Regulation of branched-chain alpha-ketoacid dehydrogenase kinase.
Isolated rabbit liver branched-chain alpha-ketoacid dehydrogenase was inhibited in a mixed manner relative to ATP by alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, alpha-ketoisovalerate, alpha-ketocaproate, alpha-ketovalerate, and alpha-chloroisocaproate with I40 values (mM), respectively, of 0.065, 0.49, 2.5, 0.2, 0.5, and 0.08. The concentration (mM) of alpha-ketoisocaproate, alpha-keto-beta-methylvalerate, and alpha-ketoisovalerate needed to activate branched-chain alpha-ketoacid dehydrogenase in the perfused rat heart to 50% of total activity was 0.07, 0.10, and 0.25, respectively. Isolated branched-chain alpha-ketoacid dehydrogenase kinase was inhibited (I40 values, mM) by octanoate (0.5), acetoacetyl-CoA (0.01), methylmalonyl-CoA (0.2), NADP+ (1.5), and heparin (12 micrograms/ml). The kinase activity, in the presence or absence of ADP, was inhibited approximately 30% by 0.1 mM isobutyryl-CoA, isovaleryl-CoA, and malonyl-CoA, while not affected by NAD+ and NADH (1 mM), CoA, acetyl-CoA, methylcrotonyl-CoA, crotonyl-CoA, beta-hydroxy-beta-methyl-glutaryl-CoA, octanoyl-CoA, succinyl-CoA, and propionyl-CoA (0.1 mM). The following compounds at 2 mM also did not inhibit branched-chain alpha-ketoacid dehydrogenase kinase; acetate, propionate, beta-hydroxybutyrate, lactate, acetoacetate, malonate, alpha-ketomalonate, succinate, citrate, oxaloacetate, FAD, and NADPH. These findings help explain the unique effects of Leu compared with Val and Ile on branched-chain amino acid metabolism and the differences between control of the kinases associated with pyruvate dehydrogenase and branched-chain alpha-ketoacid dehydrogenase.
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D009206:Myocardium / Q000201:enzymology; D010477:Perfusion; D011494:Protein Kinases / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C035627:(3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase