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This Article Full Text Full Text (PDF) All Versions of this Article: fj.07-099150v1 22/6/2064    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Sanders, R.-J. Articles by Kemp, S. PubMed PubMed Citation Articles by Sanders, R.-J. Articles by Kemp, S.

Characterization of the human -oxidation pathway for -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

¹Correspondence: Laboratory Genetic Metabolic Diseases, Room F0-224, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. E-mail: s.kemp{at}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 -oxidation, which may provide an alternative route for the breakdown of VLCFAs. The -oxidation of VLCFA is initiated by CYP4F2 and CYP4F3B, which produce -hydroxy-VLCFAs. In this article, we characterized the enzymes involved in the formation of very-long-chain dicarboxylic acids from -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 -hydroxy-VLCFAs by CYP4F2, CYP4F3B, or CYP4F3A. Enzyme kinetic studies show that oxidation of -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 -oxidation pathway for -hydroxy-very-long-chain fatty acids.

Key Words: X-linked adrenoleukodystrophy • cytochrome P450 • Sjögren-Larson syndrome • ALDH3A2