| Structural highlights
Function
PDK3_HUMAN 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.[1] [2] [3] [4] [5] [6] [7]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Pyruvate dehydrogenase kinase (PDK) isoforms are molecular switches that downregulate the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation in mitochondria. We have determined structures of human PDK1 or PDK3 bound to the inhibitors AZD7545, dichloroacetate (DCA), and radicicol. We show that the trifluoromethylpropanamide end of AZD7545 projects into the lipoyl-binding pocket of PDK1. This interaction results in inhibition of PDK1 and PDK3 activities by aborting kinase binding to the PDC scaffold. Paradoxically, AZD7545 at saturating concentrations robustly increases scaffold-free PDK3 activity, similar to the inner lipoyl domain. Good DCA density is present in the helix bundle in the N-terminal domain of PDK1. Bound DCA promotes local conformational changes that are communicated to both nucleotide-binding and lipoyl-binding pockets of PDK1, leading to the inactivation of kinase activity. Finally, radicicol inhibits kinase activity by binding directly to the ATP-binding pocket of PDK3, similar to Hsp90 and Topo VI from the same ATPase/kinase superfamily.
Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol.,Kato M, Li J, Chuang JL, Chuang DT Structure. 2007 Aug;15(8):992-1004. Epub 2007 Aug 2. PMID:17683942[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Baker JC, Yan X, Peng T, Kasten S, Roche TE. Marked differences between two isoforms of human pyruvate dehydrogenase kinase. J Biol Chem. 2000 May 26;275(21):15773-81. PMID:10748134 doi:10.1074/jbc.M909488199
- ↑ Korotchkina LG, Patel MS. Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase. J Biol Chem. 2001 Oct 5;276(40):37223-9. Epub 2001 Aug 2. PMID:11486000 doi:10.1074/jbc.M103069200
- ↑ Korotchkina LG, Sidhu S, Patel MS. Characterization of testis-specific isoenzyme of human pyruvate dehydrogenase. J Biol Chem. 2006 Apr 7;281(14):9688-96. Epub 2006 Jan 25. PMID:16436377 doi:10.1074/jbc.M511481200
- ↑ Lu CW, Lin SC, Chen KF, Lai YY, Tsai SJ. Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J Biol Chem. 2008 Oct 17;283(42):28106-14. doi: 10.1074/jbc.M803508200. Epub 2008, Aug 21. PMID:18718909 doi:10.1074/jbc.M803508200
- ↑ Kluza J, Corazao-Rozas P, Touil Y, Jendoubi M, Maire C, Guerreschi P, Jonneaux A, Ballot C, Balayssac S, Valable S, Corroyer-Dulmont A, Bernaudin M, Malet-Martino M, de Lassalle EM, Maboudou P, Formstecher P, Polakowska R, Mortier L, Marchetti P. 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 Oct 1;72(19):5035-47. doi: 10.1158/0008-5472.CAN-12-0979. Epub, 2012 Aug 3. PMID:22865452 doi:10.1158/0008-5472.CAN-12-0979
- ↑ Kato M, Chuang JL, Tso SC, Wynn RM, Chuang DT. Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex. EMBO J. 2005 May 18;24(10):1763-74. Epub 2005 Apr 28. PMID:15861126
- ↑ Kato M, Li J, Chuang JL, Chuang DT. Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure. 2007 Aug;15(8):992-1004. Epub 2007 Aug 2. PMID:17683942 doi:10.1016/j.str.2007.07.001
- ↑ Kato M, Li J, Chuang JL, Chuang DT. Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure. 2007 Aug;15(8):992-1004. Epub 2007 Aug 2. PMID:17683942 doi:10.1016/j.str.2007.07.001
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