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. 1988 Oct;85(20):7647–7651. doi: 10.1073/pnas.85.20.7647

Peroxisomal lignoceroyl-CoA ligase deficiency in childhood adrenoleukodystrophy and adrenomyeloneuropathy.

O Lazo 1, M Contreras 1, M Hashmi 1, W Stanley 1, C Irazu 1, I Singh 1
PMCID: PMC282249  PMID: 3174658

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.

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Selected References

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  1. Akanuma H., Kishimoto Y. Synthesis of ceramides and cerebrosides containing both alpha-hydroxy and nonhydroxy fatty acids from lignoceroyl-CoA by rat brain microsomes. J Biol Chem. 1979 Feb 25;254(4):1050–1060. [PubMed] [Google Scholar]
  2. Baudhuin P., Beaufay H., Rahman-Li Y., Sellinger O. Z., Wattiaux R., Jacques P., De Duve C. Tissue fractionation studies. 17. Intracellular distribution of monoamine oxidase, aspartate aminotransferase, alanine aminotransferase, D-amino acid oxidase and catalase in rat-liver tissue. Biochem J. 1964 Jul;92(1):179–184. doi: 10.1042/bj0920179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bhushan A., Singh R. P., Singh I. Characterization of rat brain microsomal acyl-coenzyme A ligases: different enzymes for the synthesis of palmitoyl-coenzyme A and lignoceroyl-coenzyme A. Arch Biochem Biophys. 1986 Apr;246(1):374–380. doi: 10.1016/0003-9861(86)90482-0. [DOI] [PubMed] [Google Scholar]
  4. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  5. Brown F. R., 3rd, McAdams A. J., Cummins J. W., Konkol R., Singh I., Moser A. B., Moser H. W. Cerebro-hepato-renal (Zellweger) syndrome and neonatal adrenoleukodystrophy: similarities in phenotype and accumulation of very long chain fatty acids. Johns Hopkins Med J. 1982 Dec;151(6):344–351. [PubMed] [Google Scholar]
  6. COOPERSTEIN S. J., LAZAROW A. A microspectrophotometric method for the determination of cytochrome oxidase. J Biol Chem. 1951 Apr;189(2):665–670. [PubMed] [Google Scholar]
  7. FOLCH J., LEES M., SLOANE STANLEY G. H. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957 May;226(1):497–509. [PubMed] [Google Scholar]
  8. Fahl W. E., Lalwani N. D., Watanabe T., Goel S. K., Reddy J. K. DNA damage related to increased hydrogen peroxide generation by hypolipidemic drug-induced liver peroxisomes. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7827–7830. doi: 10.1073/pnas.81.24.7827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ghosh M. K., Hajra A. K. A rapid method for the isolation of peroxisomes from rat liver. Anal Biochem. 1986 Nov 15;159(1):169–174. doi: 10.1016/0003-2697(86)90323-4. [DOI] [PubMed] [Google Scholar]
  10. Goldfischer S., Collins J., Rapin I., Coltoff-Schiller B., Chang C. H., Nigro M., Black V. H., Javitt N. B., Moser H. W., Lazarow P. B. Peroxisomal defects in neonatal-onset and X-linked adrenoleukodystrophies. Science. 1985 Jan 4;227(4682):67–70. doi: 10.1126/science.3964959. [DOI] [PubMed] [Google Scholar]
  11. Griffin J. W., Goren E., Schaumburg H., Engel W. K., Loriaux L. Adrenomyeloneuropathy: a probable variant of adrenoleukodystrophy. I. Clinical and endocrinologic aspects. Neurology. 1977 Dec;27(12):1107–1113. doi: 10.1212/wnl.27.12.1107. [DOI] [PubMed] [Google Scholar]
  12. Groot P. H., Scholte H. R., Hülsmann W. C. Fatty acid activation: specificity, localization, and function. Adv Lipid Res. 1976;14:75–126. doi: 10.1016/b978-0-12-024914-5.50009-7. [DOI] [PubMed] [Google Scholar]
  13. Hajra A. K., Wu D. Preparative isolation of peroxisomes from liver and kidney using metrizamide density gradient centrifugation in a vertical rotor. Anal Biochem. 1985 Jul;148(1):233–244. doi: 10.1016/0003-2697(85)90651-7. [DOI] [PubMed] [Google Scholar]
  14. Hashimoto T. Individual peroxisomal beta-oxidation enzymes. Ann N Y Acad Sci. 1982;386:5–12. doi: 10.1111/j.1749-6632.1982.tb21403.x. [DOI] [PubMed] [Google Scholar]
  15. Hashmi M., Stanley W., Singh I. Lignoceroyl-CoASH ligase: enzyme defect in fatty acid beta-oxidation system in X-linked childhood adrenoleukodystrophy. FEBS Lett. 1986 Feb 17;196(2):247–250. doi: 10.1016/0014-5793(86)80256-3. [DOI] [PubMed] [Google Scholar]
  16. Hoshi M., Kishimoto Y. Synthesis of cerebronic acid from lignoceric acid by rat brain preparation. Some properties and distribution of the -hydroxylation system. J Biol Chem. 1973 Jun 10;248(11):4123–4130. [PubMed] [Google Scholar]
  17. Igarashi M., Schaumburg H. H., Powers J., Kishmoto Y., Kolodny E., Suzuki K. Fatty acid abnormality in adrenoleukodystrophy. J Neurochem. 1976 Apr;26(4):851–860. doi: 10.1111/j.1471-4159.1976.tb04462.x. [DOI] [PubMed] [Google Scholar]
  18. Kelley R. I., Datta N. S., Dobyns W. B., Hajra A. K., Moser A. B., Noetzel M. J., Zackai E. H., Moser H. W. Neonatal adrenoleukodystrophy: new cases, biochemical studies, and differentiation from Zellweger and related peroxisomal polydystrophy syndromes. Am J Med Genet. 1986 Apr;23(4):869–901. doi: 10.1002/ajmg.1320230404. [DOI] [PubMed] [Google Scholar]
  19. Krisans S. K., Mortensen R. M., Lazarow P. B. Acyl-CoA synthetase in rat liver peroxisomes. Computer-assisted analysis of cell fractionation experiments. J Biol Chem. 1980 Oct 25;255(20):9599–9607. [PubMed] [Google Scholar]
  20. Miyazawa S., Hashimoto T., Yokota S. Identity of long-chain acyl-coenzyme A synthetase of microsomes, mitochondria, and peroxisomes in rat liver. J Biochem. 1985 Sep;98(3):723–733. doi: 10.1093/oxfordjournals.jbchem.a135330. [DOI] [PubMed] [Google Scholar]
  21. Moser H. W., Moser A. E., Singh I., O'Neill B. P. Adrenoleukodystrophy: survey of 303 cases: biochemistry, diagnosis, and therapy. Ann Neurol. 1984 Dec;16(6):628–641. doi: 10.1002/ana.410160603. [DOI] [PubMed] [Google Scholar]
  22. Moser H. W. Peroxisomal disorders. J Pediatr. 1986 Jan;108(1):89–91. doi: 10.1016/s0022-3476(86)80774-0. [DOI] [PubMed] [Google Scholar]
  23. Rizzo W. B., Avigan J., Chemke J., Schulman J. D. Adrenoleukodystrophy: very long-chain fatty acid metabolism in fibroblasts. Neurology. 1984 Feb;34(2):163–169. doi: 10.1212/wnl.34.2.163. [DOI] [PubMed] [Google Scholar]
  24. Santos M. J., Ojeda J. M., Garrido J., Leighton F. Peroxisomal organization in normal and cerebrohepatorenal (Zellweger) syndrome fibroblasts. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6556–6560. doi: 10.1073/pnas.82.19.6556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Schaumburg H. H., Powers J. M., Raine C. S., Suzuki K., Richardson E. P., Jr Adrenoleukodystrophy. A clinical and pathological study of 17 cases. Arch Neurol. 1975 Sep;32(9):577–591. doi: 10.1001/archneur.1975.00490510033001. [DOI] [PubMed] [Google Scholar]
  26. Schutgens R. B., Heymans H. S., Wanders R. J., van den Bosch H., Tager J. M. Peroxisomal disorders: a newly recognised group of genetic diseases. Eur J Pediatr. 1986 Feb;144(5):430–440. doi: 10.1007/BF00441734. [DOI] [PubMed] [Google Scholar]
  27. Shindo Y., Hashimoto T. Acyl-Coenzyme A synthetase and fatty acid oxidation in rat liver peroxisomes. J Biochem. 1978 Nov;84(5):1177–1181. doi: 10.1093/oxfordjournals.jbchem.a132234. [DOI] [PubMed] [Google Scholar]
  28. Singh H., Derwas N., Poulos A. Beta-oxidation of very-long-chain fatty acids and their coenzyme A derivatives by human skin fibroblasts. Arch Biochem Biophys. 1987 May 1;254(2):526–533. doi: 10.1016/0003-9861(87)90133-0. [DOI] [PubMed] [Google Scholar]
  29. Singh H., Poulos A. A comparative study of stearic and lignoceric acid oxidation by human skin fibroblasts. Arch Biochem Biophys. 1986 Oct;250(1):171–179. doi: 10.1016/0003-9861(86)90714-9. [DOI] [PubMed] [Google Scholar]
  30. Singh I., Moser A. E., Goldfischer S., Moser H. W. Lignoceric acid is oxidized in the peroxisome: implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4203–4207. doi: 10.1073/pnas.81.13.4203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Singh I., Moser A. E., Moser H. W., Kishimoto Y. Adrenoleukodystrophy: impaired oxidation of very long chain fatty acids in white blood cells, cultured skin fibroblasts, and amniocytes. Pediatr Res. 1984 Mar;18(3):286–290. doi: 10.1203/00006450-198403000-00016. [DOI] [PubMed] [Google Scholar]
  32. Singh I., Moser H. W., Moser A. B., Kishimoto Y. Adrenoleukodystrophy: impaired oxidation of long chain fatty acids in cultured skin fibroblasts an adrenal cortex. Biochem Biophys Res Commun. 1981 Oct 30;102(4):1223–1229. doi: 10.1016/s0006-291x(81)80142-8. [DOI] [PubMed] [Google Scholar]
  33. Singh I., Singh R., Bhushan A., Singh A. K. Lignoceroyl-CoA ligase activity in rat brain microsomal fraction: topographical localization and effect of detergents and alpha-cyclodextrin. Arch Biochem Biophys. 1985 Jan;236(1):418–426. doi: 10.1016/0003-9861(85)90642-3. [DOI] [PubMed] [Google Scholar]
  34. Tsuji S., Sano-Kawamura T., Ariga T., Miyatake T. Metabolism of [17,18-3H2]hexacosanoic acid and [15,16-3H2]lignoceric acid in cultured skin fibroblasts from patients with adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN). J Neurol Sci. 1985 Dec;71(2-3):359–367. doi: 10.1016/0022-510x(85)90074-7. [DOI] [PubMed] [Google Scholar]
  35. Völkl A., Fahimi H. D. Isolation and characterization of peroxisomes from the liver of normal untreated rats. Eur J Biochem. 1985 Jun 3;149(2):257–265. doi: 10.1111/j.1432-1033.1985.tb08920.x. [DOI] [PubMed] [Google Scholar]
  36. Wanders R. J., van Roermund C. W., van Wijland M. J., Nijenhuis A. A., Tromp A., Schutgens R. B., Brouwer-Kelder E. M., Schram A. W., Tager J. M., van den Bosch H. X-linked adrenoleukodystrophy: defective peroxisomal oxidation of very long chain fatty acids but not of very long chain fatty acyl-CoA esters. Clin Chim Acta. 1987 Jun 15;165(2-3):321–329. doi: 10.1016/0009-8981(87)90177-x. [DOI] [PubMed] [Google Scholar]

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