HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sanders, R.-J. Articles by Kemp, S. Search for Related Content 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

This article has been cited by other articles:

				M. G. McDonald, M. J. Rieder, M. Nakano, C. K. Hsia, and A. E. Rettie CYP4F2 Is a Vitamin K1 Oxidase: An Explanation for Altered Warfarin Dose in Carriers of the V433M Variant Mol. Pharmacol., June 1, 2009; 75(6): 1337 - 1346. [Abstract] [Full Text] [PDF]