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

Abstract	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 beta-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 27,000 g 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.
Authors	P A Watkins, J F Lu, L T Braiterman, S J Steinberg, K D Smith
Journal	Cell biochemistry and biophysics (Cell Biochem Biophys) Vol. 32 Spring Pg. 333-7 ( 2000) ISSN: 1085-9195 [Print] United States
PMID	11330068 (Publication Type: Journal Article)
Chemical References	Coenzyme A Ligases
Topics	Adrenoleukodystrophy (etiology, genetics) Coenzyme A Ligases (genetics, metabolism) Gene Deletion Gene Expression Regulation, Enzymologic Gene Expression Regulation, Fungal Genes, Fungal Humans Saccharomyces cerevisiae (genetics)

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