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Strategies for correcting very long chain acyl-CoA dehydrogenase deficiency.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2015 Apr 17; Vol. 290 (16), pp. 10486-94. Date of Electronic Publication: 2015 Mar 03. - Publication Year :
- 2015
-
Abstract
- Very long acyl-CoA dehydrogenase (VLCAD) deficiency is a genetic pediatric disorder presenting with a spectrum of phenotypes that remains for the most part untreatable. Here, we present a novel strategy for the correction of VLCAD deficiency by increasing mutant VLCAD enzymatic activity. Treatment of VLCAD-deficient fibroblasts, which express distinct mutant VLCAD protein and exhibit deficient fatty acid β-oxidation, with S-nitroso-N-acetylcysteine induced site-specific S-nitrosylation of VLCAD mutants at cysteine residue 237. Cysteine 237 S-nitrosylation was associated with an 8-17-fold increase in VLCAD-specific activity and concomitant correction of acylcarnitine profile and β-oxidation capacity, two hallmarks of the disorder. Overall, this study provides biochemical evidence for a potential therapeutic modality to correct β-oxidation deficiencies.<br /> (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Acetylcysteine pharmacology
Acyl-CoA Dehydrogenase chemistry
Acyl-CoA Dehydrogenase genetics
Acyl-CoA Dehydrogenase, Long-Chain deficiency
Acyl-CoA Dehydrogenase, Long-Chain genetics
Amino Acid Sequence
Carnitine metabolism
Congenital Bone Marrow Failure Syndromes
Cysteine metabolism
Dose-Response Relationship, Drug
Fatty Acids metabolism
Fibroblasts enzymology
Fibroblasts pathology
Genetic Therapy methods
Humans
Kinetics
Lipid Metabolism, Inborn Errors drug therapy
Lipid Metabolism, Inborn Errors enzymology
Lipid Metabolism, Inborn Errors genetics
Lipid Metabolism, Inborn Errors pathology
Mitochondrial Diseases drug therapy
Mitochondrial Diseases enzymology
Mitochondrial Diseases genetics
Mitochondrial Diseases pathology
Molecular Sequence Data
Muscular Diseases drug therapy
Muscular Diseases enzymology
Muscular Diseases genetics
Muscular Diseases pathology
Mutation
Oxidation-Reduction
Primary Cell Culture
Skin drug effects
Skin enzymology
Skin pathology
Acetylcysteine analogs & derivatives
Acyl-CoA Dehydrogenase metabolism
Carnitine analogs & derivatives
Fibroblasts drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 290
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25737446
- Full Text :
- https://doi.org/10.1074/jbc.M114.635102