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: P A Watkins, A E Howard, S J Mihalik
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1214 Issue 3 Pg. 288-94 (Oct 06 1994) ISSN: 0006-3002 [Print] Netherlands
• PMID: 7918611 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protons
• Repressor Proteins
• Saccharomyces cerevisiae Proteins
• phytanoyl-coenzyme A
• Tritium
• 5,8,11,14-Eicosatetraynoic Acid
• Phytanic Acid
• Coenzyme A Ligases
• FAA2 protein, S cerevisiae
• long-chain-fatty-acid-CoA ligase
• Coenzyme A

Topics

• 5,8,11,14-Eicosatetraynoic Acid (pharmacology)
• Animals
• Coenzyme A (antagonists & inhibitors, metabolism)
• Coenzyme A Ligases (antagonists & inhibitors, metabolism)
• Female
• Liver (enzymology, metabolism)
• Microbodies (metabolism)
• Oxidation-Reduction
• Phytanic Acid (analogs & derivatives, antagonists & inhibitors, metabolism)
• Protons
• Rats
• Repressor Proteins
• Saccharomyces cerevisiae Proteins
• Tritium