Diabetes Metab J.  2015 Jun;39(3):188-197. 10.4093/dmj.2015.39.3.188.

Pyruvate Dehydrogenase Kinases: Therapeutic Targets for Diabetes and Cancers

• Jeoung NH

• KMID: 2281531
• DOI: http://doi.org/10.4093/dmj.2015.39.3.188

Abstract

Impaired glucose homeostasis is one of the risk factors for causing metabolic diseases including obesity, type 2 diabetes, and cancers. In glucose metabolism, pyruvate dehydrogenase complex (PDC) mediates a major regulatory step, an irreversible reaction of oxidative decarboxylation of pyruvate to acetyl-CoA. Tight control of PDC is critical because it plays a key role in glucose disposal. PDC activity is tightly regulated using phosphorylation by pyruvate dehydrogenase kinases (PDK1 to 4) and pyruvate dehydrogenase phosphatases (PDP1 and 2). PDKs and PDPs exhibit unique tissue expression patterns, kinetic properties, and sensitivities to regulatory molecules. During the last decades, the up-regulation of PDKs has been observed in the tissues of patients and mammals with metabolic diseases, which suggests that the inhibition of these kinases may have beneficial effects for treating metabolic diseases. This review summarizes the recent advances in the role of specific PDK isoenzymes on the induction of metabolic diseases and describes the effects of PDK inhibition on the prevention of metabolic diseases using pharmacological inhibitors. Based on these reports, PDK isoenzymes are strong therapeutic targets for preventing and treating metabolic diseases.

Keyword

Diabetes mellitus, type 2; Glucose metabolism; Pyruvate dehydrogenase complex; Pyruvate dehydrogenase kinase; Pyruvate dehydrogenase kinase inhibitor; Warberg effect

MeSH Terms

Acetyl Coenzyme A
Decarboxylation
Diabetes Mellitus, Type 2
Glucose
Homeostasis
Humans
Isoenzymes
Mammals
Metabolic Diseases
Metabolism
Obesity
Oxidoreductases*
Phosphoric Monoester Hydrolases
Phosphorylation
Phosphotransferases*
Pyruvate Dehydrogenase Complex
Pyruvic Acid*
Risk Factors
Up-Regulation
Acetyl Coenzyme A
Glucose
Isoenzymes
Oxidoreductases
Phosphoric Monoester Hydrolases
Phosphotransferases
Pyruvate Dehydrogenase Complex
Pyruvic Acid

Figure

• 

  Fig. 1 Schematic diagram of the development of metabolic diseases by induction of pyruvate dehydrogenase kinase (PDK) isoenzymes. Hif-1, hypoxia inducible factor 1; PDC, pyruvate dehydrogenase complex.

• 

  Fig. 2 Regulation of pyruvate dehydrogenase complex and physiological factors for regulation of pyruvate dehydrogenase kinases (PDKs) and pyruvate dehydrogenase phosphatases (PDPs). Pyruvate dehydrogenase complex (PDC) consists of three components such as pyruvate dehydrogenase (E1), dihydrolipoyl acetyltransferase (E2), and dihydrolipoyl dehydrogenase (E3). Hif-1, hypoxia inducible factor 1; FFA, free fatty acid; GR, glucocorticoid receptor; ER, estrogen (related) receptor; TR, thyroid receptor; PPAR, peroxisome proliferate activation receptor; CoA-SH, coenzyme A; NAD, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide reduced.

• 

  Fig. 3 Aerobic glycolysis and oxidative glycolysis. The glycolysis converts glucose to pyruvate via same metabolic pathway. In aerobic glycolysis (blue arrow), lactate dehydrogenase (LDH) shifts the pyruvate to lactate because the pyruvate dehydrogenase complex (PDC) is inactivated by pyruvate dehydrogenase kinases (PDKs). In oxidative glycolysis (green arrow), PDC converts the pyruvate to β-oxidation increases acetyl-CoA (Ac-CoA), which is further oxidized via tricarboxylic acid (TCA) cycle. HK, hexokinase; Hif-1α, hypoxia inducible factor 1α; PFK1, phosphofructokinase 1; ROS, reactive oxygen species; ETS, electron transport system; G-3-Pi, glyceraldehyde-3-phosphate; DHAP, dihydroxyacetone phosphate; NADH, nicotinamide adenine dinucleotide reduced; FADH, flavin adenine dinucleotide reduced.

• 

  Fig. 4 Allosteric binding domains and substrate binding domains on the pyruvate dehydrogenase kinases (PDKs) (A) and PDK inhibitors (B-H). (A) Protein structure of PDK2 monomer and its allosteric regulator binding sites and substrate binding domains; two allosteric binding domains (pyruvate-binding domain and CoA-binding domain) and one substrate binding domain (lipoamide-binding domain) are located on the N-terminal domain and another substrate binding domain (ATP-binding domain) is located on the C-terminal domain. (B, C) Inhibitors of the pyruvate-binding domain (B, (R)-trifluoro-2-hydroxy-2-methylpropionic acid; C, N-benzyl-2,2-dichloroacetamide). (D) Pfz3, inhibitor of the coenzyme A-binding site. (E, F) Inhibitors of the lipoamide-binding domain (E, AZD7545; F, Nov3r). (G, H) Inhibitors of the nucleotide-binding domain (G, radicicol; H, M77976).

Reference

1. Rahimi Y, Camporez JP, Petersen MC, Pesta D, Perry RJ, Jurczak MJ, Cline GW, Shulman GI. Genetic activation of pyruvate dehydrogenase alters oxidative substrate selection to induce skeletal muscle insulin resistance. Proc Natl Acad Sci U S A. 2014; 111:16508–16513.

2. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963; 1:785–789.

3. Garland PB, Newsholme EA, Randle PJ. Regulation of glucose uptake by muscle. 9. Effects of fatty acids and ketone bodies, and of alloxan-diabetes and starvation, on pyruvate metabolism and on lactate-pyruvate and L-glycerol 3-phosphate-dihydroxyacetone phosphate concentration ratios in rat heart and rat diaphragm muscles. Biochem J. 1964; 93:665–678.

4. Jeoung NH, Harris RA. Role of pyruvate dehydrogenase kinase 4 in regulation of blood glucose levels. Korean Diabetes J. 2010; 34:274–283.

5. Sugden MC, Bulmer K, Holness MJ. Fuel-sensing mechanisms integrating lipid and carbohydrate utilization. Biochem Soc Trans. 2001; 29(Pt 2):272–278.

6. Harris RA, Bowker-Kinley MM, Huang B, Wu P. Regulation of the activity of the pyruvate dehydrogenase complex. Adv Enzyme Regul. 2002; 42:249–259.

7. Del Prato S, Bonadonna RC, Bonora E, Gulli G, Solini A, Shank M, DeFronzo RA. Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus. J Clin Invest. 1993; 91:484–494.

8. Mondon CE, Jones IR, Azhar S, Hollenbeck CB, Reaven GM. Lactate production and pyruvate dehydrogenase activity in fat and skeletal muscle from diabetic rats. Diabetes. 1992; 41:1547–1554.

9. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006; 3:177–185.

10. Semenza GL. HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 2010; 20:51–56.

11. Preiser JC, Moulart D, Vincent JL. Dichloroacetate administration in the treatment of endotoxin shock. Circ Shock. 1990; 30:221–228.

12. Sugden MC, Holness MJ. Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehydrogenase kinases. Arch Physiol Biochem. 2006; 112:139–149.

13. Rowles J, Scherer SW, Xi T, Majer M, Nickle DC, Rommens JM, Popov KM, Harris RA, Riebow NL, Xia J, Tsui LC, Bogardus C, Prochazka M. Cloning and characterization of PDK4 on 7q21.3 encoding a fourth pyruvate dehydrogenase kinase isoenzyme in human. J Biol Chem. 1996; 271:22376–22382.

14. Huang B, Gudi R, Wu P, Harris RA, Hamilton J, Popov KM. Isoenzymes of pyruvate dehydrogenase phosphatase. DNA-derived amino acid sequences, expression, and regulation. J Biol Chem. 1998; 273:17680–17688.

15. Huang B, Wu P, Popov KM, Harris RA. Starvation and diabetes reduce the amount of pyruvate dehydrogenase phosphatase in rat heart and kidney. Diabetes. 2003; 52:1371–1376.

16. Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J. 1998; 329(Pt 1):191–196.

17. Wu P, Blair PV, Sato J, Jaskiewicz J, Popov KM, Harris RA. Starvation increases the amount of pyruvate dehydrogenase kinase in several mammalian tissues. Arch Biochem Biophys. 2000; 381:1–7.

18. Wu P, Sato J, Zhao Y, Jaskiewicz J, Popov KM, Harris RA. Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart. Biochem J. 1998; 329(Pt 1):197–201.

19. Jeong JY, Jeoung NH, Park KG, Lee IK. Transcriptional regulation of pyruvate dehydrogenase kinase. Diabetes Metab J. 2012; 36:328–335.

20. Cairns RA, Papandreou I, Sutphin PD, Denko NC. Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy. Proc Natl Acad Sci U S A. 2007; 104:9445–9450.

21. Ding G, Huang G, Liu HD, Liang HX, Ni YF, Ding ZH, Ni GY, Hua HW. MiR-199a suppresses the hypoxia-induced proliferation of non-small cell lung cancer cells through targeting HIF1alpha. Mol Cell Biochem. 2013; 384:173–180.

22. Newington JT, Pitts A, Chien A, Arseneault R, Schubert D, Cumming RC. Amyloid beta resistance in nerve cell lines is mediated by the Warburg effect. PLoS One. 2011; 6:e19191.

23. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006; 3:187–197.

24. Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol. 1999; 15:551–578.

25. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol. 2000; 2:423–427.

26. Semenza GL. Regulation of metabolism by hypoxia-inducible factor 1. Cold Spring Harb Symp Quant Biol. 2011; 76:347–353.

27. Howangyin KY, Silvestre JS. Diabetes mellitus and ischemic diseases: molecular mechanisms of vascular repair dysfunction. Arterioscler Thromb Vasc Biol. 2014; 34:1126–1135.

28. McFate T, Mohyeldin A, Lu H, Thakar J, Henriques J, Halim ND, Wu H, Schell MJ, Tsang TM, Teahan O, Zhou S, Califano JA, Jeoung NH, Harris RA, Verma A. Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem. 2008; 283:22700–22708.

29. Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol. 2006; 70:1469–1480.

30. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thebaud B, Bonnet S, Haromy A, Harry G, Moudgil R, McMurtry MS, Weir EK, Archer SL. An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension. Circulation. 2006; 113:2630–2641.

31. 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. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007; 11:37–51.

32. Harris RA, Huang B, Wu P. Control of pyruvate dehydrogenase kinase gene expression. Adv Enzyme Regul. 2001; 41:269–288.

33. Jeoung NH, Rahimi Y, Wu P, Lee WN, Harris RA. Fasting induces ketoacidosis and hypothermia in PDHK2/PDHK4-double-knockout mice. Biochem J. 2012; 443:829–839.

34. Deuse T, Hua X, Wang D, Maegdefessel L, Heeren J, Scheja L, Bolanos JP, Rakovic A, Spin JM, Stubbendorff M, Ikeno F, Langer F, Zeller T, Schulte-Uentrop L, Stoehr A, Itagaki R, Haddad F, Eschenhagen T, Blankenberg S, Kiefmann R, Reichenspurner H, Velden J, Klein C, Yeung A, Robbins RC, Tsao PS, Schrepfer S. Dichloroacetate prevents restenosis in preclinical animal models of vessel injury. Nature. 2014; 509:641–644.

35. Byun JK, Choi YK, Kang YN, Jang BK, Kang KJ, Jeon YH, Lee HW, Jeon JH, Koo SH, Jeong WI, Harris RA, Lee IK, Park KG. Retinoic acid-related orphan receptor alpha reprograms glucose metabolism in glutamine-deficient hepatoma cells. Hepatology. 2015; 61:953–964.

36. Baker JC, Yan X, Peng T, Kasten S, Roche TE. Marked differences between two isoforms of human pyruvate dehydrogenase kinase. J Biol Chem. 2000; 275:15773–15781.

37. Tuganova A, Boulatnikov I, Popov KM. Interaction between the individual isoenzymes of pyruvate dehydrogenase kinase and the inner lipoyl-bearing domain of transacetylase component of pyruvate dehydrogenase complex. Biochem J. 2002; 366(Pt 1):129–136.

38. 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; 283:28106–28114.

39. Prigione A, Rohwer N, Hoffmann S, Mlody B, Drews K, Bukowiecki R, Blumlein K, Wanker EE, Ralser M, Cramer T, Adjaye J. HIF1alpha modulates cell fate reprogramming through early glycolytic shift and upregulation of PDK1-3 and PKM2. Stem Cells. 2014; 32:364–376.

40. Lu CW, Lin SC, Chien CW, Lin SC, Lee CT, Lin BW, Lee JC, Tsai SJ. Overexpression of pyruvate dehydrogenase kinase 3 increases drug resistance and early recurrence in colon cancer. Am J Pathol. 2011; 179:1405–1414.

41. Roche TE, Hiromasa Y. Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cell Mol Life Sci. 2007; 64:830–849.

42. 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; 397:417–425.

43. Jeoung NH, Harris RA. Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice. Am J Physiol Endocrinol Metab. 2008; 295:E46–E54.

44. Hwang B, Jeoung NH, Harris RA. Pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) deficiency attenuates the long-term negative effects of a high-saturated fat diet. Biochem J. 2009; 423:243–252.

45. Liu Z, Chen X, Wang Y, Peng H, Wang Y, Jing Y, Zhang H. PDK4 protein promotes tumorigenesis through activation of cAMP-response element-binding protein (CREB)-Ras homolog enriched in brain (RHEB)-mTORC1 signaling cascade. J Biol Chem. 2014; 289:29739–29749.

46. Takubo K, Nagamatsu G, Kobayashi CI, Nakamura-Ishizu A, Kobayashi H, Ikeda E, Goda N, Rahimi Y, Johnson RS, Soga T, Hirao A, Suematsu M, Suda T. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell. 2013; 12:49–61.

47. Kwon HS, Huang B, Unterman TG, Harris RA. Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors. Diabetes. 2004; 53:899–910.

48. Blackshear PJ, Holloway PA, Alberti KG. The metabolic effects of sodium dichloroacetate in the starved rat. Biochem J. 1974; 142:279–286.

49. McAllister A, Allison SP, Randle PJ. Effects of dichloroacetate on the metabolism of glucose, pyruvate, acetate, 3-hydroxybutyrate and palmitate in rat diaphragm and heart muscle in vitro and on extraction of glucose, lactate, pyruvate and free fatty acids by dog heart in vivo. Biochem J. 1973; 134:1067–1081.

50. Relman AS. Lactic acidosis and a possible new treatment. N Engl J Med. 1978; 298:564–565.

51. Backshear PJ, Holloway PA, Alberti KG. Metabolic interactions of dichloroacetate and insulin in experimental diabetic ketoacidosis. Biochem J. 1975; 146:447–456.

52. Ho N, Coomber BL. Pyruvate dehydrogenase kinase expression and metabolic changes following dichloroacetate exposure in anoxic human colorectal cancer cells. Exp Cell Res. 2015; 331:73–81.

53. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med. 2010; 2:31ra4.

54. Sun RC, Fadia M, Dahlstrom JE, Parish CR, Board PG, Blackburn AC. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat. 2010; 120:253–260.

55. Ruggieri V, Agriesti F, Scrima R, Laurenzana I, Perrone D, Tataranni T, Mazzoccoli C, Lo Muzio L, Capitanio N, Piccoli C. Dichloroacetate, a selective mitochondria-targeting drug for oral squamous cell carcinoma: a metabolic perspective of treatment. Oncotarget. 2015; 6:1217–1230.

56. Sutendra G, Michelakis ED. Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Front Oncol. 2013; 3:38.

57. Bebernitz GR, Aicher TD, Stanton JL, Gao J, Shetty SS, Knorr DC, Strohschein RJ, Tan J, Brand LJ, Liu C, Wang WH, Vinluan CC, Kaplan EL, Dragland CJ, DelGrande D, Islam A, Lozito RJ, Liu X, Maniara WM, Mann WR. Anilides of (R)-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase. J Med Chem. 2000; 43:2248–2257.

58. Mann WR, Dragland CJ, Vinluan CC, Vedananda TR, Bell PA, Aicher TD. Diverse mechanisms of inhibition of pyruvate dehydrogenase kinase by structurally distinct inhibitors. Biochim Biophys Acta. 2000; 1480:283–292.

59. Yang Y, Shang P, Cheng C, Wang D, Yang P, Zhang F, Li T, Lu A, Zhao Y. Novel N-phenyl dichloroacetamide derivatives as anticancer reagents: design, synthesis and biological evaluation. Eur J Med Chem. 2010; 45:4300–4306.

60. Knoechel TR, Tucker AD, Robinson CM, Phillips C, Taylor W, Bungay PJ, Kasten SA, Roche TE, Brown DG. Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands. Biochemistry. 2006; 45:402–415.

61. Ferriero R, Manco G, Lamantea E, Nusco E, Ferrante MI, Sordino P, Stacpoole PW, Lee B, Zeviani M, Brunetti-Pierri N. Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Sci Transl Med. 2013; 5:175ra31.

62. Ferriero R, Iannuzzi C, Manco G, Brunetti-Pierri N. Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate. J Inherit Metab Dis. 2015; 01. 20. [Epub].DOI: 10.1007/s10545-014-9808-2.

63. Mayers RM, Leighton B, Kilgour E. PDH kinase inhibitors: a novel therapy for type II diabetes? Biochem Soc Trans. 2005; 33(Pt 2):367–370.

64. 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; 15:992–1004.

65. 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; 67(Pt 9):763–773.