Regulation of branched-chain α-ketoacid dehydrogenase kinase

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Abstract

Isolated rabbit liver branched-chain α-ketoacid dehydrogenase was inhibited in a mixed manner relative to ATP by α-ketoisocaproate, α-keto-β-methylvalerate, α-ketoisovalerate, α-ketocaproate, α-ketovalerate, and α-chloroisocaproate with I40 values mm), respectively, of 0.065, 0.49, 2.5, 0.2, 0.5, and 0.08. The concentration (mm) of α-ketoisocaproate, α-keto-β-methylvalerate, and α-ketoisovalerate needed to activate branched-chain α-ketoacid dehydrogenase in the perfused rat heart to 50% of total activity was 0.07, 0.10, and 0.25, respectively. Isolated branched-chain α-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 μg/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, β-hydroxy-β-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 α-ketoacid dehydrogenase kinase; acetate, propionate, β-hydroxybutyrate, lactate, acetoacetate, malonate, α-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 α-ketoacid dehydrogenase.

References (50)

  • D.E. Matthews et al.

    Metabolism

    (1982)
  • H.A. Krebs et al.

    Advan. Enzyme Reg

    (1977)
  • F.L. Shinnick et al.

    Biochim. Biophys. Acta

    (1976)
  • R. Paxton et al.

    J. Biol. Chem

    (1982)
  • R.A. Harris et al.

    Biochem. Biophys. Res. Commun

    (1982)
  • R.A. Harris et al.

    J. Biol. Chem

    (1982)
  • M.E. Swendseid et al.

    Amer. J. Clin. Nutr

    (1965)
  • L. Hambraeus et al.

    J. Nutr

    (1976)
  • F.L. Shinnick et al.

    J. Nutr

    (1977)
  • U. Panten et al.

    FEBS Lett

    (1972)
  • S. Lenzen

    Biochem. Pharmacol

    (1978)
  • A. Sener et al.

    J. Biol. Chem

    (1983)
  • B. Chua et al.

    J. Biol. Chem

    (1979)
  • M.E. Tischler et al.

    J. Biol. Chem

    (1982)
  • G.P. Frick et al.

    J. Biol. Chem

    (1981)
  • H.R. Fatania et al.

    FEBS Lett

    (1983)
  • K.S. Lau et al.

    FEBS Lett

    (1982)
  • R.M. Sans et al.

    Arch. Biochem. Biophys

    (1980)
  • M.L. Pratt et al.

    J. Biol. Chem

    (1979)
  • G.M. Hathaway et al.

    J. Biol. Chem

    (1980)
  • A.A. DePaoli-Roach et al.

    Arch. Biochem. Biophys

    (1982)
  • H.S. Paul et al.

    Metabolism

    (1978)
  • F.H. Pettit et al.

    Biochem. Biophys. Res. Commun

    (1975)
  • P.P. Waymack et al.

    J. Biol. Chem

    (1980)
  • D.J. Danner et al.

    J. Biol. Chem

    (1982)
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    Supported in part by NIH Research Grants AM19259 and 5 S07 RR5371 and the Grace M. Showalter Residuary Trust.

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