Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer

Cell Mol Life Sci. 2007 Apr;64(7-8):830-49. doi: 10.1007/s00018-007-6380-z.


The fraction of pyruvate dehydrogenase complex (PDC) in the active form is reduced by the activities of dedicated PD kinase isozymes (PDK1, PDK2, PDK3 and PDK4). Via binding to the inner lipoyl domain (L2) of the dihydrolipoyl acetyltransferase (E2 60mer), PDK rapidly access their E2-bound PD substrate. The E2-enhanced activity of the widely distributed PDK2 is limited by dissociation of ADP from its C-terminal catalytic domain, and this is further slowed by pyruvate binding to the N-terminal regulatory (R) domain. Via the reverse of the PDC reaction, NADH and acetyl-CoA reductively acetylate lipoyl group of L2, which binds to the R domain and stimulates PDK2 activity by speeding up ADP dissociation. Activation of PDC by synthetic PDK inhibitors binding at the pyruvate or lipoyl binding sites decreased damage during heart ischemia and lowered blood glucose in insulin-resistant animals. PDC activation also triggers apoptosis in cancer cells that selectively convert glucose to lactate.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus / drug therapy
  • Enzyme Activation
  • Humans
  • Models, Molecular
  • Myocardial Ischemia / drug therapy
  • Neoplasms / drug therapy
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Kinases / chemistry
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Pyruvate Dehydrogenase Complex / chemistry
  • Pyruvate Dehydrogenase Complex / metabolism


  • PDK1 protein, human
  • PDK2 protein, human
  • PDK3 protein, human
  • PDK4 protein, human
  • Protein Kinase Inhibitors
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Pyruvate Dehydrogenase Complex
  • Protein Kinases
  • Protein-Serine-Threonine Kinases