title: Peroxisomal lignoceroyl-CoA ligase deficiency in childhood adrenoleukodystrophy and adrenomyeloneuropathy.
abstract: We previously reported that in childhood adrenoleukodystrophy (C-ALD) and adrenomyeloneuropathy (AMN), the peroxisomal beta-oxidation system for very long chain (greater than C22) fatty acids is defective. To further define the defect in these two forms of X chromosome-linked ALD, we examined the oxidation of [1-14C]lignoceric acid (n-tetracosanoic acid, C24:0) and [1-14C]lignoceroyl-CoA (substrates for the first and second steps of beta-oxidation, respectively). The oxidation rates of lignoceric acid in C-ALD and AMN were 43% and 36% of control values, respectively, whereas the oxidation rate of lignoceroyl-CoA was 109% (C-ALD) and 106% (AMN) of control values, respectively. On the other hand, the oxidation rates of palmitic acid (n-hexadecanoic acid) and palmitoyl-CoA in C-ALD and AMN were similar to the control values. These results suggest that lignoceroyl-CoA ligase activity may be impaired in C-ALD and AMN. To identify the specific enzymatic deficiency and its subcellular localization in C-ALD and AMN, we established a modified procedure for the subcellular fractionation of cultured skin fibroblasts. Determination of acyl-CoA ligase activities provided direct evidence that lignoceroyl-CoA ligase is deficient in peroxisomes while it is normal in mitochondrial and microsomes. Moreover, the normal oxidation of lignoceroyl-CoA as compared with the deficient oxidation of lignoceric acid in isolated peroxisomes also supports the conclusion that peroxisomal lignoceroyl-CoA ligase is impaired in both C-ALD and AMN. Palmitoyl-Coa ligase activity was found to be normal in peroxisomes as well as in mitochondria and microsomes. This normal peroxisomal palmitoyl-CoA ligase activity as compared with the deficient activity of lignoceroyl-CoA ligase in C-ALD and AMN suggests the presence of two separate acyl-CoA ligases for palmitic and lignoceric acids in peroxisomes. These data clearly demonstrate that the pathognomonic accumulation of very long chain fatty acids in C-ALD and AMN is due to a deficiency of peroxisomal very long chain (lignoceric acid) acyl-CoA ligase.
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston 29425.
authors.forename: O
authors.initials: O
authors.lastname: Lazo
authors.forename: M
authors.initials: M
authors.lastname: Contreras
authors.forename: M
authors.initials: M
authors.lastname: Hashmi
authors.forename: W
authors.initials: W
authors.lastname: Stanley
authors.forename: C
authors.initials: C
authors.lastname: Irazu
authors.forename: I
authors.initials: I
authors.lastname: Singh
mesh_terms: D000326:Adrenoleukodystrophy / Q000201:enzymology* / Q000235:genetics; D002458:Cell Fractionation; D002460:Cell Line; D003066:Coenzyme A Ligases / Q000172:deficiency*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000201:enzymology*; D005227:Fatty Acids / Q000378:metabolism*; D005347:Fibroblasts; D008040:Genetic Linkage; D006801:Humans; D008830:Microbodies / Q000201:enzymology*; D008861:Microsomes / Q000201:enzymology; D008928:Mitochondria / Q000201:enzymology; D010084:Oxidation-Reduction; D010169:Palmitic Acids / Q000378:metabolism; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D012867:Skin / Q000166:cytology; D014960:X Chromosome
chemical_list: D005227:Fatty Acids; D010169:Palmitic Acids; D010171:Palmitoyl Coenzyme A; D003066:Coenzyme A Ligases; C044125:lignoceroyl-CoA ligase; C010210:lignoceric acid