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

Seisuke Noguchi, Yusuke Kondo, Rina Ito, Takahiro Katayama, Shunsuke Kazama, Yoshihiro Kadota, Yasuyuki Kitaura, Robert Harris, Yoshiharu Shimomura

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)916-920
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume504
Issue number4
DOIs
StatePublished - Oct 12 2018
Externally publishedYes

Fingerprint

thiamin-diphosphate kinase
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
Thiamine Pyrophosphate
Phosphotransferases
Branched Chain Amino Acids
Phosphorylation
Isoleucine
Coenzymes
Valine
Leucine
Inhibitory Concentration 50
Muscle
Skeletal Muscle
Chemical activation
Oxidation

Keywords

  • Branched-chain amino acids
  • Branched-chain α-ketoacid dehydrogenase complex
  • Branched-chain α-ketoacid dehydrogenase kinase
  • Calcium ion
  • Thiamine pyrophosphate

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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; Shimomura, Yoshiharu.

In: Biochemical and Biophysical Research Communications, Vol. 504, No. 4, 12.10.2018, p. 916-920.

Research output: Contribution to journalArticle

Noguchi, Seisuke ; Kondo, Yusuke ; Ito, Rina ; Katayama, Takahiro ; Kazama, Shunsuke ; Kadota, Yoshihiro ; Kitaura, Yasuyuki ; Harris, Robert ; Shimomura, Yoshiharu. / Ca2+-dependent inhibition of branched-chain α-ketoacid dehydrogenase kinase by thiamine pyrophosphate. In: Biochemical and Biophysical Research Communications. 2018 ; Vol. 504, No. 4. pp. 916-920.
@article{2251356b0ef9407db70bf0373d27bbe6,
title = "Ca2+-dependent inhibition of branched-chain α-ketoacid dehydrogenase kinase by thiamine pyrophosphate",
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",
author = "Seisuke Noguchi and Yusuke Kondo and Rina Ito and Takahiro Katayama and Shunsuke Kazama and Yoshihiro Kadota and Yasuyuki Kitaura and Robert Harris and Yoshiharu Shimomura",
year = "2018",
month = "10",
day = "12",
doi = "10.1016/j.bbrc.2018.09.038",
language = "English (US)",
volume = "504",
pages = "916--920",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "4",

}

TY - JOUR

T1 - Ca2+-dependent inhibition of branched-chain α-ketoacid dehydrogenase kinase by thiamine pyrophosphate

AU - Noguchi, Seisuke

AU - Kondo, Yusuke

AU - Ito, Rina

AU - Katayama, Takahiro

AU - Kazama, Shunsuke

AU - Kadota, Yoshihiro

AU - Kitaura, Yasuyuki

AU - Harris, Robert

AU - Shimomura, Yoshiharu

PY - 2018/10/12

Y1 - 2018/10/12

N2 - 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.

AB - 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.

KW - Branched-chain amino acids

KW - Branched-chain α-ketoacid dehydrogenase complex

KW - Branched-chain α-ketoacid dehydrogenase kinase

KW - Calcium ion

KW - Thiamine pyrophosphate

UR - http://www.scopus.com/inward/record.url?scp=85053318572&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053318572&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2018.09.038

DO - 10.1016/j.bbrc.2018.09.038

M3 - Article

VL - 504

SP - 916

EP - 920

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 4

ER -