Clofibric acid, phenylpyruvate, and dichloroacetate inhibition of branched-chain alpha-ketoacid dehydrogenase kinase in vitro and in perfused rat heart.
Branched-chain alpha-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 microM 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 alpha-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 alpha-keto[1-14C]isovalerate) through branched-chain alpha-ketoacid dehydrogenase in perfused rat heart. These findings suggest that, although clofibric acid and phenylpyruvate can inhibit substrate utilization by the branched-chain alpha-ketoacid dehydrogenase complex, the major effect of these compounds on branched-chain amino acid metabolism is due to inhibition of branched-chain alpha-ketoacid dehydrogenase kinase with subsequent activation of and increased flux through the complex.
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D002994:Clofibrate / Q000031:analogs & derivatives*; D002995:Clofibric Acid / Q000494:pharmacology*; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D010477:Perfusion; D010667:Phenylpyruvic Acids / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
D000085:Acetates; D010667:Phenylpyruvic Acids; D047428:Protein Kinase Inhibitors; D002995:Clofibric Acid; D003999:Dichloroacetic Acid; D011494:Protein Kinases; C035627:(3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase; D002994:Clofibrate; C031606:phenylpyruvic acid