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Journal of Lipid Research, Vol. 44, 2349-2355, December 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Further studies on the substrate spectrum of phytanoyl-CoA hydroxylase

Veerle Foulon, Stanny Asselberghs, Wendy Geens, Guy P. Mannaerts, Minne Casteels and Paul P. Van Veldhoven¹

Departement Moleculaire Celbiologie, Afdeling Farmacologie, Katholieke Universiteit Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium

¹ To whom correspondence should be addressed. e-mail: paul.vanveldhoven{at}med.kuleuven.ac.be

Refsum disease is a peroxisomal disorder characterized by adult-onset retinitis pigmentosa, anosmia, sensory neuropathy, ataxia, and an accumulation of phytanic acid in plasma and tissues. Approximately 45% of cases are caused by mutations in phytanoyl-CoA hydroxylase (PAHX), the enzyme catalyzing the second step in the peroxisomal -oxidation of 3-methyl-branched fatty acids. To study the substrate specificity of human PAHX, different 3-alkyl-branched substrates were synthesized and incubated with a recombinant polyhistidine-tagged protein. The enzyme showed activity not only toward racemic phytanoyl-CoA and the isomers of 3-methylhexadecanoyl-CoA, but also toward a variety of other mono-branched 3-methylacyl-CoA esters with a chain length down to seven carbon atoms. Furthermore, PAHX hydroxylated a 3-ethylacyl-CoA quite well, whereas a 3-propylacyl-CoA was a poor substrate. Hydroxylation of neither 2- or 4-methyl-branched acyl-CoA esters, nor long or very long straight-chain acyl-CoA esters could be detected.

The results presented in this paper show that the substrate specificity of PAHX, with regard to the length of both the acyl-chain and the branch at position 3, is broader than expected. Hence, Refsum disease might be characterized by an accumulation of not only phytanic acid but also other 3-alkyl-branched fatty acids.

Supplementary key words -oxidation • 3-methyl-branched fatty acids • phytanic acid • peroxisomes • dioxygenases • stereochemistry

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