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

The Journal of Biological Chemistry
Margarita TenopoulouPaschalis-Thomas Doulias

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.

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Citations

Oct 17, 2015·Annual Review of Physiology·Sander M HoutenRonald J A Wanders
Aug 2, 2016·Scientific Reports·Chun ZhangFei Liao
Nov 28, 2017·Current Genetic Medicine Reports·Eric S Goetzman

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