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

Cell Biochemistry and Biophysics
Paul A WatkinsK D Smith

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 yeas...Continue Reading

Citations

Apr 12, 2012·The Journal of Biological Chemistry·Carlo W T van RoermundKlaas J Hellingwerf
May 29, 2004·Biochimica Et Biophysica Acta·Pedro BritesRonald J A Wanders
Apr 17, 2003·FEMS Microbiology Reviews·J Kalervo HiltunenAner Gurvitz
Aug 29, 2014·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Andreas B JordyJacob Jeppesen
Feb 9, 2005·The Journal of Biological Chemistry·Concetta C DiRussoPaul N Black

❮ Previous
Next ❯

Related Concepts

Related Feeds

Adrenoleukodystrophy

Adrenoleukodystrophy (ALD), the most frequent peroxisomal disorder, is an X-linked disorder caused by a defect in the metabolism of long chain fatty acids leading to demyelination, neurodegeneration, and death. Here is the latest research.