Peroxisomal fatty acid uptake mechanism in Saccharomyces cerevisiae

J Biol Chem. 2012 Jun 8;287(24):20144-53. doi: 10.1074/jbc.M111.332833. Epub 2012 Apr 9.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily D
  • ATP Binding Cassette Transporter, Subfamily D, Member 1
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Adrenoleukodystrophy / genetics
  • Adrenoleukodystrophy / metabolism
  • Biological Transport, Active / physiology
  • Coenzyme A Ligases / genetics
  • Coenzyme A Ligases / metabolism
  • Fatty Acid Transport Proteins / genetics
  • Fatty Acid Transport Proteins / metabolism*
  • Fatty Acids / genetics
  • Fatty Acids / metabolism*
  • Humans
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Oxidation-Reduction
  • Peroxisomes / genetics
  • Peroxisomes / metabolism*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • ABCD1 protein, human
  • ABCD2 protein, human
  • ATP Binding Cassette Transporter, Subfamily D
  • ATP Binding Cassette Transporter, Subfamily D, Member 1
  • ATP-Binding Cassette Transporters
  • FAT1 protein, S cerevisiae
  • Fatty Acid Transport Proteins
  • Fatty Acids
  • Multiprotein Complexes
  • PXA1 protein, S cerevisiae
  • PXA2 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Coenzyme A Ligases
  • FAA2 protein, S cerevisiae