| Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis. | |
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MedLine Citation:
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PMID: 17237499 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Late-onset GM2 gangliosidosis is composed of two related, autosomal recessive, neurodegenerative diseases, both resulting from deficiency of lysosomal, heterodimeric beta-hexosaminidase A (Hex A, alphabeta). Pharmacological chaperones (PC) are small molecules that can stabilize the conformation of a mutant protein, allowing it to pass the quality control system of the endoplasmic reticulum. To date all successful PCs have also been competitive inhibitors. Screening for Hex A inhibitors in a library of 1040 Food Drug Administration-approved compounds identified pyrimethamine (PYR (2,4-diamino 5-(4-chlorophenyl)-6-ethylpyrimidine)) as the most potent inhibitor. Cell lines from 10 late-onset Tay-Sachs (11 alpha-mutations, 2 novel) and 7 Sandhoff (9 beta-mutations, 4 novel) disease patients, were cultured with PYR at concentrations corresponding to therapeutic doses. Cells carrying the most common late-onset mutation, alphaG269S, showed significant increases in residual Hex A activity, as did all 7 of the beta-mutants tested. Cells responding to PC treatment included those carrying mutants resulting in reduced Hex heat stability and partial splice junction mutations of the inherently less stable alpha-subunit. PYR, which binds to the active site in domain II, was able to function as PC even to domain I beta-mutants. We concluded that PYR functions as a mutation-specific PC, variably enhancing residual lysosomal Hex A levels in late-onset GM2 gangliosidosis patient cells. |
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Authors:
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Gustavo H B Maegawa; Michael Tropak; Justin Buttner; Tracy Stockley; Fernando Kok; Joe T R Clarke; Don J Mahuran |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2007-01-21 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 282 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2007 Mar |
Date Detail:
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Created Date: 2007-03-19 Completed Date: 2007-05-02 Revised Date: 2010-09-16 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 9150-61 Citation Subset: IM |
Affiliation:
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Division of Clinical and Metabolic Genetics, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Dimerization Dose-Response Relationship, Drug Enzyme Inhibitors / pharmacology Fibroblasts / metabolism Folic Acid Antagonists / pharmacology Gangliosidoses, GM2 / drug therapy*, metabolism* Hexosaminidase A Humans Lysosomes / metabolism Models, Molecular Molecular Chaperones Mutation Mutation, Missense Protein Folding Pyrimethamine / pharmacology* beta-N-Acetylhexosaminidases / antagonists & inhibitors |
| Grant Support | |
ID/Acronym/Agency:
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R21 NS051214-01/NS/NINDS NIH HHS; R21 NS051214-02/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Folic Acid Antagonists; 0/Molecular Chaperones; 58-14-0/Pyrimethamine; EC 3.2.1.52/Hexosaminidase A; EC 3.2.1.52/beta-N-Acetylhexosaminidases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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