title: Peroxisomal fatty acid uptake mechanism in Saccharomyces cerevisiae.
abstract: Peroxisomes play a major role in human cellular lipid metabolism, including fatty acid β-oxidation. The most frequent peroxisomal disorder is X-linked adrenoleukodystrophy, which is caused by mutations in ABCD1. The biochemical hallmark of X-linked adrenoleukodystrophy is the accumulation of very long chain fatty acids (VLCFAs) due to impaired peroxisomal β-oxidation. Although this suggests a role of ABCD1 in VLCFA import into peroxisomes, no direct experimental evidence is available to substantiate this. To unravel the mechanism of peroxisomal VLCFA transport, we use Saccharomyces cerevisiae as a model organism. Here we provide evidence that in this organism very long chain acyl-CoA esters are hydrolyzed by the Pxa1p-Pxa2p complex prior to the actual transport of their fatty acid moiety into the peroxisomes with the CoA presumably being released into the cytoplasm. The Pxa1p-Pxa2p complex functionally interacts with the acyl-CoA synthetases Faa2p and/or Fat1p on the inner surface of the peroxisomal membrane for subsequent re-esterification of the VLCFAs. Importantly, the Pxa1p-Pxa2p complex shares this molecular mechanism with HsABCD1 and HsABCD2.
authors.affiliation: Departments of Pediatrics and Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands. c.vanroermund@amc.uva.nl
authors.forename: Carlo W T
authors.initials: CW
authors.lastname: van Roermund
authors.forename: Lodewijk
authors.initials: L
authors.lastname: Ijlst
authors.forename: Wiktor
authors.initials: W
authors.lastname: Majczak
authors.forename: Hans R
authors.initials: HR
authors.lastname: Waterham
authors.forename: Hendrik
authors.initials: H
authors.lastname: Folkerts
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Klaas J
authors.initials: KJ
authors.lastname: Hellingwerf
mesh_terms: D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000326:Adrenoleukodystrophy / Q000235:genetics / Q000378:metabolism; D001693:Biological Transport, Active / Q000502:physiology; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism; D050612:Fatty Acid Transport Proteins / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C115572:ABCD1 protein, human; C431694:ABCD2 protein, human; D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C105342:FAT1 protein, S cerevisiae; D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids; D046912:Multiprotein Complexes; C098338:PXA1 protein, S cerevisiae; C103561:PXA2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D003066:Coenzyme A Ligases; C090799:FAA2 protein, S cerevisiae