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

Noguchi, Seisuke, Kondo, Yusuke, Ito, Rina, Katayama, Takahiro, Kazama, Shunsuke, Kadota, Yoshihiro, Kitaura, Yasuyuki, Harris, Robert A., Shimomura, Yoshiharu
Biochemical and biophysical research communications 2018 v.504 no.4 pp. 916-920
calcium, exercise, inhibitory concentration 50, isoleucine, leucine, metabolism, mitochondria, oxidation, oxidoreductases, phosphorylation, protein kinases, skeletal muscle, thiamin, valine
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.