A new family of protein kinases- The mitochondrial protein kinases

Robert Harris, Kirill M. Popov, Yu Zhao, Natalia Y. Kedishvili, Yoshiharu Shimomura, David Crabb

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Molecular cloning has provided evidence for a new family of protein kinases in eukaryotic cells. These kinases show no sequence similarity with other eukaryotic protein kinases, but are related by sequence to the histidine protein kinases found in prokaryotes. These protein kinases, responsible for phosphorylation and inactivation of the branched-chain α-ketoacid dehydrogenase and pyruvate dehydrogenase complexes, are located exclusively in mitochondrial matrix space and have most likely evolved from genes originally present in respiration-dependent bacteria endocytosed by primitive eukaryotic cells. Long-term regulatory mechanisms involved in the control of the activities of these two kinases are of considerable interest. Dietary protein deficiency increases the activity of branched-chain α-ketoacid dehydrogenase kinase associated with the branched-chain α-ketoacid dehydrogenase complex. The amount of branched-chain α-ketoacid dehydrogenase kinase protein associated with the branched-chain α-ketoacid dehydrogenase complex and the message level for branched-chain α-ketoacid dehydrogenase kinase are both greatly increased in the liver of rats starved for protein, suggesting increased expression of the gene encoding branched-chain α-ketoacid dehydrogenase kinase. The increase in branched-chain α-ketoacid dehydrogenase kinase activity results in greater phosphorylation and lower activity of the branched-chain α-ketoacid dehydrogenase complex. The metabolic consequence is conservation of branched chain amino acids for protein synthesis during periods of dietary protein deficiency. Two isoforms of pyruvate dehydrogenase kinase have been identified and cloned. Pyruvate dehydrogenase kinase 1, the first isoform cloned, corresponds to the 48 kDa subunit of the pyruvate dehydrogenase kinase isolated from rat heart tissue. Pyruvate dehydrogenase kinase 2, the second isoform cloned, corresponds to the 45 kDa subunit of this enzyme. In addition, it also appears to correspond to a possibly free or soluble form of pyruvate dehydrogenase kinase that was originally named kinase activator protein. Assuming that differences in kinetic and/or regulatory properties of these isoforms exist, tissue specific expression of these enzymes and/or control of their association with the complex will probably prove to be important for the long term regulation of the activity of the pyruvate dehydrogenase complex. Starvation and the diabetic state are known to greatly increase activity of the pyruvate dehydrogenase kinase in the liver, heart and muscle of the rat. This contributes in these states to the phosphorylation and inactivation of the pyruvate dehydrogenase complex and conservation of pyruvate and lactate for gluconeogenesis. Whether the mechanism responsible for the increase in activity of pyruvate dehydrogenase kinase involves an induced increase in protein amount of pyruvate dehydrogenase kinase (as found for the branched-chain α-ketoacid dehydrogenase kinase in response to dietary protein deficiency), an isoenzyme shift, or activation of the pyruvate dehydrogenase kinases by unknown mechanisms remains to be established.

Original languageEnglish
JournalAdvances in Enzyme Regulation
Volume35
Issue numberC
DOIs
StatePublished - 1995

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3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
Mitochondrial Proteins
Protein Kinases
Phosphotransferases
Pyruvate Dehydrogenase Complex
Protein Deficiency
Phosphorylation
Dietary Proteins
Protein Isoforms
Rats
Eukaryotic Cells
Liver
Conservation
Proteins
Period Circadian Proteins
Tissue
pyruvate dehydrogenase (acetyl-transferring) kinase
Branched Chain Amino Acids
Gene encoding
Gluconeogenesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

A new family of protein kinases- The mitochondrial protein kinases. / Harris, Robert; Popov, Kirill M.; Zhao, Yu; Kedishvili, Natalia Y.; Shimomura, Yoshiharu; Crabb, David.

In: Advances in Enzyme Regulation, Vol. 35, No. C, 1995.

Research output: Contribution to journalArticle

Harris, Robert ; Popov, Kirill M. ; Zhao, Yu ; Kedishvili, Natalia Y. ; Shimomura, Yoshiharu ; Crabb, David. / A new family of protein kinases- The mitochondrial protein kinases. In: Advances in Enzyme Regulation. 1995 ; Vol. 35, No. C.
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