Document Detail

Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis.
MedLine Citation:
PMID:  17237499     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-01-21
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  282     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-03-19     Completed Date:  2007-05-02     Revised Date:  2010-09-16    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  9150-61     Citation Subset:  IM    
Division of Clinical and Metabolic Genetics, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
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MeSH Terms
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Fibroblasts / metabolism
Folic Acid Antagonists / pharmacology
Gangliosidoses, GM2 / drug therapy*,  metabolism*
Hexosaminidase A
Lysosomes / metabolism
Models, Molecular
Molecular Chaperones
Mutation, Missense
Protein Folding
Pyrimethamine / pharmacology*
beta-N-Acetylhexosaminidases / antagonists & inhibitors
Grant Support
R21 NS051214-01/NS/NINDS NIH HHS; R21 NS051214-02/NS/NINDS NIH HHS
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Folic Acid Antagonists; 0/Molecular Chaperones; 58-14-0/Pyrimethamine; EC A; EC

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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