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J. Biol. Chem., Vol. 280, Issue 29, 26838-26844, July 22, 2005

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Characterization of the Final Step in the Conversion of Phytol into Phytanic Acid^*

Daan M. van den Brink, Joram N. I. van Miert, Georges Dacremont¶, Jean-François Rontani||, and Ronald J. A. Wanders**

From the Departments of Clinical Chemistry and Pediatrics, University of Amsterdam, Academic Medical Center, Emma Children's Hospital, 1105 AZ Amsterdam, The Netherlands, ^¶University of Ghent, 9000 Ghent, Belgium, and ^||Laboratoire de Microbiologie, Géochimie et Ecologie Marines (UMR 6117), Centre d'Océanologie de Marseille, Campus de Luminy, 13288 Marseille, France

Phytol is a branched-chain fatty alcohol that is a naturally occurring precursor of phytanic acid, a fatty acid involved in the pathogenesis of Refsum disease. The conversion of phytol into phytanic acid is generally believed to take place via three enzymatic steps that involve 1) oxidation to its aldehyde, 2) further oxidation to phytenic acid, and 3) reduction of the double bond at the 2,3 position, yielding phytanic acid. Our recent investigations of this mechanism have elucidated the enzymatic steps leading to phytenic acid production, but the final step of the pathway has not been investigated so far. In this study, we describe the characterization of phytenic acid reduction in rat liver. NADPH-dependent conversion of phytenic acid into phytanic acid was detected, although at a slow rate. However, it was shown that phytenic acid can be activated to its CoA ester and that reduction of phytenoyl-CoA is much more efficient than that of phytenic acid. Furthermore, in rat hepatocytes cultured in the presence of phytol, phytenoyl-CoA could be detected, showing that it is a bona fide intermediate of phytol degradation. Subcellular fractionation experiments revealed that phytenoyl-CoA reductase activity is present in peroxisomes and mitochondria. With these findings, we have accomplished the full elucidation of the mechanism by which phytol is converted into phytanic acid.

Received for publication, February 18, 2005 , and in revised form, April 22, 2005.

^* This work was supported by a grant from the Meelmeijer Fund and Grant QLG3-2002-00696 from the European Commission. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Laboratory for Genetic Metabolic Diseases (F0-224), Dept. of Pediatrics, Academic Medical Center, University of Amsterdam, P. O. Box 22700, 1100 DE Amsterdam, The Netherlands. Tel.: 31-205664197; Fax: 31-206962596; E-mail: R.J.Wanders{at}amc.uva.nl.

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