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Gene Review

PDK2  -  pyruvate dehydrogenase kinase, isozyme 2

Homo sapiens

Synonyms: PDH kinase 2, PDHK2, PDKII, Pyruvate dehydrogenase kinase isoform 2
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Disease relevance of PDK2


High impact information on PDK2

  • Recent biochemical studies suggested that TORC2 is the elusive PDK2 for Akt/PKB Ser473 phosphorylation in the hydrophobic motif [4].
  • The serine-threonine kinase Akt is a downstream target of phosphoinositide 3-kinase (PI 3-kinase); it is activated by the phosphoinositide 3-phosphate-dependent kinases PDK1 and PDK2 [5].
  • Phosphorylation of PDC by the pyruvate dehydrogenase kinases (PDK2 and PDK4) inhibits PDC activity [6].
  • The E2 60-mer bound approximately 18 PDK2 dimers with a Kd similar to GST-L2 [7].
  • The gain in binding interactions upon lipoate reduction likely aids reduction-engendered stimulation of PDK2 activity; loosening of binding as a result of adenine nucleotides and phosphorylation may instigate movement of lipoyl domain-held kinase to a new E1 substrate [7].

Biological context of PDK2


Anatomical context of PDK2

  • The highest amount of PDK2 mRNA was found in heart and skeletal muscle, the lowest amount in placenta and lung [9].
  • Brain, kidney, pancreas, and liver expressed an intermediate amount of PDK2 (brain > kidney = pancreas > liver) [9].
  • PDK2 and PDK4 mRNAs were positively correlated with fasting plasma insulin concentration, 2-h plasma insulin concentration in response to oral glucose, and percentage body fat, whereas both isoforms were negatively correlated with insulin-mediated glucose uptake rates [1].
  • In contrast, PDK2 activity was found to be highly enriched in a novel cytoskeletal subcellular fraction associated with plasma membranes [12].
  • PI(3, 4, 5)P3 is a second messenger essential for the translocation of Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (PDK) 1 and PDK2 [13].

Associations of PDK2 with chemical compounds

  • E2 activation of PDK2 resulted in a greatly enhanced sensitivity to inhibition by pyruvate or DCA; pyruvate was effective at significantly lower levels than DCA [14].
  • ATP and ADP decreased the affinity of PDK2 for E2 by 3-5-fold and adenosine 5'-(beta,gamma-imino)triphosphate or phosphorylation of E1 similarly reduced PDK2 binding to E2.E1 [7].
  • Secondly, thiamin pyrophosphate markedly decreases the amount of phosphate that PDK1 incorporates in sites 2 and 3 and that PDK2 incorporates in site 2 [15].
  • Using a cultured human skeletal muscle cell model system, we found that expression of both PDK2 and PDK4 mRNA is upregulated in response to glucose deprivation and fatty acid supplementation, the effects of which are reversed by insulin treatment [16].
  • During E2-aided catalysis, PDK2 had approximately 3 times more ADP than ATP bound at its active site, and the pyruvate analogue, dichloroacetate, led to 16-fold more ADP than ATP being bound (no added ADP) [11].

Enzymatic interactions of PDK2

  • The identification of PDK1 as a kinase that phosphorylates the AGC family of kinases led to a hunt for 'PDK2', a hypothetical regulated kinase(s) that would be required for full activation of the AGC kinases [17].
  • Conversion of all of the lipoyl groups in the E2 60mer to the oxidized form (E2(ox)) greatly reduced k(cat) and the K(m) of PDK2 for ATP [18].

Regulatory relationships of PDK2

  • PDK2 was activated only by assembled E2, and this activated state beget high responsiveness to those effectors [14].

Other interactions of PDK2

  • In contrast to PDk1 and PDK2, which are expressed in all tissues tested, the message for PDK3 was found almost exclusively in heart and skeletal muscle, indicating that PDK3 may serve specialized functions characteristic of muscle tissues [9].
  • Although PDK2 phosphorylates site 1 and 2, it incorporates less phosphate in site 2 than PDK3 or PDK4 [15].
  • On the other hand, progress in molecular genetics has led to the identification of PKD1 and PDK2 genes, and their respective gene products, polycystin 1 and 2 [19].
  • PIF is situated carboxy-terminal to the kinase domain of PRK2, and contains a consensus motif for phosphorylation by PDK2 similar to that found in PKBalpha, except that the residue equivalent to Ser473 is aspartic acid [20].
  • Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2 [21].

Analytical, diagnostic and therapeutic context of PDK2


  1. Insulin downregulates pyruvate dehydrogenase kinase (PDK) mRNA: potential mechanism contributing to increased lipid oxidation in insulin-resistant subjects. Majer, M., Popov, K.M., Harris, R.A., Bogardus, C., Prochazka, M. Mol. Genet. Metab. (1998) [Pubmed]
  2. Formation of functional heterodimers by isozymes 1 and 2 of pyruvate dehydrogenase kinase. Boulatnikov, I., Popov, K.M. Biochim. Biophys. Acta (2003) [Pubmed]
  3. A translation frameshift mutation induced by a cytosine insertion in the polycystic kidney disease 2 gene (PDK2). Xenophontos, S., Constantinides, R., Hayashi, T., Mochizuki, T., Somlo, S., Pierides, A., Deltas, C.C. Hum. Mol. Genet. (1997) [Pubmed]
  4. SIN1/MIP1 Maintains rictor-mTOR Complex Integrity and Regulates Akt Phosphorylation and Substrate Specificity. Jacinto, E., Facchinetti, V., Liu, D., Soto, N., Wei, S., Jung, S.Y., Huang, Q., Qin, J., Su, B. Cell (2006) [Pubmed]
  5. The akt kinase: molecular determinants of oncogenicity. Aoki, M., Batista, O., Bellacosa, A., Tsichlis, P., Vogt, P.K. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  6. Estrogen-related Receptors Stimulate Pyruvate Dehydrogenase Kinase Isoform 4 Gene Expression. Zhang, Y., Ma, K., Sadana, P., Chowdhury, F., Gaillard, S., Wang, F., McDonnell, D.P., Unterman, T.G., Elam, M.B., Park, E.A. J. Biol. Chem. (2006) [Pubmed]
  7. Facilitated interaction between the pyruvate dehydrogenase kinase isoform 2 and the dihydrolipoyl acetyltransferase. Hiromasa, Y., Roche, T.E. J. Biol. Chem. (2003) [Pubmed]
  8. Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase. Korotchkina, L.G., Patel, M.S. J. Biol. Chem. (2001) [Pubmed]
  9. Diversity of the pyruvate dehydrogenase kinase gene family in humans. Gudi, R., Bowker-Kinley, M.M., Kedishvili, N.Y., Zhao, Y., Popov, K.M. J. Biol. Chem. (1995) [Pubmed]
  10. High-fat/low-carbohydrate diet reduces insulin-stimulated carbohydrate oxidation but stimulates nonoxidative glucose disposal in humans: an important role for skeletal muscle pyruvate dehydrogenase kinase 4. Chokkalingam, K., Jewell, K., Norton, L., Littlewood, J., van Loon, L.J., Mansell, P., Macdonald, I.A., Tsintzas, K. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  11. Pyruvate dehydrogenase kinase isoform 2 activity limited and further inhibited by slowing down the rate of dissociation of ADP. Bao, H., Kasten, S.A., Yan, X., Roche, T.E. Biochemistry (2004) [Pubmed]
  12. Phosphoinositide-dependent kinase-2 is a distinct protein kinase enriched in a novel cytoskeletal fraction associated with adipocyte plasma membranes. Hresko, R.C., Murata, H., Mueckler, M. J. Biol. Chem. (2003) [Pubmed]
  13. PI3K-Akt pathway: its functions and alterations in human cancer. Osaki, M., Oshimura, M., Ito, H. Apoptosis (2004) [Pubmed]
  14. Marked differences between two isoforms of human pyruvate dehydrogenase kinase. Baker, J.C., Yan, X., Peng, T., Kasten, S., Roche, T.E. J. Biol. Chem. (2000) [Pubmed]
  15. Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites. Kolobova, E., Tuganova, A., Boulatnikov, I., Popov, K.M. Biochem. J. (2001) [Pubmed]
  16. Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells. Abbot, E.L., McCormack, J.G., Reynet, C., Hassall, D.G., Buchan, K.W., Yeaman, S.J. FEBS J. (2005) [Pubmed]
  17. Kinase phosphorylation: Keeping it all in the family. Peterson, R.T., Schreiber, S.L. Curr. Biol. (1999) [Pubmed]
  18. Pyruvate dehydrogenase kinase isoform 2 activity stimulated by speeding up the rate of dissociation of ADP. Bao, H., Kasten, S.A., Yan, X., Hiromasa, Y., Roche, T.E. Biochemistry (2004) [Pubmed]
  19. Polycystic kidney disease: <<30 ans après>>. Grünfeld, J.P., Chauveau, D., Joly, D., Fonck, C., Oualim, Z. J. Nephrol. (1999) [Pubmed]
  20. PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2. Balendran, A., Casamayor, A., Deak, M., Paterson, A., Gaffney, P., Currie, R., Downes, C.P., Alessi, D.R. Curr. Biol. (1999) [Pubmed]
  21. Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Kobayashi, T., Cohen, P. Biochem. J. (1999) [Pubmed]
  22. Targeted upregulation of pyruvate dehydrogenase kinase (PDK)-4 in slow-twitch skeletal muscle underlies the stable modification of the regulatory characteristics of PDK induced by high-fat feeding. Holness, M.J., Kraus, A., Harris, R.A., Sugden, M.C. Diabetes (2000) [Pubmed]
  23. Human skeletal muscle PDH kinase activity and isoform expression during a 3-day high-fat/low-carbohydrate diet. Peters, S.J., Harris, R.A., Wu, P., Pehleman, T.L., Heigenhauser, G.J., Spriet, L.L. Am. J. Physiol. Endocrinol. Metab. (2001) [Pubmed]
  24. Gene expressions and copy numbers associated with metastatic phenotypes of uterine cervical cancer. Lyng, H., Br??vig, R.S., Svendsrud, D.H., Holm, R., Kaalhus, O., Knutstad, K., Oksefjell, H., Sundf??r, K., Kristensen, G.B., Stokke, T. BMC Genomics (2006) [Pubmed]
  25. Oxysterol-binding protein-related protein (ORP) 9 is a PDK-2 substrate and regulates Akt phosphorylation. Lessmann, E., Ngo, M., Leitges, M., Minguet, S., Ridgway, N.D., Huber, M. Cell. Signal. (2007) [Pubmed]
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