title: The human peroxisomal ABC half transporter ALDP functions as a homodimer and accepts acyl-CoA esters.
abstract: Peroxisomes play a major role in human cellular lipid metabolism, including the beta-oxidation of fatty acids. The most frequent peroxisomal disorder is X-linked adrenoleukodystrophy (X-ALD), which is caused by mutations in the ABCD1 gene. The protein involved, called ABCD1, or alternatively ALDP, is a member of the ATP-binding-cassette (ABC) transporter family and is located in the peroxisomal membrane. The biochemical hallmark of X-ALD is the accumulation of very long-chain fatty acids (VLCFAs), due to an impaired peroxisomal beta-oxidation. Although this suggests a role of ALDP in VLCFA import, no experimental evidence is available to substantiate this. In the yeast Saccharomyces cerevisiae, peroxisomes are the exclusive site of fatty acid beta-oxidation. Earlier work has shown that uptake of fatty acids into peroxisomes may occur via two routes, either as free fatty acids thus requiring intraperoxisomal activation into acyl-CoA esters or as long-chain acyl-CoA esters. The latter route involves the two peroxisomal half ABC transporters Pxa1p and Pxa2p that form a heterodimeric complex in the peroxisomal membrane. Using different strategies, including the analysis of intracellular acyl-CoA esters by tandem-MS, we show that the Pxa1p/Pxa2p heterodimer is involved in the transport of a spectrum of acyl-CoA esters. Interestingly, we found that the mutant phenotype of the pxa1/pxa2Delta mutant can be rescued, at least partially, by the sole expression of the human ABCD1 cDNA coding for ALDP, the protein that is defective in the human disease X-linked adrenoleukodystrophy. Our data indicate that ALDP can function as a homodimer and is involved in the transport of acyl-CoA esters across the peroxisomal membrane.
authors.affiliation: Lab Genetic Metabolic Diseases, Rm. F0-226, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. c.vanroermund@amc.uva.nl
authors.forename: Carlo W T
authors.initials: CW
authors.lastname: van Roermund
authors.forename: Wouter F
authors.initials: WF
authors.lastname: Visser
authors.forename: Lodewijk
authors.initials: L
authors.lastname: Ijlst
authors.forename: Arno
authors.initials: A
authors.lastname: van Cruchten
authors.forename: Maxim
authors.initials: M
authors.lastname: Boek
authors.forename: Wim
authors.initials: W
authors.lastname: Kulik
authors.forename: Hans R
authors.initials: HR
authors.lastname: Waterham
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders