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 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.

Keywords: Enzyme; Mitochondrial Metabolism; Nitric Oxide; Pediatric Disorder; Post-transcriptional Regulation; S-Nitrosylation; Very Long Chain Acyl-CoA Dehydrogenase; Very Long Chain Acyl-CoA Dehydrogenase Deficiency; β-Oxidation Disorder.