Abstract
Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid derived from dietary sources and broken down in the peroxisome to pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) via α-oxidation. Pristanic acid then undergoes β-oxidation in peroxisomes. Phytanic acid naturally occurs as a mixture of (3S,7R,11R)- and (3R,7R,11R)-diastereomers. In contrast to the α-oxidation system, peroxisomal β-oxidation is stereospecific and only accepts (2S)-isomers. Therefore, a racemase called α-methylacyl-CoA racemase is required to convert (2R)-pristanic acid into its (2S)-isomer. To further investigate the stereochemistry of the peroxisomal oxidation systems and their substrates, we have developed a method using gas-liquid chromatography-mass spectrometry to analyze the isomers of phytanic, pristanic, and trimethylundecanoic acid in plasma from patients with various peroxisomal fatty acid oxidation defects. In this study, we show that in plasma of patients with a peroxisomal β-oxidation deficiency, the relative amounts of the two diastereomers of pristanic acid are almost equal, whereas in patients with a defect of α-methylacyl-CoA racemase, (2R)-pristanic acid is the predominant isomer. Furthermore, we show that in α-methylacyl-CoA racemase deficiency, not only pristanic acid accumulates, but also one of the metabolites of pristanic acid, (2,6,10)-trimethylundecanoic acid, providing direct in vivo evidence for the requirement of this racemase for the complete degradation of pristanic acid. —Ferdinandusse, S., H. Rusch, A. E. M. van Lint, G. Dacremont, R. J. A. Wanders, and P. Vreken. Stereochemistry of the peroxisomal branched-chain fatty acid α- and β-oxidation systems in patients suffering from different peroxisomal disorders.
Highlights
Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid derived from dietary sources and broken down in the peroxisome to pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) via ␣-oxidation
To obtain more insight in the stereochemistry of the peroxisomal oxidation systems and their substrates, we developed a method to determine the relative amounts of phytanic, pristanic, and trimethylundecanoic acid diastereomers in plasma samples of patients suffering from the various peroxisomal disorders described above
Gas-liquid chromatography-mass spectrometry (GC-MS) analysis of chemically synthesized standards of phytanic, pristanic, and trimethylundecanoic acid as their (R)-1-phenylethylamine derivatives resulted in two clusters of peaks for all three branched-chain fatty acids
Summary
Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid derived from dietary sources and broken down in the peroxisome to pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) via ␣-oxidation. We show that in plasma of patients with a peroxisomal -oxidation deficiency, the relative amounts of the two diastereomers of pristanic acid are almost equal, whereas in patients with a defect of ␣-methylacyl-CoA racemase, (2R)-pristanic acid is the predominant isomer. After activation of pristanic acid to its CoA-ester, pristanoylCoA is converted into 2,3-pristenoyl-CoA by branchedchain acyl-CoA oxidase (BCOX) This compound is hydrated to 3-hydroxy-pristanoyl-CoA and subsequently dehydrogenated to 3-keto-pristanoyl-CoA. In 1967, Ackman and Hansen studied the stereochemical composition of phytanic and pristanic acid in ruminant fats and fish oils They found that there are two diastereomers of these fatty acids present, namely the (S,R,R)- and (R,R,R)-isomers.
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