Original Article

Stereochemistry of the -oxidation of 3-methyl-branched fatty acids in rat liver

Correspondence to: Kathleen Croes

The stereochemistry of the -oxidation of 3-methyl-branched fatty acids was studied in rat liver. R- and S-3-methylhexadecanoic acid were equally well -oxidized in intact hepatocytes and homogenates. Subcellular fractionation studies showed that -oxidation of both isomers is confined to peroxisomes. Dehydrogenation of 2-methylpentadecanal, the end-product of the peroxisomal -oxidation of 3-methylhexadecanoic acid, to 2-methylpentadecanoic acid, followed by derivatization with R-1-phenylethylamine and subsequent separation of the stereoisomers by gas chromatography, revealed that the configuration of the methyl-branch is preserved throughout the whole -oxidation process. Metabolism and formation of the 2-hydroxy-3-methylhexadecanoyl-CoA intermediate were also investigated. Separation of the methyl esters of the four isomers of 2-hydroxy-3-methylhexadecanoic acid was achieved by gas chromatography after derivatization of the hydroxy group with R-2-methoxy-2-trifluoromethylphenylacetic acid chloride and the absolute configuration of the four isomers was determined. Although purified peroxisomes are capable of metabolizing all four isomers of 2-hydroxy-3-methylhexadecanoyl-CoA, they can only form the (2S,3R) and the (2R,3S) isomers.

Our experiments exclude the racemization of the 3-methyl branch during the -oxidation process. The configuration of the 3-methyl branch does not influence the rate of -oxidation, but determines the side of the 2-hydroxylation, hence the configuration of the 2-hydroxy-3-methylacyl-CoA intermediates formed during the process.—Croes, K., M. Casteels, M. Dieuaide-Noubhani, G. P. Mannaerts, and P. P. Van Veldhoven. Stereochemistry of the -oxidation of 3-methyl-branched fatty acids in rat liver. J. Lipid Res. 1999. 40: 601–609.

Supplementary key words: peroxisome, phytanic acid, Refsum's disease, hydroxylation

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