Strategies for correcting very long chain acyl-CoA dehydrogenase deficiency [Molecular Bases of Disease]

March 3rd, 2015 by Tenopoulou, M., Chen, J., Bastin, J., Bennett, M. J., Ischiropoulos, H., Doulias, P.-T.

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 through 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-acetyl-cysteine (SNAC) induced site specific S-nitrosylation of VLCAD mutants at cysteine residue 237. Cysteine 237 S-nitrosylation was associated with an 8 to 17-fold increase in VLCAD specific activity and concomitant correction of acylcarnitine profile and β-oxidation capacity, two hallmarks of the disorder. Overall, the current study provides biochemical evidence for a potential therapeutic modality to correct β-oxidation deficiencies.