TY - JOUR
T1 - Phytanic acid must be activated to phytanoyl-CoA prior to its α-oxidation in rat liver peroxisomes
AU - Watkins, Paul A.
AU - Howard, Annette E.
AU - Mihalik, Stephanie J.
N1 - Funding Information:
We would like to thank Carol I. Chen, Anne M. Rainville, and Jamie J. Perry for excellent technical assistance. [2,3-3H]Dihydrophytol was kindly provided by Dr. William Rizzo, Medical College of Virginia, Richmond, VA. TDGA (McN-3802) was a gift from M.F. Ralston, McNeil Pharmaceutical,S pring House, PA. This work was supportedi n part by Basic Research Grant 92-0597 from the March of Dimes Birth Defects Foundation.
PY - 1994/10/6
Y1 - 1994/10/6
N2 - α-Oxidation of the branched-chain fatty acid, phytanic acid, is defective in patients with Refsum's disease, the disorders of peroxisome biogenesis (e.g., Zeilweger 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 H-release from [2,3-3H]phytanic acid in a dose-dependent manner. However, this inhibitor had little effect on H-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 [2,3-33H]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 α-oxidation.
AB - α-Oxidation of the branched-chain fatty acid, phytanic acid, is defective in patients with Refsum's disease, the disorders of peroxisome biogenesis (e.g., Zeilweger 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 H-release from [2,3-3H]phytanic acid in a dose-dependent manner. However, this inhibitor had little effect on H-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 [2,3-33H]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 α-oxidation.
KW - Acyl-CoA synthetase
KW - Peroxisome
KW - Phytanic acid
KW - Refsum's disease
KW - α-Oxidation
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U2 - 10.1016/0005-2760(94)90075-2
DO - 10.1016/0005-2760(94)90075-2
M3 - Article
C2 - 7918611
AN - SCOPUS:0028027674
SN - 0005-2760
VL - 1214
SP - 288
EP - 294
JO - Biochimica et Biophysica Acta (BBA)/Lipids and Lipid Metabolism
JF - Biochimica et Biophysica Acta (BBA)/Lipids and Lipid Metabolism
IS - 3
ER -