title: Phytanic acid must be activated to phytanoyl-CoA prior to its alpha-oxidation in rat liver peroxisomes.
abstract: alpha-Oxidation of the branched-chain fatty acid, phytanic acid, is defective in patients with Refsum's disease, the disorders of peroxisome biogenesis (e.g., Zellweger syndrome), and in rhizomelic chondrodysplasia punctata. 3H-Release from [2,3-3H]phytanic acid, which is impaired in cultured skin fibroblasts from these patients, was investigated in rat liver peroxisomes. Cofactors necessary for optimal 3H-release, ATP, Mg2+, and coenzyme A, were also necessary for optimal acyl-CoA synthetase activity, suggesting that the substrate for 3H-release might be phytanoyl-CoA. 5,8,11,14-Eicosatetraynoic acid (ETYA), an inhibitor of long-chain acyl-CoA synthetase activity, blocked phytanoyl-CoA synthesis as well as 3H-release from [2,3-3H]phytanic acid in a dose-dependent manner. However, this inhibitor had little effect on 3H-release from [2,3-3H]phytanoyl-CoA. Tetradecylglycidic acid (TDGA) inhibited 3H-release from [2,3-3H]phytanic acid in peroxisomal but not in mitochondrial fractions from rat liver. This agent inhibited 3H-release from [2,3-3H]phytanic acid and [2,3-3H]phytanoyl-CoA equally. In contrast to ETYA, which appeared to decrease 3H-release as a consequence of synthetase inhibition, TDGA appeared to act directly on the enzyme catalyzing 3H-release. This enzyme was partially purified from rat liver. The purified enzyme, which did not possess phytanoyl-CoA synthetase activity, catalyzed tritium release from [2,3-3H]phytanoyl-CoA. This enzyme catalyzed 3H-release from [2,3-3H]phytanic acid only if a source of phytanoyl-CoA synthetase was present. We conclude that in rat liver peroxisomes, phytanic acid must be activated to its coenzyme A derivative prior to subsequent alpha-oxidation.
authors.affiliation: Kennedy Krieger Research Institute, Baltimore, MD 21205.
authors.forename: P A
authors.initials: PA
authors.lastname: Watkins
authors.forename: A E
authors.initials: AE
authors.lastname: Howard
authors.forename: S J
authors.initials: SJ
authors.lastname: Mihalik
mesh_terms: D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D000818:Animals; D003065:Coenzyme A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008830:Microbodies / Q000378:metabolism*; D010084:Oxidation-Reduction; D010831:Phytanic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011522:Protons; D051381:Rats; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014316:Tritium; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D011522:Protons; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; C089917:phytanoyl-coenzyme A; D014316:Tritium; D015117:5,8,11,14-Eicosatetraynoic Acid; D010831:Phytanic Acid; D003066:Coenzyme A Ligases; C090799:FAA2 protein, S cerevisiae; D000098859:Long-Chain-Fatty-Acid-CoA Ligase; D003065:Coenzyme A