Fatty Acid Metabolism in Cultured Skin Fibroblasts from Patients with Peroxisomal Disorders: Lignoceroyl-CoA Ligase Deficiency in Childhood Adrenoleukodystrophy

  • M. Hashmi
  • W. Stanley
  • I. Singh
Conference paper
Part of the Proceedings in Life Sciences book series (LIFE SCIENCES)

Abstract

We have previously reported that the peroxisomal B-oxidation system for very long chain (>C22) fatty acids is defective in the peroxisomal disorders, adrenoleukodystrophy (ALD) and Zellweger’s cerebro-hepato-renal syndrome (CHRS), (Singh, et. al. Proc. Natl. Acad. Sci. 81, 4203, 1984). In order to elucidate the specific enzyme defect, we examined the oxidation of [1-14C]lignoceric acid and [1-14C]lignoceroyl-CoA (substrates for the 1st and 2nd steps of the B-oxidation cycle). In agreement with our previous observation, we found that oxidation of lignoceric acid (substrate for the 1st step) in fibroblasts from childhood ALD was only 32% of the control. However, the rates of oxidation of lignoceroyl-CoA (substrate for the 2nd step) in cultured fibroblasts from childhood ALD and control were essential equivalent (44,853 ± 8,243 and 41,530 ± 3,708 CPM/mg protein/hr respectively). These studies indicate that oxidation of lignoceric acid is defective while degradation of lignoceroyl-CoA is normal in childhood AL. This identifies lignoceroyl-CoA ligase as the enzyme impaired in childhood ALD. Since lignoceric acid is oxidized in peroxisomes, it is likely that peroxisomal lignoceroyl- CoA ligase activity is defective in chilhood ALD. We also examined this oxidation in CHRS cells and found that degradation of both of these substrates is defective. These studies indicate that the molecular mechanism for the pathognomonic accumulation of very long chain fatty acids in X-linked childhood ALD is different from that in CHRS.

Keywords

Migration Hydration Neurol Cyclodextrin Dehydrogenation 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Rhodin, J. (1954) Aktiebolaget Godvil Stockholm. Karolinska Institute. Dissertation.Google Scholar
  2. 2.
    Tolbert, N.E., Essner, E. (1981) J. Cell Biol. 91, 2715–2835.CrossRefGoogle Scholar
  3. 3.
    De Duve, C. (1969) Proc. Natl. Acad. Sci. B, 173, 71–83.Google Scholar
  4. 4.
    Goldfischer, S., Moore, C.L., Johnson, A.B., Spio, A.J., Valsamis, M.P., Wisniewski, H.K. Ritch, R.H., Norton, W.T., Rapin, I. and Gartner, L.M. (1973) Science 182, 62–64.PubMedCrossRefGoogle Scholar
  5. 5.
    Bowen, P., Lee, CSN, Zellweger, H., Lindenberg, R. (1964) Bull Johns Hopkins Hosp. 114, 404–414.Google Scholar
  6. 6.
    Kelley, R.I. (1983) Am. J. Med. Genet. 16, 503–517.Google Scholar
  7. 7.
    Wilson, G.N., Holmes, R.G., Custer, J., Lipkowitz, J.L, Stover, J., Datta, N., and Hajra, A. (1986) Am. J. Med. Genet. 24, 69–82.PubMedCrossRefGoogle Scholar
  8. 8.
    Igarashi, M., Schaumburg, H.H., Powers, J.H., Kishimoto, Y., Kolodny, E., and Suzuki, K. (1976) J. Neurochem. 26, 851–860.PubMedCrossRefGoogle Scholar
  9. 9.
    Moser, A.E., Singh, I., Brown, F.R., Solish, G.I., Kelley, R.I., Benke, P.J. and Moser, H.W. (1984) New Eng. J. Med. 310, 1141–1146.PubMedCrossRefGoogle Scholar
  10. 10.
    Brown, F.R., Adams, A.J., Cummins, J.W., Konkol, R., Singh, I., Moser, A.B., and Moser, H.W. (1982) Johns Hopkins Medical Journal 151, 344–351.PubMedGoogle Scholar
  11. 11.
    Singh, R.P. and Singh, I. (1986) Neurochem. Res. 11, 281–289.PubMedCrossRefGoogle Scholar
  12. 12.
    Singh, I., Moser, A.B., Goldfischer, S., Moser, H.W. (1984) Proc. Natl. Acad. Sci. USA. 81, 4203–4207.Google Scholar
  13. 13.
    Singh, I., Moser, H.W., Moser, A. E. and Kishimoto, Y. (1981) Biochem. Biophys. Res. Commun. 102, 1223–1229.PubMedCrossRefGoogle Scholar
  14. 14.
    Singh, I., Moser, H.W., Moser, A.E. and Kishimoto, Y. (1984) Pediatr. Res. 18, 286–289.PubMedCrossRefGoogle Scholar
  15. 15.
    Jaffe, R., Crumsine, P., Hashida, Y. and Moser, H.W. (1982) Am. J. Pathol. 108, 100–111.PubMedGoogle Scholar
  16. 16.
    Rizzo, W., Avigan, J., Knazek, R. and Shulman, D. (1984) Neurol. 34, 163–169.Google Scholar
  17. 17.
    Tsuji, S., Sano-Kawamura, T., Ariga, T., Miyatake, T. (1985) J. Neurol. Sci. 71, 359–367.PubMedCrossRefGoogle Scholar
  18. 18.
    Moser, H.W., A.B., Singh, I., and O’Neill, B.P. (1984) Annals Neurol. 16, 628–641.CrossRefGoogle Scholar
  19. 19.
    Hoshi, M. and Kishimoto, Y. (1973) J. Biol. Chem. 248, 4123–4130.PubMedGoogle Scholar
  20. 20.
    Akanuma, H. and Kishimoto, Y. (1979) J. Biol. Chem. 250, 1050–1057.Google Scholar
  21. 21.
    Lazarow, P.B. (1978) J. Biol. Chem. 253, 1522–1528.PubMedGoogle Scholar
  22. 22.
    Hryb, D.J. and Hogg, J.F. (1979) Biochem. Biophys. Res. Commun. 87, 1200–1205.PubMedCrossRefGoogle Scholar
  23. 23.
    Bronfman, M., Inestrosa, N.C. and Leighton, F. (1981) Biochem. Biophys. Res. Commun. 88, 1030–1136.CrossRefGoogle Scholar
  24. 24.
    Hashmi, M., Stanley, W. and Singh, I. (1986) Febs. Letts. 196, 247–250.CrossRefGoogle Scholar
  25. 25.
    Arias, J.A., Moser, A.B. and Goldfischer, S.L. (1985) J. Cell Biol. 100, 1789–1792.PubMedCrossRefGoogle Scholar
  26. 26.
    Pfeifer, U., and Sandhage, K. (1979) Virchows Arch. A. Pathol. 384, 269–284.Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1987

Authors and Affiliations

  • M. Hashmi
    • 1
  • W. Stanley
    • 1
    • 2
  • I. Singh
    • 1
  1. 1.Departments of PediatricsMedical University of South CarolinaCharlestonUSA
  2. 2.Departments of PathologyMedical University of South CarolinaCharlestonUSA

Personalised recommendations