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J. Biol. Chem., Vol. 276, Issue 41, 38115-38120, October 12, 2001
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From the Department of Neurogenetics, Kennedy Krieger Institute and
the Department of Neurology, Johns Hopkins University School of
Medicine, Baltimore, Maryland 21205
Docosahexaenoic acid (DHA,
C22:6n-3) is essential for normal brain and retinal
development. The nature and subcellular location of the terminal steps
in DHA biosynthesis have been controversial. Rather than direct
Peroxisomal Straight-chain Acyl-CoA Oxidase and D-bifunctional
Protein Are Essential for the Retroconversion Step in Docosahexaenoic
Acid Synthesis*
,
4-desaturation of C22:5n-3, it has been proposed that
this intermediate is elongated to C24:5n-3, desaturated to C24:6n-3, and "retroconverted" to DHA via peroxisomal
-oxidation. However, this hypothesis has recently been challenged.
The goal of this study was to determine the mechanism and specific
enzymes required for the retroconversion step in human skin
fibroblasts. Cells from patients with deficiencies of either acyl-CoA
oxidase or D-bifunctional protein, the first two enzymes of the
peroxisomal straight-chain fatty acid -oxidation pathway, exhibited
impaired (5-20% of control) conversion of either
[1-14C]18:3n-3 or
[1-14C]22:5n-3 to DHA as did cells from
peroxisome biogenesis disorder patients comprising eight distinct
genotypes. In contrast, normal DHA synthesis was observed in cells from
patients with rhizomelic chondrodysplasia punctata, Refsum disease,
X-linked adrenoleukodystrophy, and deficiency of mitochondrial medium-
or very long-chain acyl-CoA dehydrogenase. Acyl-CoA oxidase-deficient
cells accumulated 2-5 times more radiolabeled C24:6n-3
than did controls. Our data are consistent with the retroconversion
hypothesis and demonstrate that peroxisomal -oxidation enzymes
acyl-CoA oxidase and D-bifunctional protein are essential for this
process in human skin fibroblasts.
*
This work was supported by National Institutes of Health
Grants HD39860, HD10981, HD24061, and RR00052.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Neurogenetics, Kennedy Krieger Institute, 707 N. Broadway,
Baltimore, MD 21205. Tel.: 410-502-8149; Fax: 410-502-8279;
E-mail:su@kennedykrieger.org.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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