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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily D
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ATP Binding Cassette Transporter, Subfamily D, Member 1
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism*
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Adrenoleukodystrophy / genetics
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Adrenoleukodystrophy / metabolism
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Biological Transport, Active / physiology
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Coenzyme A Ligases / genetics
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Coenzyme A Ligases / metabolism
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Fatty Acid Transport Proteins / genetics
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Fatty Acid Transport Proteins / metabolism*
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Fatty Acids / genetics
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Fatty Acids / metabolism*
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Humans
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism
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Oxidation-Reduction
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Peroxisomes / genetics
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Peroxisomes / metabolism*
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism*
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism*
Substances
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ABCD1 protein, human
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ABCD2 protein, human
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ATP Binding Cassette Transporter, Subfamily D
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ATP Binding Cassette Transporter, Subfamily D, Member 1
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ATP-Binding Cassette Transporters
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FAT1 protein, S cerevisiae
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Fatty Acid Transport Proteins
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Fatty Acids
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Multiprotein Complexes
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PXA1 protein, S cerevisiae
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PXA2 protein, S cerevisiae
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Saccharomyces cerevisiae Proteins
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Coenzyme A Ligases
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FAA2 protein, S cerevisiae