Strategies for correcting very long chain acyl-CoA dehydrogenase deficiency.
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.
From the Division of Neonatology, Department of Pediatrics Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 19104.
Margarita
M
Tenopoulou
the Michael Palmieri Metabolic Laboratory at Children's Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, and.
Jie
J
Chen
the INSERM U1124, Université Paris Descartes, 75270 Paris Cedex 6, France.
Jean
J
Bastin
the Michael Palmieri Metabolic Laboratory at Children's Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, and.
Michael J
MJ
Bennett
From the Division of Neonatology, Department of Pediatrics Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 19104, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, and.
Harry
H
Ischiropoulos
From the Division of Neonatology, Department of Pediatrics Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 19104, doulias@email.chop.edu.
Paschalis-Thomas
PT
Doulias
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D042964:Acyl-CoA Dehydrogenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency / Q000235:genetics; D000595:Amino Acid Sequence; D002331:Carnitine / Q000031:analogs & derivatives* / Q000378:metabolism; D000080984:Congenital Bone Marrow Failure Syndromes; D003545:Cysteine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007700:Kinetics; D008052:Lipid Metabolism, Inborn Errors / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009154:Mutation; D010084:Oxidation-Reduction; D061251:Primary Cell Culture; D012867:Skin / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
D005227:Fatty Acids; C116917:acylcarnitine; C024940:S-nitroso-N-acetylcysteine; D042964:Acyl-CoA Dehydrogenase; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D003545:Cysteine; D002331:Carnitine; D000111:Acetylcysteine
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