title: Mouse very long-chain acyl-CoA synthetase in X-linked adrenoleukodystrophy.
abstract: X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder characterized by accumulation of very long-chain fatty acids (VLCFA). This accumulation has been attributed to decreased VLCFA beta-oxidation and peroxisomal very long-chain acyl-CoA synthetase (VLCS) activity. The X-ALD gene, ABCD1, encodes a peroxisomal membrane ATP binding cassette transporter, ALDP, that is hypothesized to affect VLCS activity in peroxisomes by direct interaction with the VLCS enzyme. Recently, a VLCS gene that encodes a protein with significant sequence identity to known rat and human peroxisomal VLCS protein has been identified in mice. We find that the mouse VLCS gene (Vlcs) encodes an enzyme (Vlcs) with VLCS activity that localizes to peroxisomes and is expressed in X-ALD target tissues. We show that the expression of Vlcs in the peroxisomes of X-ALD mouse fibroblasts improves VLCFA beta-oxidation in these cells, implying a role for this enzyme in the biochemical abnormality of X-ALD. X-ALD mice, which accumulate VLCFA in tissues, show no change in the expression of Vlcs, the subcellular localization of Vlcs, or general peroxisomal VLCS activity. These observations imply that ALDP is not necessary for the proper expression or localization of Vlcs protein, and the control of VLCFA levels does not depend on the direct interaction of Vlcs and ALDP.
authors.affiliation: Kennedy Krieger Institute, the Department of Pediatrics, The Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Ann K
authors.initials: AK
authors.lastname: Heinzer
authors.forename: Stephan
authors.initials: S
authors.lastname: Kemp
authors.forename: Jyh-Feng
authors.initials: JF
authors.lastname: Lu
authors.forename: Paul A
authors.initials: PA
authors.lastname: Watkins
authors.forename: Kirby D
authors.initials: KD
authors.lastname: Smith
mesh_terms: D000326:Adrenoleukodystrophy / Q000201:enzymology* / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D019556:COS Cells; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003066:Coenzyme A Ligases / Q000096:biosynthesis* / Q000235:genetics; D018076:DNA, Complementary / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology; D051379:Mice; D008856:Microscopy, Fluorescence; D008862:Microsomes, Liver / Q000201:enzymology; D008969:Molecular Sequence Data; D020675:Peroxisomes / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins; D013347:Subcellular Fractions / Q000378:metabolism; D014018:Tissue Distribution; D014162:Transfection; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D018076:DNA, Complementary; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D002374:Catalase; D003066:Coenzyme A Ligases; C090799:FAA2 protein, S cerevisiae; D000098859:Long-Chain-Fatty-Acid-CoA Ligase