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Characterization of the human omega-oxidation pathway for omega-hydroxy-very-long-chain fatty acids

(2008) FASEB JOURNAL. 22(6). p.2064-2071
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Abstract
Very-long-chain fatty acids (VLCFAs) have long been known to be degraded exclusively in peroxisomes via beta-oxidation. A defect in peroxisomal beta-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 omega-oxidation, which may provide an alternative route for the breakdown of VLCFAs. The omega-oxidation of VLCFA is initiated by CYP4F2 and CYP4F3B, which produce omega-hydroxy-VLCFAs. In this article, we characterized the enzymes involved in the formation of very-long-chain dicarboxylic acids from omega-hydroxy-VLCFAs. We demonstrate that very-long-chain dicarboxylic acids are produced via 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 Sjogren-Larsson syndrome. The second pathway involves the NADPH-dependent hydroxylation of omega-hydroxy-VLCFAs by CYP4F2, CYP4F3B, or CYP4F3A. Enzyme kinetic studies show that oxidation of omega-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.
Keywords
Sjogren-Larson syndrome, ALDH3A2, LOCALIZATION, OXIDOREDUCTASE, IDENTIFICATION, FAMILY, GENE, RAT-LIVER, ALDEHYDE DEHYDROGENASE, FIBROBLASTS, X-linked adrenoleukodystrophy, cytochrome P450, X-LINKED ADRENOLEUKODYSTROPHY, SJOGREN-LARSSON-SYNDROME

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Citation

Please use this url to cite or link to this publication:

MLA
Sanders, Robert-Jan et al. “Characterization of the Human Omega-oxidation Pathway for Omega-hydroxy-very-long-chain Fatty Acids.” FASEB JOURNAL 22.6 (2008): 2064–2071. Print.
APA
Sanders, R.-J., Ofman, R., Dacremont, G., Wanders, R. J. A., & Kemp, S. (2008). Characterization of the human omega-oxidation pathway for omega-hydroxy-very-long-chain fatty acids. FASEB JOURNAL, 22(6), 2064–2071.
Chicago author-date
Sanders, Robert-Jan, Rob Ofman, Georges Dacremont, Ronald J. A. Wanders, and Stephan Kemp. 2008. “Characterization of the Human Omega-oxidation Pathway for Omega-hydroxy-very-long-chain Fatty Acids.” Faseb Journal 22 (6): 2064–2071.
Chicago author-date (all authors)
Sanders, Robert-Jan, Rob Ofman, Georges Dacremont, Ronald J. A. Wanders, and Stephan Kemp. 2008. “Characterization of the Human Omega-oxidation Pathway for Omega-hydroxy-very-long-chain Fatty Acids.” Faseb Journal 22 (6): 2064–2071.
Vancouver
1.
Sanders R-J, Ofman R, Dacremont G, Wanders RJA, Kemp S. Characterization of the human omega-oxidation pathway for omega-hydroxy-very-long-chain fatty acids. FASEB JOURNAL. 2008;22(6):2064–71.
IEEE
[1]
R.-J. Sanders, R. Ofman, G. Dacremont, R. J. A. Wanders, and S. Kemp, “Characterization of the human omega-oxidation pathway for omega-hydroxy-very-long-chain fatty acids,” FASEB JOURNAL, vol. 22, no. 6, pp. 2064–2071, 2008.
@article{745741,
  abstract     = {Very-long-chain fatty acids (VLCFAs) have long been known to be degraded exclusively in peroxisomes via beta-oxidation. A defect in peroxisomal beta-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 omega-oxidation, which may provide an alternative route for the breakdown of VLCFAs. The omega-oxidation of VLCFA is initiated by CYP4F2 and CYP4F3B, which produce omega-hydroxy-VLCFAs. In this article, we characterized the enzymes involved in the formation of very-long-chain dicarboxylic acids from omega-hydroxy-VLCFAs. We demonstrate that very-long-chain dicarboxylic acids are produced via 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 Sjogren-Larsson syndrome. The second pathway involves the NADPH-dependent hydroxylation of omega-hydroxy-VLCFAs by CYP4F2, CYP4F3B, or CYP4F3A. Enzyme kinetic studies show that oxidation of omega-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.},
  author       = {Sanders, Robert-Jan and Ofman, Rob and Dacremont, Georges and Wanders, Ronald J. A. and Kemp, Stephan},
  issn         = {0892-6638},
  journal      = {FASEB JOURNAL},
  keywords     = {Sjogren-Larson syndrome,ALDH3A2,LOCALIZATION,OXIDOREDUCTASE,IDENTIFICATION,FAMILY,GENE,RAT-LIVER,ALDEHYDE DEHYDROGENASE,FIBROBLASTS,X-linked adrenoleukodystrophy,cytochrome P450,X-LINKED ADRENOLEUKODYSTROPHY,SJOGREN-LARSSON-SYNDROME},
  language     = {eng},
  number       = {6},
  pages        = {2064--2071},
  title        = {Characterization of the human omega-oxidation pathway for omega-hydroxy-very-long-chain fatty acids},
  url          = {http://dx.doi.org/10.1096/fj.07-099150},
  volume       = {22},
  year         = {2008},
}

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