Characterization of the human ω-oxidation pathway for ω-hydroxy-very-long-chain fatty acids Robert-Jan Sanders * , Rob Ofman * , Georges Dacremont † , Ronald J. A. Wanders * and Stephan Kemp * ,1 * Academic Medical Center, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Departments of Pediatrics/Emma Children’s Hospital and Clinical Chemistry, Amsterdam, The Netherlands; and † Department of Pediatrics, State University of Ghent, Ghent, Belgium 1 Correspondence: Laboratory Genetic Metabolic Diseases, Room F0-224, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. E-mail: s.kemp@amc.uva.nl 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 ω-oxidation, which may provide an alternative route for the breakdown of VLCFAs. The ω-oxidation of VLCFA is initiated by CYP4F2 and CYP4F3B, which produce ω-hydroxy-VLCFAs. In this article, we characterized the enzymes involved in the formation of very-long-chain dicarboxylic acids from ω-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 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 ω-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.—Sanders, R.-J., Ofman, R., Dacremont, G., Wanders, R. J. A., Kemp, S. Characterization of the human ω-oxidation pathway for ω-hydroxy-very-long-chain fatty acids. Key Words: X-linked adrenoleukodystrophy • cytochrome P450 • Sjögren-Larson syndrome • ALDH3A2
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Characterization of the human Ω-oxidation pathway for Ω-hydroxy-very-long-chain fatty acids
Sanders, Robert-Jan; Ofman, Rob; Dacremont, Georges; Wanders, Ronald J. A.; Kemp, Stephan
Follow The FASEB Journal
, Volume 22 (6): 2064
Fed of American Socs for Experimental Biology – Jun 1, 2008
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