[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial

Function

Kinase that plays a key role in the regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism. Mediates cellular responses to insulin. Plays an important role in maintaining normal blood glucose levels and in metabolic adaptation to nutrient availability. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. Plays a role in the regulation of cell proliferation and in resistance to apoptosis under oxidative stress. Plays a role in p53/TP53-mediated apoptosis.

Classification

Family (Pfam)

PF10436 BCDHK_Adom3, PF02518 HATPase_c

InterPro

AK/P_DHK_N_sf, BCDHK/PDK_N, BCKD/PDK, HATPase_C_sf, HATPase_dom, His_kinase_dom

Functional cluster

Tubulins & Mitochondrial Metabolic Enzymes

Experimental structures · PDB · 38

• 2BTZ X-ray 2.20A
• 2BU2 X-ray 2.40A
• 2BU5 X-ray 2.35A
• 2BU6 X-ray 2.40A
• 2BU7 X-ray 2.40A
• 2BU8 X-ray 2.50A
• 4MP2 X-ray 1.75A
• 4MP7 X-ray 1.80A
• 4MPC X-ray 1.70A
• 4MPE X-ray 1.95A
• 4MPN X-ray 1.75A
• 4V25 X-ray 2.60A
• … and 26 more

A predicted model is available from AlphaFold.

Gene Ontology · 18

• GO:0005759 mitochondrial matrix
• GO:0005739 mitochondrion
• GO:0045254 pyruvate dehydrogenase complex
• GO:0005524 ATP binding
• GO:0042803 protein homodimerization activity
• GO:0004672 protein kinase activity
• GO:0004740 pyruvate dehydrogenase (acetyl-transferring) kinase activity
• GO:0031670 cellular response to nutrient
• GO:0034614 cellular response to reactive oxygen species
• GO:0042593 glucose homeostasis
• GO:0006006 glucose metabolic process
• GO:0008286 insulin receptor signaling pathway
• GO:0072332 intrinsic apoptotic signaling pathway by p53 class mediator
• GO:0006111 regulation of gluconeogenesis
• GO:0010906 regulation of glucose metabolic process
• GO:0010565 regulation of ketone metabolic process
• GO:0006885 regulation of pH
• GO:0010510 regulation of pyruvate decarboxylation to acetyl-CoA

Drugs targeting this protein · 1

• SODIUM DICHLOROACETATE inhibitor

Related proteins · sequence + function similarity

• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial 1.00
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial 1.00
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial 0.97
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial 0.96
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial 0.96
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase, mitochondrial 0.95
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial 0.95
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial 0.95
• Probable [pyruvate dehydrogenase (acetyl-transferring)] kinase, mitochondrial 0.94
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase, mitochondrial 0.93
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial 0.93
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial 0.93

Co-cited proteins · studied together in the literature

• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial 1 shared papers
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 3, mitochondrial 2 shared papers
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial 1 shared papers
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial 1 shared papers
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial 1 shared papers

Literature · 16 cited papers

• An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
• p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. Cancer Res. · 2012
• Chronic CSE treatment induces the growth of normal oral keratinocytes via PDK2 upregulation, increased glycolysis and HIF1alpha stabilization. PLoS ONE · 2011
• Pivotal role of the C-terminal DW-motif in mediating inhibition of pyruvate dehydrogenase kinase 2 by dichloroacetate. J. Biol. Chem. · 2009
• Three members of the human pyruvate dehydrogenase kinase gene family are direct targets of the peroxisome proliferator-activated receptor beta/delta. J. Mol. Biol. · 2007
• Patterns of somatic mutation in human cancer genomes. Nature · 2007
• A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell · 2007
• DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage. Nature · 2006
• Ligand-induced effects on pyruvate dehydrogenase kinase isoform 2. J. Biol. Chem. · 2006
• Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands. Biochemistry · 2006
• Pyruvate dehydrogenase kinase isoform 2 activity limited and further inhibited by slowing down the rate of dissociation of ADP. Biochemistry · 2004
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• … and 4 more in the literature graph