TY - JOUR
T1 - Peroxisomal fatty acid uptake mechanism in Saccharomyces cerevisiae.
AU - van Roermund, C.W.T.
AU - Ijlst, L.
AU - Majczak, W.
AU - Waterham, H.R.
AU - Folkerts, H.
AU - Wanders, R.J.A.
AU - Hellingwerf, K.J.
PY - 2012
Y1 - 2012
N2 - Peroxisomes play a major role in human cellular lipid metabolism, including fatty acid beta-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 beta-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.
AB - Peroxisomes play a major role in human cellular lipid metabolism, including fatty acid beta-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 beta-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.
U2 - https://doi.org/10.1074/jbc.M111.332833
DO - https://doi.org/10.1074/jbc.M111.332833
M3 - Article
C2 - 22493507
SN - 0021-9258
VL - 287
SP - 20144
EP - 20153
JO - The Journal of Biological Chemistry
JF - The Journal of Biological Chemistry
IS - 24
ER -