The resident mitochondrial protein kinases (mPKs) comprising pyruvate dehydrogenase kinases (PDKs), and branched-chain 1-ketoacid dehydrogenase kinase (BCK) are the molecular switches that control carbohydrate and branched-chain amino acid degradation. Mitochondrial PDKs (isoforms 1, 2, 3 and 4) down-regulate activity of the mitochondrial pyruvate dehydrogenase complex by reversible phosphorylation, in response to hormonal and nutritional stimuli. Certain PDK isoforms are over-expressed in disease states such as type 2 diabetes, obesity and cancer, resulting in decreased glucose oxidation. Towards understanding the structure and function of these PDKs, the P.I.'s laboratory has solved the crystal structures for three (PDK1, PDK3 and PDK4) of the four PDK isoforms and various PDK-inhibitor/activator complexes. Based on these advances, the P.I. proposes to continue investigation into the structure, function and regulation of mammalian PDKs.
The Specific Aims are: 1) To decipher the allosteric mechanisms by which the L2 domain and the synthetic ligands modulate PDK activities;2) To offer biochemical and structural basis for the hyperactivity of PDK4 and to identify the E1p substrate-binding site in this kinase isoform;3) To isolate a new generation of small-molecule inhibitors that are specific for PDK4 by high-through-put screening and characterize these novel inhibitors both in vitro and in cell culture. Standard methods including X-ray crystallography, isothermal titration calorimetry, kinase activity assays and the high-through-put screening method will be employed to achieve these Specific Aims. The availability of PDK4-specific inhibitors will foster new strategies to mitigate defective glucose oxidation in obesity and type 2 diabetes.
The mitochondrial protein kinases to be studied in this project are molecular switches that control carbohydrate and amino acid degradation in the liver and skeletal muscle. Aberrant functions of these protein kinases have been implicated in obesity and type 2 diabetes. Understanding the structure and function of pyruvate dehydrogenase kinase (PDK) isoforms and the development of PDK isoform #4-specific inhibitors will foster new strategies to mitigate defective glucose oxidation in these human diseases.
|Wu, Cheng-Yang; Satapati, Santhosh; Gui, Wenjun et al. (2018) A novel inhibitor of pyruvate dehydrogenase kinase stimulates myocardial carbohydrate oxidation in diet-induced obesity. J Biol Chem 293:9604-9613|
|Wu, Cheng-Yang; Tso, Shih-Chia; Chuang, Jacinta L et al. (2018) Targeting hepatic pyruvate dehydrogenase kinases restores insulin signaling and mitigates ChREBP-mediated lipogenesis in diet-induced obese mice. Mol Metab 12:12-24|
|White, Phillip J; McGarrah, Robert W; Grimsrud, Paul A et al. (2018) The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase. Cell Metab 27:1281-1293.e7|
|Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang et al. (2017) Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors. J Med Chem 60:1142-1150|
|Perez-Siles, Gonzalo; Ly, Carolyn; Grant, Adrienne et al. (2016) Pathogenic mechanisms underlying X-linked Charcot-Marie-Tooth neuropathy (CMTX6) in patients with a pyruvate dehydrogenase kinase 3 mutation. Neurobiol Dis 94:237-44|
|Sun, Haipeng; Olson, Kristine C; Gao, Chen et al. (2016) Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 133:2038-49|
|Scheuermann, Thomas H; Brautigam, Chad A (2015) High-precision, automated integration of multiple isothermal titration calorimetric thermograms: new features of NITPIC. Methods 76:87-98|
|Tso, Shih-Chia; Qi, Xiangbing; Gui, Wen-Jun et al. (2014) Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket. J Biol Chem 289:4432-43|
|Tso, Shih-Chia; Gui, Wen-Jun; Wu, Cheng-Yang et al. (2014) Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain ?-ketoacid dehydrogenase kinase. J Biol Chem 289:20583-93|
|Kennerson, Marina L; Yiu, Eppie M; Chuang, David T et al. (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. Hum Mol Genet 22:1404-16|
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