Prediction of the responsiveness to pharmacological chaperones: lysosomal human alpha-galactosidase, a case of study(493 views) Andreotti G, Guarracino MR, Cammisa M, Correra A, Cubellis MV
Orphanet Journal Of Rare Diseases (ISSN: 1750-1172), 2010 Dec 8; 5: 36-36.
Istituto di Chimica Biomolecolare-CNR, Pozzuoli, Italy.
High Performance Computing and Networking Institute-CNR, Napoli, Italy
Dipartimento di Biologia Strutturale e Funzionale, Universita' Federico II, Napoli, Italy
Istituto di Biostrutture e Bioimmagini-CNR, Napoli, Italy
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Flanagan, J. J., Rossi, B., Tang, K., Wu, X., Mascioli, K., Donaudy, F., Tuzzi, M. R., Porto, C., The pharmacological chaperone 1-deoxynojirimycin increases the activity and lysosomal trafficking of multiple mutant forms of acid alpha-glucosidase (2009) Hum Mutat, 30, pp. 1683-92. , 10. 1002/humu. 21121. 19862843
Tropak, M. B., Reid, S. P., Guiral, M., Withers, S. G., Mahuran, D., Pharmacological enhancement of beta-hexosaminidase activity in fibroblasts from adult Tay-Sachs and Sandhoff Patients (2004) J Biol Chem, 279, pp. 13478-87. , 10. 1074/jbc. M308523200. 14724290
Loo, T. W., Clarke, D. M., Chemical and pharmacological chaperones as new therapeutic agents (2007) Expert Rev Mol Med, 9, pp. 1-18. , 10. 1017/S1462399407000361. 17597553
Fan, J. Q., A counterintuitive approach to treat enzyme deficiencies: Use of enzyme inhibitors for restoring mutant enzyme activity (2008) Biol Chem, 389, pp. 1-11. , 10. 1515/BC. 2008. 009. 18095864
Benjamin, E. R., Flanagan, J. J., Schilling, A., Chang, H. H., Agarwal, L., Katz, E., Wu, X., Desnick, R. J., The pharmacological chaperone 1-deoxygalactonojirimycin increases alpha-galactosidase A levels in Fabry patient cell lines (2009) J Inherit Metab Dis, 32, pp. 424-40. , 10. 1007/s10545-009-1077-0. 19387866
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Guce, A. I., Clark, N. E., Salgado, E. N., Ivanen, D. R., Kulminskaya, A. A., Brumer, H., Garman, S. C., Catalytic mechanism of human alpha-galactosidase J Biol Chem, 285, pp. 3625-32. , 10. 1074/jbc. M109. 060145. 19940122
Lieberman, R. L., D'Aquino, J. A., Ringe, D., Petsko, G. A., Effects of pH and iminosugar pharmacological chaperones on lysosomal glycosidase structure and stability (2009) Biochemistry, 48, pp. 4816-27. , 10. 1021/bi9002265. 19374450
Petock, J. M., Torshin, I. Y., Weber, I. T., Harrison, R. W., Analysis of protein structures reveals regions of rare backbone conformation at functional sites (2003) Proteins, 53, pp. 872-9. , 10. 1002/prot. 10484. 14635129
Cubellis, M. V., Caillez, F., Blundell, T. L., Lovell, S. C., Properties of polyproline II, a secondary structure element implicated in protein-protein interactions (2005) Proteins, 58, pp. 880-92. , 10. 1002/prot. 20327. 15657931
Worth, C. L., Bickerton, G. R., Schreyer, A., Forman, J. R., Cheng, T. M., Lee, S., Gong, S., Blundell, T. L., A structural bioinformatics approach to the analysis of nonsynonymous single nucleotide polymorphisms (nsSNPs) and their relation to disease (2007) J Bioinform Comput Biol, 5, pp. 1297-318. , 10. 1142/S0219720007003120. 18172930
Topham, C. M., Srinivasan, N., Blundell, T. L., Prediction of the stability of protein mutants based on structural environment-dependent amino acid substitution and propensity tables (1997) Protein Eng, 10, pp. 7-21. , 10. 1093/protein/10. 1. 7. 9051729
Gromiha, M. M., An, J., Kono, H., Oobatake, M., Uedaira, H., Prabakaran, P., Sarai, A., ProTherm, version 2. 0: Thermodynamic database for proteins and mutants (2000) Nucleic Acids Res, 28, pp. 283-5. , 10. 1093/nar/28. 1. 283. 10592247
http: //www. informedia. cs. cmu. edu/yanrong/MATLABArsenal/MATLABArsenal. htm, MATLAB-ArsenalAltschul, S. F., Madden, T. L., Schaffer, A. A., Zhang, J., Zhang, Z., Miller, W., Lipman, D. J., Gapped BLAST and PSI-BLAST: A new generation of protein database search programs (1997) Nucleic Acids Res, 25, pp. 3389-402. , 10. 1093/nar/25. 17. 3389. 9254694
Solis, M. A., Pascual, B., Bosca, M., Ramos, V., Carda, C., Monteagudo, C., Torregrosa, I., Miguel, A., New mutation in female patient with renal variant of Fabry disease and HIV J Nephrol, 23, pp. 231-3. , 20155722
Borglum, A. D., Byskov, A., Cubellis, M. V., Kruse, T. A., An EcoRI polymorphism for the PLAUR gene (1991) Nucleic Acids Res, 19, p. 6661. , 10. 1093/nar/19. 23. 6661-a. 1684424
http: //www. hgmd. cf. ac. uk/ac/index. php, HGMDMehta, A. B., Anderson-Fabry disease: Developments in diagnosis and treatment (2009) Int J Clin Pharmacol Ther, 47 (SUPPL. 1), pp. 1966-74. , 20040315
Smith, R. E., Lovell, S. C., Burke, D. F., Montalvao, R. W., Blundell, T. L., Andante: Reducing side-chain rotamer search space during comparative modeling using environment-specific substitution probabilities (2007) Bioinformatics, 23, pp. 1099-105. , 10. 1093/bioinformatics/btm073. 17341496
Connolly, M. L., Solvent-accessible surfaces of proteins and nucleic acids (1983) Science, 221, pp. 709-13. , 10. 1126/science. 6879170. 6879170
Prediction of the responsiveness to pharmacological chaperones: lysosomal human alpha-galactosidase, a case of study
Background: The pharmacological chaperones therapy is a promising approach to cure genetic diseases. It relies on substrate competitors used at sub-inhibitory concentration which can be administered orally, reach difficult tissues and have low cost. Clinical trials are currently carried out for Fabry disease, a lysosomal storage disorder caused by inherited genetic mutations of alpha-galactosidase. Regrettably, not all genotypes respond to these drugs. Results: We collected the experimental data available in literature on the enzymatic activity of ninety-six missense mutants of lysosomal alpha-galactosidase measured in the presence of pharmacological chaperones. We associated with each mutation seven features derived from the analysis of 3D-structure of the enzyme, two features associated with their thermo-dynamic stability and four features derived from sequence alone. Structural and thermodynamic analysis explains why some mutants of human lysosomal alpha-galactosidase cannot be rescued by pharmacological chaperones: approximately forty per cent of the non responsive cases examined can be correctly associated with a negative prognostic feature. They include mutations occurring in the active site pocket, mutations preventing disulphide bridge formation and severely destabilising mutations. Despite this finding, prediction of mutations responsive to pharmacological chaperones cannot be achieved with high accuracy relying on combinations of structure-and thermodynamic-derived features even with the aid of classical and state of the art statistical learning methods. We developed a procedure to predict responsive mutations with an accuracy as high as 87%: the method scores the mutations by using a suitable position-specific substitution matrix. Our approach is of general applicability since it does not require the knowledge of 3D-structure but relies only on the sequence. Conclusions: Responsiveness to pharmacological chaperones depends on the structural/functional features of the disease-associated protein, whose complex interplay is best reflected on sequence conservation by evolutionary pressure. We propose a predictive method which can be applied to screen novel mutations of alpha galactosidase. The same approach can be extended on a genomic scale to find candidates for therapy with pharmacological chaperones among proteins with unknown tertiary structures.
Prediction of the responsiveness to pharmacological chaperones: lysosomal human alpha-galactosidase, a case of study