Disease relevance of Bckdk

• Dietary protein deficiency increases the activity of branched-chain alpha-ketoacid dehydrogenase kinase associated with the branched-chain alpha-ketoacid dehydrogenase complex [1].
• Here, we describe the construction of a rat pheochromocytoma cell (PC12) model harboring a doxycycline-controlled BCKD-kinase transgene [2].

High impact information on Bckdk

• The results indicate that BCKD kinase, similar to pyruvate dehydrogenase kinase isozymes, belongs to the superfamily of ATPase/kinase [3].
• However, despite its sequence similarity to bacterial histidine protein kinases, BCKD kinase does not function as a histidine protein kinase [3].
• Incubation of the BCKD kinase with increasing concentrations of urea resulted in dissociation of the tetramer to dimers and eventually to monomers as separated on a sucrose density gradient [3].
• The tetrameric assembly of BCKD kinase was confirmed by the presence of four 5'-adenylyl-imidodiphosphate-binding sites (K(D) = 4.1 x 10(-6)m) per molecule of the kinase [3].
• Inhibition of branched chain alpha-ketoacid dehydrogenase kinase activity by alpha-chloroisocaproate [4].

Biological context of Bckdk

• In addition to a magnesium ion, which is essential for catalysis, a potassium ion bound adjacent to the triphosphate moiety of ATP in a rat mitochondrial protein kinase, BCK (branched-chain alpha-ketoacid dehydrogenase kinase), has been shown to be indispensable for nucleotide binding and hydrolysis [5].
• The fifth member of this family corresponds to the branched-chain alpha-ketoacid dehydrogenase kinase, an enzyme responsible for phosphorylation and inactivation of the branched-chain alpha-ketoacid dehydrogenase complex, the most important regulatory enzyme in the pathway for the disposal of branched-chain amino acids [6].
• In cells over-expressing BCKD-kinase, addition of 25 mM leucine to the medium results in cell death [2].
• Alanine scanning mutagenesis of residues in the immediate vicinity of the phosphorylation site (serine 293) indicates that only arginine 288 is required for recognition of serine 293 as a phosphorylation site by the branched-chain alpha-ketoacid dehydrogenase kinase [6].

Associations of Bckdk with chemical compounds

• Expression and characterization of branched-chain alpha-ketoacid dehydrogenase kinase from the rat. Is it a histidine-protein kinase [7]?
• Proteolysis maps of branched-chain alpha-ketoacid dehydrogenase kinase and the two subunits of pyruvate dehydrogenase kinase are different, suggesting that all subunits are different entities [8].
• Rather, clofibric acid is a potent inhibitor of the activity of the branched-chain alpha-ketoacid dehydrogenase kinase and this may be the molecular mechanism responsible for the myotonic effects of clofibric acid in man [8].
• BCKD activity is regulated through the action of the complex-specific BCKD kinase that phosphorylates two serine residues in the E1alpha subunit [9].
• Because the alpha-keto acid of leucine regulates the activity of BCKD kinase, it has been suggested as a potential target for leucine regulation of mTOR [10].

Analytical, diagnostic and therapeutic context of Bckdk

• We recently reported molecular cloning of the branched chain alpha-ketoacid dehydrogenase kinase, the first mitochondrial protein kinase to be cloned (Popov, K. M., Zhao, Y., Shimomura, Y., Kuntz, M. J., and Harris, R. A. (1992) J. Biol. Chem. 267, 13127-13130) [11].
• In the present study, we report that the rat BCKD kinase exists as a homotetramer of M(r) = 185,000, based on results of gel filtration and dynamic light scattering [3].
• With rats fed a low-protein diet and subsequently starved, inhibition of branched-chain alpha-ketoacid dehydrogenase kinase by branched-chain alpha-ketoacids generated as a consequence of endogenous proteolysis most likely promotes the greater branched-chain alpha-ketoacid dehydrogenase activity state [12].

References