Abstract
Recently, pharmacological chaperone therapy for Pompe disease with small molecules such as imino sugars has attracted interest. But mutant acid α-glucosidase (GAA) species responsive to imino sugars are limited. To elucidate the characteristics of a mutant GAA responsive to imino sugars, we performed biochemical and structural analyses. Among cultured fibroblast cell lines derived from Japanese Pompe patients, only one carrying p.S529V/p.S619R amino acid substitutions responded to 1-deoxynojirimycin (DNJ), and an expression study revealed that DNJ, N-butyl-deoxynojirimycin and nojirimycin-1-sulfonic acid increased the enzyme activity of the S529V mutant GAA expressed in Chinese hamster ovary cells. The results of western blotting analysis suggested that these imino sugars facilitated the intracellular transportation of the mutant GAA and stabilized it. Among these imino sugars, DNJ exhibited the strongest action on the mutant GAA. Structural analysis revealed that DNJ almost completely occupied the active site pocket, and interacted with amino acid residues comprising it through van der Waals contacts and hydrogen bonds. This information will be useful for improvement of pharmacological chaperone therapy for Pompe disease.
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Acknowledgements
We thank Dr J Ponder (Department of Biochemistry and Molecular Biophysics, Washington University) for providing us with the TINKER software. We also thank Ms Y Tanabe for typing the manuscript. This work was supported by Program for Research on Intractable Diseases of Health and Labor Research Grants (HS); the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (ID: 09-15, HS); the JAPS Asia/Africa Scientific Platform Program (HS); the Japan Society for the Promotion of Science (JAPS ID: 21390314, HS); and the High-Tech Research Center Project of the Ministry of Education, Culture, Sports, Science and Technology of Japan (S0801043, HS).
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Tajima, Y., Saito, S., Ohno, K. et al. Biochemical and structural study on a S529V mutant acid α-glucosidase responsive to pharmacological chaperones. J Hum Genet 56, 440–446 (2011). https://doi.org/10.1038/jhg.2011.36
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DOI: https://doi.org/10.1038/jhg.2011.36
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