Pyruvate dehydrogenase kinase

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{{STRUCTURE_1jm6| PDB=1jm6 | SIZE=400| SCENE= |right|CAPTION=Human pyruvate dehydrogenase kinase isozyme 1 complex with ADP and K+ ion [[1jm6]] }}
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<StructureSection load='' size='350' side='right' caption='Human pyruvate dehydrogenase kinase isozyme 4 dimer complex with AMPPNP and Mg+2 ion (green) (PDB entry [[2e0a]])' scene='48/485629/Cv/1'>
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__TOC__
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== Function ==
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Please use the "3D" button above this box to insert a Jmol applet (molecule) on this page.
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'''Pyruvate dehydrogenase kinase''' (PDK) is part of the pyruvate dehydrogenase complex. This complex is located in the mitochondria and converts pyruvate to acetyl-CoA as part of the citric acid cycle. PDK phosphphorylates serine residues on pyruvate dehydrogenase using ATP. There are 4 isozymes of PDK. The isozymes differ in length, activity and phosphorylation sites<ref>PMID:11486000</ref>.
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*'''PDK1''' is abundant in heart cells. PDK1 expression was found to predict future major adverse cardiovascular events<ref>PMID:36866436</ref>.
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to a Jmol applet. Check out the other buttons as well!
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*'''PDK2''' is abundant in mitochondria.
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*'''PDK3''' is abundant in testis.
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'''Pyruvate dehydrogenase kinase''' (PDK) is part of the pyruvate dehydrogenase complex. This complex is located in the mitochondria and converts pyruvate to acetyl-CoA as part of the citric acid cycle. PDK phosphphorylates serine residues on pyruvate dehydrogenase using ATP. There are 4 isozymes of PDK. The isozymes differ in length, activity and phosphorylation sites.
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*'''PDK4''' is abundant in muscle and heart. It is important during starvation for regulation of pyruvate dehydrogenate complex activity and glucose homoeostasis<ref>PMID:16606348</ref>.
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== Relevance ==
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Inhibition of PDK decreases the damage caused by heart ischemia and are used in diabetes and cancer patients<ref>PMID:17310282</ref><ref>PMID:23471124</ref>.
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== Structural highlights ==
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<scene name='48/485629/Cv/11'>The active site cleft of PDK4 binds AMPPNP</scene><ref>PMID:21904029</ref>. Water molecules are shown as red spheres. <scene name='48/485629/Cv/12'>Mg coordination site</scene>.
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</StructureSection>
==3D structures of pyruvate dehydrogenase kinase==
==3D structures of pyruvate dehydrogenase kinase==
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'''PDK isozyme 1'''
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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{{#tree:id=OrganizedByTopic|openlevels=0|
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*PDK isozyme 1
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**[[2q8f ]]– hPDK1 – human<br />
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**[[2q8g]] – hPDK1 + drug<br />
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**[[2q8h]] – hPDK1 + dichloro-acetic acid
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[[2q8f ]]– hPDK1 – human<br />
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*PDK isozyme 2
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[[2q8g]] – hPDK1 + drug<br />
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[[2q8h]] – hPDK1 + dichloro-acetic acid
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'''PDK isozyme 2'''
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**[[2btz]] – hPDK2 <br />
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**[[2bu2]] – hPDK2 + benzonitrile derivative + ATP<br />
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**[[2bu5]] - hPDK2 + benzonitrile derivative<br />
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**[[2bu6]] - hPDK2 + propanamide derivative<br />
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**[[2bu7]] - hPDK2 + acetamide derivative<br />
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**[[2bu8]] - hPDK2 + dichloro-acetic acid + ADP<BR />
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**[[4mp2]], [[4mp7]], [[4mpc]], [[4mpe]], [[4mpn]], [[4v25]], [[4v26]], [[5j6a]], [[5j71]], [[5m4k]], [[5m4m]], [[5m4n]], [[5m4p]], [[6lil]], [[6lio]], [[6lin]], [[6tmz]], [[6tmp]], [[6tmq]], [[6tn0]], [[6tn2]], [[7ebh]], [[7eas]], [[7vbu]], [[7vbv]], [[7vbx]] – hPDK2 + inhibitor<br />
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**[[3crk]], [[3crl]] – hPDK2 + pyruvate dehydrogenase E2<br />
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**[[1jm6]] – PDK2 + ADP – rat<br />
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[[1jm6]] – PDK2 + ADP – rat<br />
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*PDK isozyme 3
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[[2btz]] – hPDK2 <br />
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[[2bu2]] – hPDK2 + benzonitrile derivative + ATP<br />
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[[2bu5]] - hPDK2 + benzonitrile derivative<br />
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[[2bu6]] - hPDK2 + propanamide derivative<br />
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[[2bu7]] - hPDK2 + acetamide derivative<br />
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[[2bu8]] - hPDK2 + dichloro-acetic acid + ADP<BR />
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[[3crk]], [[3crl]] – hPDK2 + acetyltransferase component of pyruvate dehydrogenase complex
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'''PDK isozyme 3'''
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**[[1y8n]], [[1y8o]], [[1y8p]], [[2pnr]] – hPDK3 + acetyltransferase component of pyruvate dehydrogenase complex <br />
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**[[2q8i]] – hPDK3 + radicicol
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[[1y8n]], [[1y8o]], [[1y8p]], [[2pnr]] – hPDK3 + acetyltransferase component of pyruvate dehydrogenase complex <br />
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*PDK isozyme 4
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[[2q8i]] – hPDK3 + radicicol
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'''PDK isozyme 4'''
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**[[2e0a]] – hPDK4 + AMPPNP<br />
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**[[2zkj]], [[3d2r]] – hPDK4 + ADP<BR />
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**[[7ea0]], [[7eat]], [[7ebb]], [[7ebg]] – hPDK4 + inhibitor<br />
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**[[2zdx]], [[2zdy]] – hPDK4 (mutant) + inhibitor
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}}
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== References ==
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<references/>
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[[2e0a]] – hPDK4 + AMPPNP<br />
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[[Category: Topic Page]]
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[[2zkj]], [[3d2r]] – hPDK4 + ADP<BR />
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[[2zdx]], [[2zdy]] – hPDK4 (mutant) + inhibitor
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Current revision

Human pyruvate dehydrogenase kinase isozyme 4 dimer complex with AMPPNP and Mg+2 ion (green) (PDB entry 2e0a)

Drag the structure with the mouse to rotate

3D structures of pyruvate dehydrogenase kinase

Updated on 04-August-2024

References

  1. ↑ 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
  2. ↑ Forteza MJ, Berg M, Edsfeldt A, Sun J, Baumgartner R, Kareinen I, Casagrande FB, Hedin U, Zhang S, Vuckovic I, Dzeja PP, Polyzos KA, Gisterå A, Trauelsen M, Schwartz TW, Dib L, Herrmann J, Monaco C, Matic L, Gonçalves I, Ketelhuth DFJ. Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk. Cardiovasc Res. 2023 Jul 4;119(7):1524-1536. PMID:36866436 doi:10.1093/cvr/cvad038
  3. ↑ Jeoung NH, Wu P, Joshi MA, Jaskiewicz J, Bock CB, Depaoli-Roach AA, Harris RA. Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation. Biochem J. 2006 Aug 1;397(3):417-25. PMID:16606348 doi:10.1042/BJ20060125
  4. ↑ Roche TE, Hiromasa Y. 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. PMID:17310282 doi:10.1007/s00018-007-6380-z
  5. ↑ Sutendra G, Michelakis ED. Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Front Oncol. 2013 Mar 7;3:38. doi: 10.3389/fonc.2013.00038. eCollection 2013. PMID:23471124 doi:http://dx.doi.org/10.3389/fonc.2013.00038
  6. ↑ Kukimoto-Niino M, Tokmakov A, Terada T, Ohbayashi N, Fujimoto T, Gomi S, Shiromizu I, Kawamoto M, Matsusue T, Shirouzu M, Yokoyama S. Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4. Acta Crystallogr D Biol Crystallogr. 2011 Sep;67(Pt 9):763-73. doi:, 10.1107/S090744491102405X. Epub 2011 Aug 9. PMID:21904029 doi:10.1107/S090744491102405X

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