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Pyruvate dehydrogenase kinase

April 11, 2024

Pyruvate dehydrogenase kinase (also pyruvate dehydrogenase complex kinase, PDC kinase, or PDK; EC 2.7.11.2) is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP.

Pyruvate dehydrogenase kinase
The areas around the three phosphorylation sites are shown in red. Site 1 is in the bottom left corner, site 2 in the top right, and site 3 in the bottom right.
Identifiers
EC no.2.7.11.2
CAS no.2620256
Databases
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BRENDABRENDA entry
ExPASyNiceZyme view
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MetaCycmetabolic pathway
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PDK thus participates in the regulation of the pyruvate dehydrogenase complex of which pyruvate dehydrogenase is the first component. Both PDK and the pyruvate dehydrogenase complex are located in the mitochondrial matrix of eukaryotes. The complex acts to convert pyruvate (a product of glycolysis in the cytosol) to acetyl-coA, which is then oxidized in the mitochondria to produce energy, in the citric acid cycle. By downregulating the activity of this complex, PDK will decrease the oxidation of pyruvate in mitochondria and increase the conversion of pyruvate to lactate in the cytosol.

The opposite action of PDK, namely the dephosphorylation and activation of pyruvate dehydrogenase, is catalyzed by a phosphoprotein phosphatase called pyruvate dehydrogenase phosphatase.

(Pyruvate dehydrogenase kinase should not be confused with Phosphoinositide-dependent kinase-1, which is also sometimes known as "PDK1".)

Phosphorylation sites edit

PDK can phosphorylate a serine residue on pyruvate dehydrogenase at three possible sites. Some evidence has shown that phosphorylation at site 1 will nearly completely deactivate the enzyme while phosphorylation at sites 2 and 3 had only a small contribution to complex inactivation.[1] Therefore, it is phosphorylation at site 1 that is responsible for pyruvate dehydrogenase deactivation.

Isozymes edit

There are four known isozymes of PDK in humans:

The primary sequencing between the four isozymes are conserved with 70% identity. The greatest differences occur near the N-terminus.[2]

PDK1 is the largest of the four with 436 residues while PDK2, PDK3 and PDK4 have 407, 406, and 411 residues respectively. The isozymes have different activity and phosphorylation rates at each site. At site 1 in order from fastest to slowest, PDK2 > PDK4 ≈ PDK1 > PDK3. For site 2, PDK3 > PDK4 > PDK2 > PDK1. Only PDK1 can phosphorylate site 3. However, it has been shown that these activities are sensitive to slight changes in pH so the microenvironment of the PDK isozymes may change the reaction rates.[3][4]

Isozyme abundance has also been shown to be tissue specific. PDK1 is ample in heart cells. PDK3 is most abundant in testis. PDK2 is present in most tissues but low in spleen and lung cells. PDK4 is predominantly found in skeletal muscle and heart tissues.[5]

Mechanism edit

Pyruvate dehydrogenase is deactivated when phosphorylated by PDK. Normally, the active site of pyruvate dehydrogenase is in a stabilized and ordered conformation supported by a network of hydrogen bonds. However, phosphorylation by PDK at site 1 causes steric clashes with another nearby serine residue due to both the increased size and negative charges associated with the phosphorylated residue.[6] This disrupts the hydrogen bond network and disorders the conformation of two phosphorylation loops. These loops prevent the reductive acetylation step, thus halting overall activity of the enzyme.[7] The conformational changes and mechanism of deactivation for phosphorylation at sites 2 and 3 are not known at this time.

Regulation edit

 
PDK isozyme 4 with ADP bound in the active site. ADP has been shown to be a competitive inhibitor.[8]

Pyruvate dehydrogenase kinase is activated by ATP, NADH and acetyl-CoA. It is inhibited by ADP, NAD+, CoA-SH and pyruvate.[9]

Each isozyme responds to each of these factors slightly differently. NADH stimulates PDK1 activity by 20% and PDK2 activity by 30%. NADH with acetyl-CoA increases activity in these enzymes by 200% and 300% respectively. In similar conditions, PDK3 is unresponsive to NADH and inhibited by NADH with acetyl-CoA. PDK4 has a 200% activity increase with NADH, but adding acetyl-CoA does not increase activity further.[5]

Disease relevance edit

PDK isoforms are elevated in obesity, diabetes, heart failure, and cancer.[10] Some studies have shown that cells that lack insulin (or are insensitive to insulin) overexpress PDK4.[11] As a result, the pyruvate formed from glycolysis cannot be oxidized which leads to hyperglycaemia due to the fact that glucose in the blood cannot be used efficiently. Therefore, several drugs target PDK4 hoping to treat type II diabetes.[12]

PDK1 has shown to have increased activity in hypoxic cancer cells due to the presence of HIF-1. PDK1 shunts pyruvate away from the citric acid cycle and keeps the hypoxic cell alive.[13] Therefore, PDK1 inhibition has been suggested as an antitumor therapy since PDK1 prevents apoptosis in these cancerous cells.[14] Similarly, PDK3 has been shown to be overexpressed in colon cancer cell lines.[15] Three proposed inhibitors are AZD7545 and dichloroacetate which both bind to PDK1, and Radicicol which binds to PDK3.[16]

Mutations in the PDK3 gene are a rare cause of X-linked Charcot-Marie-Tooth disease (CMTX6).[17][18]

In dogs, specifically Doberman Pinschers, a mutation in the PDK4 gene is associated with dilated cardiomyopathy (DCM).[19][20][21]

References edit

  1. ^ Yeaman SJ, Hutcheson ET, Roche TE, Pettit FH, Brown JR, Reed LJ, Watson DC, Dixon GH (June 1978). "Sites of phosphorylation on pyruvate dehydrogenase from bovine kidney and heart". Biochemistry. 17 (12): 2364–70. doi:10.1021/bi00605a017. PMID 678513.
  2. ^ Popov KM, Kedishvili NY, Zhao Y, Gudi R, Harris RA (November 1994). "Molecular cloning of the p45 subunit of pyruvate dehydrogenase kinase". The Journal of Biological Chemistry. 269 (47): 29720–4. doi:10.1016/S0021-9258(18)43940-3. PMID 7961963.
  3. ^ Korotchkina LG, Patel MS (October 2001). "Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase". The Journal of Biological Chemistry. 276 (40): 37223–9. doi:10.1074/jbc.M103069200. PMID 11486000.
  4. ^ Kolobova E, Tuganova A, Boulatnikov I, Popov KM (August 2001). "Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites". The Biochemical Journal. 358 (Pt 1): 69–77. doi:10.1042/0264-6021:3580069. PMC 1222033. PMID 11485553.
  5. ^ a b Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM (January 1998). "Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex". The Biochemical Journal. 329 (1): 191–6. doi:10.1042/bj3290191. PMC 1219031. PMID 9405293.
  6. ^ Korotchkina LG, Patel MS (February 2001). "Probing the mechanism of inactivation of human pyruvate dehydrogenase by phosphorylation of three sites". The Journal of Biological Chemistry. 276 (8): 5731–8. doi:10.1074/jbc.M007558200. PMID 11092882.
  7. ^ Kato M, Wynn RM, Chuang JL, Tso SC, Machius M, Li J, Chuang DT (December 2008). "Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops". Structure. 16 (12): 1849–59. doi:10.1016/j.str.2008.10.010. PMC 2849990. PMID 19081061.
  8. ^ Roche TE, Reed LJ (August 1974). "Monovalent cation requirement for ADP inhibition of pyruvate dehydrogenase kinase". Biochemical and Biophysical Research Communications. 59 (4): 1341–8. doi:10.1016/0006-291X(74)90461-6. PMID 4370205.
  9. ^ Sugden MC, Holness MJ (May 2003). "Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs". American Journal of Physiology. Endocrinology and Metabolism. 284 (5): E855-62. doi:10.1152/ajpendo.00526.2002. PMID 12676647.
  10. ^ Park S, Jeon JH, Lee IK (2018). "Role of the Pyruvate Dehydrogenase Complex in Metabolic Remodeling: Differential Pyruvate Dehydrogenase Complex Functions in Metabolism". Diabetes Medical Journal. 42 (4): 270–281. doi:10.4093/dmj.2018.0101. PMC 6107359. PMID 30136450.
  11. ^ Majer M, Popov KM, Harris RA, Bogardus C, Prochazka M (October 1998). "Insulin downregulates pyruvate dehydrogenase kinase (PDK) mRNA: potential mechanism contributing to increased lipid oxidation in insulin-resistant subjects". Molecular Genetics and Metabolism. 65 (2): 181–6. doi:10.1006/mgme.1998.2748. PMID 9787110.
  12. ^ Holness MJ, Sugden MC (December 2003). "Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation". Biochemical Society Transactions. 31 (Pt 6): 1143–51. doi:10.1042/bst0311143. PMID 14641014.
  13. ^ Kim JW, Tchernyshyov I, Semenza GL, Dang CV (March 2006). "HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia". Cell Metabolism. 3 (3): 177–85. doi:10.1016/j.cmet.2006.02.002. PMID 16517405.
  14. ^ Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED (January 2007). "A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth". Cancer Cell. 11 (1): 37–51. doi:10.1016/j.ccr.2006.10.020. PMID 17222789.
  15. ^ Lu CW, Lin SC, Chien CW, Lin SC, Lee CT, Lin BW, Lee JC, Tsai SJ (September 2011). "Overexpression of pyruvate dehydrogenase kinase 3 increases drug resistance and early recurrence in colon cancer". The American Journal of Pathology. 179 (3): 1405–14. doi:10.1016/j.ajpath.2011.05.050. PMC 3157210. PMID 21763680.
  16. ^ Kato M, Li J, Chuang JL, Chuang DT (August 2007). "Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol". Structure. 15 (8): 992–1004. doi:10.1016/j.str.2007.07.001. PMC 2871385. PMID 17683942.
  17. ^ Online Mendelian Inheritance in Man (OMIM): Charcot-Marie-tooth disease, X-linked dominant, 6; CMTX6 - 300905
  18. ^ Kennerson ML, Yiu EM, Chuang DT, Kidambi A, Tso SC, Ly C, Chaudhry R, Drew AP, Rance G, Delatycki MB, Züchner S, Ryan MM, Nicholson GA (April 2013). "A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene". Human Molecular Genetics. 22 (7): 1404–16. doi:10.1093/hmg/dds557. PMC 3596851. PMID 23297365.
  19. ^ Bolfer L, Estrada AH, Larkin C, Conlon TJ, Lourenco F, Taggart K, et al. (March 2020). "Functional Consequences of PDK4 Deficiency in Doberman Pinscher Fibroblasts". Scientific Reports. 10 (1): 3930. Bibcode:2020NatSR..10.3930B. doi:10.1038/s41598-020-60879-6. PMC 7054397. PMID 32127618.
  20. ^ Taggart K, Estrada A, Thompson P, Lourenco F, Kirmani S, Suzuki-Hatano S, Pacak CA (2017). "PDK4 Deficiency Induces Intrinsic Apoptosis in Response to Starvation in Fibroblasts from Doberman Pinschers with Dilated Cardiomyopathy". BioResearch Open Access. 6 (1): 182–191. doi:10.1089/biores.2017.0023. PMC 5745584. PMID 29285418.
  21. ^ Meurs KM, Lahmers S, Keene BW, White SN, Oyama MA, Mauceli E, Lindblad-Toh K (August 2012). "A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher". Human Genetics. 131 (8): 1319–25. doi:10.1007/s00439-012-1158-2. PMID 22447147. S2CID 253975177.

External links edit

April 11, 2024
pyruvate, dehydrogenase, kinase, also, pyruvate, dehydrogenase, complex, kinase, kinase, kinase, enzyme, which, acts, inactivate, enzyme, pyruvate, dehydrogenase, phosphorylating, using, areas, around, three, phosphorylation, sites, shown, site, bottom, left, . Pyruvate dehydrogenase kinase also pyruvate dehydrogenase complex kinase PDC kinase or PDK EC 2 7 11 2 is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP Pyruvate dehydrogenase kinaseThe areas around the three phosphorylation sites are shown in red Site 1 is in the bottom left corner site 2 in the top right and site 3 in the bottom right IdentifiersEC no 2 7 11 2CAS no 2620256DatabasesIntEnzIntEnz viewBRENDABRENDA entryExPASyNiceZyme viewKEGGKEGG entryMetaCycmetabolic pathwayPRIAMprofilePDB structuresRCSB PDB PDBe PDBsumSearchPMCarticlesPubMedarticlesNCBIproteinsPDK thus participates in the regulation of the pyruvate dehydrogenase complex of which pyruvate dehydrogenase is the first component Both PDK and the pyruvate dehydrogenase complex are located in the mitochondrial matrix of eukaryotes The complex acts to convert pyruvate a product of glycolysis in the cytosol to acetyl coA which is then oxidized in the mitochondria to produce energy in the citric acid cycle By downregulating the activity of this complex PDK will decrease the oxidation of pyruvate in mitochondria and increase the conversion of pyruvate to lactate in the cytosol The opposite action of PDK namely the dephosphorylation and activation of pyruvate dehydrogenase is catalyzed by a phosphoprotein phosphatase called pyruvate dehydrogenase phosphatase Pyruvate dehydrogenase kinase should not be confused with Phosphoinositide dependent kinase 1 which is also sometimes known as PDK1 Contents 1 Phosphorylation sites 2 Isozymes 3 Mechanism 4 Regulation 5 Disease relevance 6 References 7 External linksPhosphorylation sites editPDK can phosphorylate a serine residue on pyruvate dehydrogenase at three possible sites Some evidence has shown that phosphorylation at site 1 will nearly completely deactivate the enzyme while phosphorylation at sites 2 and 3 had only a small contribution to complex inactivation 1 Therefore it is phosphorylation at site 1 that is responsible for pyruvate dehydrogenase deactivation Isozymes editThere are four known isozymes of PDK in humans PDK1 PDK2 PDK3 PDK4The primary sequencing between the four isozymes are conserved with 70 identity The greatest differences occur near the N terminus 2 PDK1 is the largest of the four with 436 residues while PDK2 PDK3 and PDK4 have 407 406 and 411 residues respectively The isozymes have different activity and phosphorylation rates at each site At site 1 in order from fastest to slowest PDK2 gt PDK4 PDK1 gt PDK3 For site 2 PDK3 gt PDK4 gt PDK2 gt PDK1 Only PDK1 can phosphorylate site 3 However it has been shown that these activities are sensitive to slight changes in pH so the microenvironment of the PDK isozymes may change the reaction rates 3 4 Isozyme abundance has also been shown to be tissue specific PDK1 is ample in heart cells PDK3 is most abundant in testis PDK2 is present in most tissues but low in spleen and lung cells PDK4 is predominantly found in skeletal muscle and heart tissues 5 Mechanism editPyruvate dehydrogenase is deactivated when phosphorylated by PDK Normally the active site of pyruvate dehydrogenase is in a stabilized and ordered conformation supported by a network of hydrogen bonds However phosphorylation by PDK at site 1 causes steric clashes with another nearby serine residue due to both the increased size and negative charges associated with the phosphorylated residue 6 This disrupts the hydrogen bond network and disorders the conformation of two phosphorylation loops These loops prevent the reductive acetylation step thus halting overall activity of the enzyme 7 The conformational changes and mechanism of deactivation for phosphorylation at sites 2 and 3 are not known at this time Regulation edit nbsp PDK isozyme 4 with ADP bound in the active site ADP has been shown to be a competitive inhibitor 8 Pyruvate dehydrogenase kinase is activated by ATP NADH and acetyl CoA It is inhibited by ADP NAD CoA SH and pyruvate 9 Each isozyme responds to each of these factors slightly differently NADH stimulates PDK1 activity by 20 and PDK2 activity by 30 NADH with acetyl CoA increases activity in these enzymes by 200 and 300 respectively In similar conditions PDK3 is unresponsive to NADH and inhibited by NADH with acetyl CoA PDK4 has a 200 activity increase with NADH but adding acetyl CoA does not increase activity further 5 Disease relevance editPDK isoforms are elevated in obesity diabetes heart failure and cancer 10 Some studies have shown that cells that lack insulin or are insensitive to insulin overexpress PDK4 11 As a result the pyruvate formed from glycolysis cannot be oxidized which leads to hyperglycaemia due to the fact that glucose in the blood cannot be used efficiently Therefore several drugs target PDK4 hoping to treat type II diabetes 12 PDK1 has shown to have increased activity in hypoxic cancer cells due to the presence of HIF 1 PDK1 shunts pyruvate away from the citric acid cycle and keeps the hypoxic cell alive 13 Therefore PDK1 inhibition has been suggested as an antitumor therapy since PDK1 prevents apoptosis in these cancerous cells 14 Similarly PDK3 has been shown to be overexpressed in colon cancer cell lines 15 Three proposed inhibitors are AZD7545 and dichloroacetate which both bind to PDK1 and Radicicol which binds to PDK3 16 Mutations in the PDK3 gene are a rare cause of X linked Charcot Marie Tooth disease CMTX6 17 18 In dogs specifically Doberman Pinschers a mutation in the PDK4 gene is associated with dilated cardiomyopathy DCM 19 20 21 References edit Yeaman SJ Hutcheson ET Roche TE Pettit FH Brown JR Reed LJ Watson DC Dixon GH June 1978 Sites of phosphorylation on pyruvate dehydrogenase from bovine kidney and heart Biochemistry 17 12 2364 70 doi 10 1021 bi00605a017 PMID 678513 Popov KM Kedishvili NY Zhao Y Gudi R Harris RA November 1994 Molecular cloning of the p45 subunit of pyruvate dehydrogenase kinase The Journal of Biological Chemistry 269 47 29720 4 doi 10 1016 S0021 9258 18 43940 3 PMID 7961963 Korotchkina LG Patel MS October 2001 Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase The Journal of Biological Chemistry 276 40 37223 9 doi 10 1074 jbc M103069200 PMID 11486000 Kolobova E Tuganova A Boulatnikov I Popov KM August 2001 Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites The Biochemical Journal 358 Pt 1 69 77 doi 10 1042 0264 6021 3580069 PMC 1222033 PMID 11485553 a b Bowker Kinley MM Davis WI Wu P Harris RA Popov KM January 1998 Evidence for existence of tissue specific regulation of the mammalian pyruvate dehydrogenase complex The Biochemical Journal 329 1 191 6 doi 10 1042 bj3290191 PMC 1219031 PMID 9405293 Korotchkina LG Patel MS February 2001 Probing the mechanism of inactivation of human pyruvate dehydrogenase by phosphorylation of three sites The Journal of Biological Chemistry 276 8 5731 8 doi 10 1074 jbc M007558200 PMID 11092882 Kato M Wynn RM Chuang JL Tso SC Machius M Li J Chuang DT December 2008 Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation role of disordered phosphorylation loops Structure 16 12 1849 59 doi 10 1016 j str 2008 10 010 PMC 2849990 PMID 19081061 Roche TE Reed LJ August 1974 Monovalent cation requirement for ADP inhibition of pyruvate dehydrogenase kinase Biochemical and Biophysical Research Communications 59 4 1341 8 doi 10 1016 0006 291X 74 90461 6 PMID 4370205 Sugden MC Holness MJ May 2003 Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs American Journal of Physiology Endocrinology and Metabolism 284 5 E855 62 doi 10 1152 ajpendo 00526 2002 PMID 12676647 Park S Jeon JH Lee IK 2018 Role of the Pyruvate Dehydrogenase Complex in Metabolic Remodeling Differential Pyruvate Dehydrogenase Complex Functions in Metabolism Diabetes Medical Journal 42 4 270 281 doi 10 4093 dmj 2018 0101 PMC 6107359 PMID 30136450 Majer M Popov KM Harris RA Bogardus C Prochazka M October 1998 Insulin downregulates pyruvate dehydrogenase kinase PDK mRNA potential mechanism contributing to increased lipid oxidation in insulin resistant subjects Molecular Genetics and Metabolism 65 2 181 6 doi 10 1006 mgme 1998 2748 PMID 9787110 Holness MJ Sugden MC December 2003 Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation Biochemical Society Transactions 31 Pt 6 1143 51 doi 10 1042 bst0311143 PMID 14641014 Kim JW Tchernyshyov I Semenza GL Dang CV March 2006 HIF 1 mediated expression of pyruvate dehydrogenase kinase a metabolic switch required for cellular adaptation to hypoxia Cell Metabolism 3 3 177 85 doi 10 1016 j cmet 2006 02 002 PMID 16517405 Bonnet S Archer SL Allalunis Turner J Haromy A Beaulieu C Thompson R Lee CT Lopaschuk GD Puttagunta L Bonnet S Harry G Hashimoto K Porter CJ Andrade MA Thebaud B Michelakis ED January 2007 A mitochondria K channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth Cancer Cell 11 1 37 51 doi 10 1016 j ccr 2006 10 020 PMID 17222789 Lu CW Lin SC Chien CW Lin SC Lee CT Lin BW Lee JC Tsai SJ September 2011 Overexpression of pyruvate dehydrogenase kinase 3 increases drug resistance and early recurrence in colon cancer The American Journal of Pathology 179 3 1405 14 doi 10 1016 j ajpath 2011 05 050 PMC 3157210 PMID 21763680 Kato M Li J Chuang JL Chuang DT August 2007 Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545 dichloroacetate and radicicol Structure 15 8 992 1004 doi 10 1016 j str 2007 07 001 PMC 2871385 PMID 17683942 Online Mendelian Inheritance in Man OMIM Charcot Marie tooth disease X linked dominant 6 CMTX6 300905 Kennerson ML Yiu EM Chuang DT Kidambi A Tso SC Ly C Chaudhry R Drew AP Rance G Delatycki MB Zuchner S Ryan MM Nicholson GA April 2013 A new locus for X linked dominant Charcot Marie Tooth disease CMTX6 is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 PDK3 gene Human Molecular Genetics 22 7 1404 16 doi 10 1093 hmg dds557 PMC 3596851 PMID 23297365 Bolfer L Estrada AH Larkin C Conlon TJ Lourenco F Taggart K et al March 2020 Functional Consequences of PDK4 Deficiency in Doberman Pinscher Fibroblasts Scientific Reports 10 1 3930 Bibcode 2020NatSR 10 3930B doi 10 1038 s41598 020 60879 6 PMC 7054397 PMID 32127618 Taggart K Estrada A Thompson P Lourenco F Kirmani S Suzuki Hatano S Pacak CA 2017 PDK4 Deficiency Induces Intrinsic Apoptosis in Response to Starvation in Fibroblasts from Doberman Pinschers with Dilated Cardiomyopathy BioResearch Open Access 6 1 182 191 doi 10 1089 biores 2017 0023 PMC 5745584 PMID 29285418 Meurs KM Lahmers S Keene BW White SN Oyama MA Mauceli E Lindblad Toh K August 2012 A splice site mutation in a gene encoding for PDK4 a mitochondrial protein is associated with the development of dilated cardiomyopathy in the Doberman pinscher Human Genetics 131 8 1319 25 doi 10 1007 s00439 012 1158 2 PMID 22447147 S2CID 253975177 External links editpyruvate dehydrogenase kinase at the U S National Library of Medicine Medical Subject Headings MeSH EC 2 7 11 2 Portal nbsp Biology Retrieved from https en wikipedia org w index php title Pyruvate dehydrogenase kinase amp oldid 1181850904, wikipedia, wiki, book, books, library,

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