Inhibition of branched chain alpha-ketoacid dehydrogenase kinase activity by alpha-chloroisocaproate.
alpha-Chloroisocaproate has been shown to inhibit phosphorylation and inactivation of rabbit liver branched chain alpha-ketoacid dehydrogenase complex. Phosphorylation of pyruvate dehydrogenase was also inhibited by this alpha-ketoisocaproate analog, but phosphorylation of branched chain alpha-ketoacid dehydrogenase was much more sensitive than phosphorylation of pyruvate dehydrogenase (I50 values of 7.5 and 675 microM, respectively). Phosphorylation of glycogen synthase by six other protein kinases was not inhibited by alpha-chloroisocaproate (1 mM). Although less sensitive than phosphorylation of the complex, branched chain alpha-ketoacid dehydrogenase was also found inhibited by alpha-chloroisocaproate. The latter inhibition was competitive with respect to the alpha-ketoacid substrates of the dehydrogenase (Ki values of approximately 0.5 mM). alpha-Chloroisocaproate greatly stimulated the capacity of the perfused rat heart to decarboxylate [1-14C]leucine and promoted conversion of practically all (99%) of the complex into the active form.
D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D000818:Animals; D002208:Caproates / Q000494:pharmacology*; D004789:Enzyme Activation; D006843:Hydrocarbons, Chlorinated; D007658:Ketone Oxidoreductases / Q000302:isolation & purification; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D009097:Multienzyme Complexes / Q000302:isolation & purification; D009206:Myocardium / Q000201:enzymology*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000302:isolation & purification; D051381:Rats; D011919:Rats, Inbred Strains
D002208:Caproates; D006843:Hydrocarbons, Chlorinated; D009097:Multienzyme Complexes; D047428:Protein Kinase Inhibitors; C036533:2-chloroisocaproic acid; D007658:Ketone Oxidoreductases; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D011494:Protein Kinases; C035627:(3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase