Ca2+-dependent inhibition of branched-chain α-ketoacid dehydrogenase kinase by thiamine pyrophosphate

Biochem Biophys Res Commun. 2018 Oct 12;504(4):916-920. doi: 10.1016/j.bbrc.2018.09.038. Epub 2018 Sep 15.

Abstract

Catabolism of the branched-chain amino acids (BCAAs: leucine, isoleucine, and valine) is regulated by the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which in turn is regulated by phosphorylation catalyzed by BCKDH kinase (BDK). Thiamine pyrophosphate (TPP) is required as a coenzyme for the E1 component of the BCKDH complex and can also bring about activation of the complex by inhibiting BDK. The present study shows that free Ca2+ in the physiological range greatly increases the sensitivity of BDK to inhibition by TPP (IC50 of 2.5 μM in the presence of 1 μM free Ca2+). This novel mechanism may be responsible for the stimulation of BCAA oxidation by conditions that increase mitochondrial free Ca2+ levels, e.g. in skeletal muscle during exercise.

Keywords: Branched-chain amino acids; Branched-chain α-ketoacid dehydrogenase complex; Branched-chain α-ketoacid dehydrogenase kinase; Calcium ion; Thiamine pyrophosphate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / metabolism
  • Animals
  • Calcium / metabolism*
  • Calcium / pharmacology
  • Male
  • Mitochondria, Muscle / metabolism
  • Muscle, Skeletal / metabolism
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / metabolism*
  • Rats, Sprague-Dawley
  • Serine / metabolism
  • Thiamine Pyrophosphate / metabolism*
  • Thiamine Pyrophosphate / pharmacology

Substances

  • Protein Kinase Inhibitors
  • Serine
  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
  • Protein Kinases
  • (3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase
  • Thiamine Pyrophosphate
  • Calcium