| Autor: |
Sanders, Robert-Jan, Ofman, Rob, Dacremont, Georges, Wanders, Ronald J. A., Kemp, Stephan |
| Předmět: |
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| Zdroj: |
FASEB Journal; Jun2008, Vol. 22 Issue 6, p2064-2071, 8p, 1 Diagram, 2 Charts, 6 Graphs |
| Abstrakt: |
Very-long-chain fatty acids (VLCFAs) have long been known to be degraded exclusively in peroxisomes via β-oxidation. A defect in peroxisomal β-oxidation results in elevated levels of VLCFAs and is associated with the most frequent inherited disorder of the central nervous system white matter, X-linked adrenoleukodystrophy. Recently, we demonstrated that VLCFAs can also undergo to-oxidation, which may provide an alternative route for the breakdown of VLCFAs. The co-oxidation of VLCFA is initiated by CYP4F2 and CYP4F3B, which produce to-hydroxy-VLCFAs. In this article, we characterized the enzymes involved in the formation of very-long-chain dicarboxylic acids from to-hydroxy-VLCFAs. We demonstrate that very-long-chain dicarboxylic acids are produced v/a two independent pathways. The first is mediated by an as yet unidentified, microsomal NAD+-dependent alcohol dehydrogenase and fatty aldehyde dehydrogenase, which is encoded by the ALDH3A2 gene and is deficient in patients with Sjögren-Larsson syndrome. The second pathway involves the NADPH-dependent hydroxylation of ω-hydroxy-VLCFAs by CYP4F2, CYP4F3B, or CYP4F3A. Enzyme kinetic studies show that oxidation of to-hydroxy-VLCFAs occurs predominantly via the NAD+-dependent route. Overall, our data demonstrate that in humans all enzymes are present for the complete conversion of VLCFAs to their corresponding very-long-chain dicarboxylic acids. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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