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Strategies for correcting very long chain acyl-CoA dehydrogenase deficiency.


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 ?-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 ?-oxidation capacity, two hallmarks of the disorder. Overall, this study provides biochemical evidence for a potential therapeutic modality to correct ?-oxidation deficiencies.

SUBMITTER: Tenopoulou M 

PROVIDER: S-EPMC4400356 | BioStudies | 2015-01-01

REPOSITORIES: biostudies

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