Characterization of the human ω‐oxidation pathway for ω‐hydroxy‐very‐long‐chain fatty acids

Abstract

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 adre‐ noleukodystrophy. Recently, we demonstrated that VL CFAs 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 indepen dent pathways. The first is mediated by an as yet unidentified, microsomal NAD + ‐dependent alcohol de hydrogenase 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 com plete 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. FASEB J. 22, 2064–2071 (2008)