[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 3, mitochondrial

Function

Inhibits pyruvate dehydrogenase activity by phosphorylation of the E1 subunit PDHA1, and thereby regulates glucose metabolism and aerobic respiration. Can also phosphorylate PDHA2. Decreases glucose utilization and increases fat metabolism in response to prolonged fasting, and as adaptation to a high-fat diet. Plays a role in glucose homeostasis and in maintaining normal blood glucose levels in function of nutrient levels and under starvation. Plays a role in the generation of reactive oxygen species.

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 · 5

• 1Y8N X-ray 2.60A
• 1Y8O X-ray 2.48A
• 1Y8P X-ray 2.63A
• 2PNR X-ray 2.50A
• 2Q8I X-ray 2.60A

A predicted model is available from AlphaFold.

Gene Ontology · 14

• GO:0005759 mitochondrial matrix
• GO:0005739 mitochondrion
• GO:0005524 ATP binding
• GO:0004672 protein kinase activity
• GO:0004674 protein serine/threonine kinase activity
• GO:0004740 pyruvate dehydrogenase (acetyl-transferring) kinase activity
• GO:0071398 cellular response to fatty acid
• GO:0071333 cellular response to glucose stimulus
• GO:0097411 hypoxia-inducible factor-1alpha signaling pathway
• GO:0018105 peptidyl-serine phosphorylation
• GO:0035357 peroxisome proliferator activated receptor signaling pathway
• GO:0010906 regulation of glucose metabolic process
• GO:0010510 regulation of pyruvate decarboxylation to acetyl-CoA
• GO:2000377 regulation of reactive oxygen species metabolic process

Disease associations

• Charcot-Marie-Tooth disease X-linked dominant 6 MONDO:0010479

Drugs targeting this protein · 1

• SODIUM DICHLOROACETATE inhibitor

Related proteins · sequence + function similarity

• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 3, mitochondrial 0.99
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial 0.92
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial 0.92
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial 0.92
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial 0.92
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial 0.92
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial 0.92
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial 0.92
• Probable [pyruvate dehydrogenase (acetyl-transferring)] kinase, mitochondrial 0.92
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial 0.91
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial 0.91
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase, mitochondrial 0.90

Co-cited proteins · studied together in the literature

• Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial 3 shared papers
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial 2 shared papers
• Pyruvate dehydrogenase E1 component subunit alpha, testis-specific form, mitochondrial 1 shared papers
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial 2 shared papers
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial 2 shared papers
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial 2 shared papers
• [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, 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
• Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial 1 shared papers

Literature · 18 cited papers

• N-terminome analysis of the human mitochondrial proteome. Proteomics · 2015
• A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. Hum. Mol. Genet. · 2013
• Inactivation of the HIF-1alpha/PDK3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity of pro-oxidants. Cancer Res. · 2012
• System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation. Sci. Signal. · 2011
• Butyrate elicits a metabolic switch in human colon cancer cells by targeting the pyruvate dehydrogenase complex. Int. J. Cancer · 2011
• Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J. Biol. Chem. · 2008
• Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure · 2007
• 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
• Crystal structure of an asymmetric complex of pyruvate dehydrogenase kinase 3 with lipoyl domain 2 and its biological implications. J. Mol. Biol. · 2007
• Patterns of somatic mutation in human cancer genomes. Nature · 2007
• Characterization of testis-specific isoenzyme of human pyruvate dehydrogenase. J. Biol. Chem. · 2006
• Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex. EMBO J. · 2005
• … and 6 more in the literature graph