Clofibric acid, phenylpyruvate, and dichloroacetate inhibition of branched-chain α-ketoacid dehydrogenase kinase in vitro and in perfused rat heart

Ralph Paxton, Robert Harris

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Branched-chain α-ketoacid dehydrogenase kinase, purified from rabbit liver, was inhibited by clofibric acid, phenylpyruvate, and dichloroacetate in a mixed manner relative to ATP. I40 values relative to 75 μm ATP were 0.33, 1.7, and 3.0 mm, respectively. Inhibition of the kinase by acetate, pyruvate, and lactate was minimal; whereas a p-hydroxyphenyl substitution of these compounds increased their potency as kinase inhibitors, a phenyl substitution gave the most potent inhibitors. Clofibric acid, phenylpyruvate, and dichloroacetate activated branched-chain α-ketoacid dehydrogenase in perfused rat hearts. Perfusate concentrations that gave 50% activation (A50) were 0.1, 0.32, and 0.63 mm, respectively. A50 concentrations of clofibric acid and phenylpyruvate also increased flux (decarboxylation of α-keto[1-14C]isovalerate) through branched-chain α-ketoacid dehydrogenase in perfused rat heart. These findings suggest that, although clofibric acid and phenylpyruvate can inhibit substrate utilization by the branched-chain α-ketoacid dehydrogenase complex, the major effect of these compounds on branched-chain amino acid metabolism is due to inhibition of branched-chain α-ketoacid dehydrogenase kinase with subsequent activation of and increased flux through the complex.

Original languageEnglish
Pages (from-to)58-66
Number of pages9
JournalArchives of Biochemistry and Biophysics
Volume231
Issue number1
DOIs
StatePublished - May 15 1984

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Clofibric Acid
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
Rats
Phosphotransferases
Substitution reactions
Acetate Kinase
Adenosine Triphosphate
Chemical activation
Fluxes
Enzyme inhibition
Branched Chain Amino Acids
Decarboxylation
Pyruvate Kinase
Pyruvic Acid
Metabolism
Liver
Lactic Acid
phenylpyruvic acid
In Vitro Techniques
Rabbits

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

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title = "Clofibric acid, phenylpyruvate, and dichloroacetate inhibition of branched-chain α-ketoacid dehydrogenase kinase in vitro and in perfused rat heart",
abstract = "Branched-chain α-ketoacid dehydrogenase kinase, purified from rabbit liver, was inhibited by clofibric acid, phenylpyruvate, and dichloroacetate in a mixed manner relative to ATP. I40 values relative to 75 μm ATP were 0.33, 1.7, and 3.0 mm, respectively. Inhibition of the kinase by acetate, pyruvate, and lactate was minimal; whereas a p-hydroxyphenyl substitution of these compounds increased their potency as kinase inhibitors, a phenyl substitution gave the most potent inhibitors. Clofibric acid, phenylpyruvate, and dichloroacetate activated branched-chain α-ketoacid dehydrogenase in perfused rat hearts. Perfusate concentrations that gave 50{\%} activation (A50) were 0.1, 0.32, and 0.63 mm, respectively. A50 concentrations of clofibric acid and phenylpyruvate also increased flux (decarboxylation of α-keto[1-14C]isovalerate) through branched-chain α-ketoacid dehydrogenase in perfused rat heart. These findings suggest that, although clofibric acid and phenylpyruvate can inhibit substrate utilization by the branched-chain α-ketoacid dehydrogenase complex, the major effect of these compounds on branched-chain amino acid metabolism is due to inhibition of branched-chain α-ketoacid dehydrogenase kinase with subsequent activation of and increased flux through the complex.",
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AU - Harris, Robert

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AB - Branched-chain α-ketoacid dehydrogenase kinase, purified from rabbit liver, was inhibited by clofibric acid, phenylpyruvate, and dichloroacetate in a mixed manner relative to ATP. I40 values relative to 75 μm ATP were 0.33, 1.7, and 3.0 mm, respectively. Inhibition of the kinase by acetate, pyruvate, and lactate was minimal; whereas a p-hydroxyphenyl substitution of these compounds increased their potency as kinase inhibitors, a phenyl substitution gave the most potent inhibitors. Clofibric acid, phenylpyruvate, and dichloroacetate activated branched-chain α-ketoacid dehydrogenase in perfused rat hearts. Perfusate concentrations that gave 50% activation (A50) were 0.1, 0.32, and 0.63 mm, respectively. A50 concentrations of clofibric acid and phenylpyruvate also increased flux (decarboxylation of α-keto[1-14C]isovalerate) through branched-chain α-ketoacid dehydrogenase in perfused rat heart. These findings suggest that, although clofibric acid and phenylpyruvate can inhibit substrate utilization by the branched-chain α-ketoacid dehydrogenase complex, the major effect of these compounds on branched-chain amino acid metabolism is due to inhibition of branched-chain α-ketoacid dehydrogenase kinase with subsequent activation of and increased flux through the complex.

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