Fig. 1Schematic 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. 2Regulation 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. 3Aerobic 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. 4Allosteric 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).