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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)333-337
Number of pages5
JournalCell Biochemistry and Biophysics
StatePublished - 2000


  • Peroxisomes
  • Saccharomyces cerevisiae
  • Very-long chain acyl-CoA synthetase (VLCS)
  • Very-long chain fatty acids (VLCFAs)
  • X-linked adrenoleukodystrophy (X-ALD)
  • Yeast

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology


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