Palmitoyl: Protein thioesterase (PPT1) inhibitors can act as pharmacological chaperones in infantile Batten disease

Dawson, Glyn, Schroeder, Christina and Dawson, Philip E. (2010) Palmitoyl: Protein thioesterase (PPT1) inhibitors can act as pharmacological chaperones in infantile Batten disease. Biochemical and Biophysical Research Communications, 395 1: 66-69. doi:10.1016/j.bbrc.2010.03.137


Author Dawson, Glyn
Schroeder, Christina
Dawson, Philip E.
Title Palmitoyl: Protein thioesterase (PPT1) inhibitors can act as pharmacological chaperones in infantile Batten disease
Journal name Biochemical and Biophysical Research Communications   Check publisher's open access policy
ISSN 0006-291X
1090-2104
Publication date 2010-04-23
Sub-type Article (original research)
DOI 10.1016/j.bbrc.2010.03.137
Volume 395
Issue 1
Start page 66
End page 69
Total pages 4
Place of publication Maryland Heights, MO, United States
Publisher Academic Press
Language eng
Formatted abstract
Competitive inhibitors of lysosomal hydrolases (pharmacological chaperones) have been used to treat some lysosomal storage diseases which result from mis-sense mutations and mis-folded protein but have not been tried in Batten disease, for which there is no current therapy. We synthesized a large number of novel, non-hydrolyzable competitive inhibitors of palmitoyl:protein thioesterase (PPT1) and showed that some could act as chemical chaperones. One inhibitor (CS38: βAGDap(Pal)VKIKK) was taken up by lymphoblasts from patients with mutations leading to the T75P/R151X substitutions and enhanced PPT1 activity 2-fold. A similar 2-fold stimulation with another inhibitor (AcGDap(Palm)GG(R)7) was observed in patients with a G108R amino acid substitution in PPT1. Residual PPT1 activity in both was thermally unstable at pH 7.4 (but not at 4.7) consistent with a mis-folded, unstable PPT1 degraded by the ER stress response. Patients with null mutations did not respond to the pharmacological chaperones.
Keyword Pharmacological chaperones
Thioesterase inhibitor
Lymphoblasts
Fibroblasts
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: ERA 2012 Admin Only
Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 22 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 24 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Fri, 14 Oct 2011, 13:37:26 EST by Susan Allen on behalf of Institute for Molecular Bioscience