title: Characterization of the human omega-oxidation pathway for omega-hydroxy-very-long-chain fatty acids.
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 Sjögren-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.
authors.affiliation: Academic Medical Center, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam, The Netherlands.
authors.forename: Robert-Jan
authors.initials: RJ
authors.lastname: Sanders
authors.forename: Rob
authors.initials: R
authors.lastname: Ofman
authors.forename: Georges
authors.initials: G
authors.lastname: Dacremont
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Stephan
authors.initials: S
authors.lastname: Kemp
mesh_terms: D000326:Adrenoleukodystrophy; D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D003998:Dicarboxylic Acids / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D053858:Metabolic Networks and Pathways; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction
chemical_list: D003998:Dicarboxylic Acids; D005227:Fatty Acids; D009243:NAD; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C465349:CYP4F3 protein, human; D000445:Aldehyde Oxidoreductases; C038828:long-chain-aldehyde dehydrogenase