning for human β-galactosidase. Journal of Biological Chemistry, 289 (21), 14560-14568. |
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