PDHK4 an ubiquitously expressed, atypical protein kinase associated with the mitochondrial matrix. The PDHKs play crucial roles in switching metabolic flux from oxidative phosphorylation towards glycolysis. PDHK4 is abundant in heart, skeletal muscle, kidney, and pancreatic islets. Contains a HATPase_c catalytic domain, found in several ATP-binding proteins including protein histidine kinases (PHKs), PHDKs, DNA gyrase B, topoisomerases, heat shock proteins, and DNA mismatch repair proteins. PDHK regulates glucose oxidation through inhibitory phosphorylation of the E1 alpha subunit of the mitochondrial pyruvate dehydrogenase complex (PDHC) at any one of 3 inhibitory serine residues. Inhibitory sites 1, 2, and 3 correspond to S293, S300, and S232 in human PDHA1, respectively. Four PDHK isoenzymes have been described, each with different site specificity: all four phosphorylate sites 1 and 2 but at different rates; for site 1 PDHK2 >PDHK4 >PDHK1 >PDHK3; for site 2, PDHK3> PDHK4 > PDHK2 > PDHK1. Only PDHK1 phosphorylates site 3. PDHKs are recruited to the PDHC by binding to a lipoyl group covalently attached to the inner lipoyl domain of the E2 component. PDHA1 deficiency is the most common enzyme defect in patients with primary lactic acidosis. Suppression of PDH by PDHK inhibits the conversion of pyruvate to acetyl-CoA, attenuates mitochondrial respiration, and may contribute to the increased lactate production observed in many tumors. The PDH pathway is repressed in a majority of non-small cell lung carcinomas. Inhibited by AZD7545, dichloroacetate (DCA), and radicicol. Radicicol inhibits kinase activity by binding directly to the ATP-binding pocket of PDHK, similar to HSP90 from the same ATPase/kinase superfamily. Note: This description may include information from UniProtKB.
Protein type: ATYPICAL group; EC 2.7.11.2; Kinase, protein; Mitochondrial; PDHK family; Protein kinase, atypical
Chromosomal Location of Human Ortholog: 6 A1|6 2.06 cM
Cellular Component:  mitochondrion
Molecular Function:  ATP binding; kinase activity; nucleotide binding; protein kinase activity; protein serine/threonine/tyrosine kinase activity; pyruvate dehydrogenase (acetyl-transferring) kinase activity; transferase activity
Biological Process:  carbohydrate metabolic process; cellular response to fatty acid; cellular response to starvation; glucose homeostasis; glucose metabolic process; insulin receptor signaling pathway; negative regulation of anoikis; phosphorylation; protein phosphorylation; reactive oxygen species metabolic process; regulation of acetyl-CoA biosynthetic process from pyruvate; regulation of bone resorption; regulation of cellular ketone metabolic process; regulation of fatty acid biosynthetic process; regulation of fatty acid oxidation; regulation of glucose metabolic process; regulation of pH; response to starvation
Reference #:  O70571 (UniProtKB)
Alt. Names/Synonyms: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial; [Pyruvate dehydrogenase [lipoamide]] kinase isozyme 4, mitochondrial; AV005916; Pdk4; pyruvate dehydrogenase kinase 4; Pyruvate dehydrogenase kinase isoform 4; pyruvate dehydrogenase kinase, isoenzyme 4
Gene Symbols: Pdk4
Molecular weight: 46,596 Da
Basal Isoelectric point: 6.61  Predict pI for various phosphorylation states
CST Pathways:  Warburg Effect
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PDHK4

Protein Structure Not Found.


Cross-references to other databases:  STRING  |  Reactome  |  BioGPS  |  KinBase  |  Pfam  |  ENZYME  |  Phospho.ELM  |  NetworKIN  |  UniProtKB  |  Entrez-Gene  |  Ensembl Gene