Peroxisomal fatty acid uptake mechanism in Saccharomyces cerevisiae.

[x-linked adrenoleukodystrophy]

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 ABCD 1 . 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 ABCD 1 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 Pxa 1 p -Pxa 2 p complex prior to the actual transport of their fatty acid moiety into the peroxisomes with the CoA presumably being released into the cytoplasm . The Pxa 1 p -Pxa 2 p complex functionally interacts with the acyl-CoA synthetases Faa 2 p and /or Fat 1 p on the inner surface of the peroxisomal membrane for subsequent re -esterification of the VLCFAs . Importantly , the Pxa 1 p -Pxa 2 p complex shares this molecular mechanism with HsABCD 1 and HsABCD 2 .