Cell Biochemistry and Biophysics

, Volume 32, Issue 1–3, pp 333–337 | Cite as

Disruption of a yeast very-long-chain acyl-CoA synthetase gene simulates the cellular phenotype of X-linked adrenoleukodystrophy

  • Paul A. Watkins
  • Jyh-Feng Lu
  • Lelita T. Braiterman
  • Steven J. Steinberg
  • Kirby D. Smith
Part VI Papers from Poster Session


X-linked adrenoleukodystrophy (X-ALD) is characterized biochemically by elevated levels of saturated very long-chain fatty acids (VLCFAs) in plasma and tissues. In X-ALD, peroxisomal very-long-chain acyl-CoA synthetase (VLCS) fails to activate VLCFAs, preventing their degradation via β-oxidation. However, the product of the defective XALD gene (ALDP) is not a VLCS, but rather a peroxisomal membrane protein (PMP). Disruption of either or both of two yeast PMP genes related to the XALD gene did not produce a biochemical phenotype resembling that found in X-ALD fibroblasts. The authors identified a candidate yeast VLCS gene (the FAT1 locus) by its homology to rat liver VLCS. Disruption of this gene decreased VLCS activity, but had no effect on long-chain acyl-CoA synthetase activity. In FAT1-disruption strains, VLCS activity was reduced to 30–40% of wild-type in both a microsome-rich 27,000g supernatant fraction and a peroxisome- and mitochondria-rich pellet fraction of yeast spheroplast homogenates. Separation of the latter organelles by density gradient centrifugation revealed that VLCS activity was peroxisomal and not mitochondrial. VLCS gene-disruption strains had increased cellular VLCFA levels, compared to wild-type yeast. The extent of both the decrease in peroxisomal VLCS activity and the VLCFA accumulation in this yeast model resembles that observed in cells from X-ALD patients. Characterization of the gene(s) responsible for the residual peroxisomal VLCS activity may suggest new therapeutic approaches in X-ALD.

Index Entries

Peroxisomes yeast Saccharomyces cerevisiae very-long chain fatty acids (VLCFAs) very-long chain acyl-CoA synthetase (VLCS) X-linked adrenoleukodystrophy (X-ALD) 


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Copyright information

© Humana Press, Inc. 2000

Authors and Affiliations

  • Paul A. Watkins
    • 1
  • Jyh-Feng Lu
    • 2
  • Lelita T. Braiterman
    • 2
  • Steven J. Steinberg
    • 1
  • Kirby D. Smith
    • 2
  1. 1.Kennedy Krieger Institute and Department of NeurologyJohns Hopkins University School of MedicineBaltimore
  2. 2.Kennedy Krieger Institute and Department of PediatricsJohns Hopkins University School of MedicineBaltimoreMD

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