Improved liver function and regeneration with A20

主要的线粒体蛋白激酶（mPKs）包括丙酮酸脱氢酶激酶（PDKs），和 分支链！酮酸脱氢酶激酶（BCK）是控制碳水化合物的分子开关 和支链氨基酸降解。线粒体PDK（同种型1、2、3和4）被拴系到线粒体PDK（同种型1、2、3和4）。 哺乳动物丙酮酸脱氢酶复合物（PDC）的E2 p/E3 BP核心。这些mPKs下调 线粒体PDC活性的可逆磷酸化，在响应激素和营养刺激。 某些PDK同种型在疾病状态如2型糖尿病、肥胖症和癌症中过表达， 导致葡萄糖氧化受损。为了理解这些PDK的结构和功能， P.I.的实验室已经确定了异构体1、2和3以及各种PDK抑制剂的晶体结构。 活化剂络合物。基于这些进步，P.I.建议继续调查 哺乳动物PDKs的结构、功能和调节。具体目的是：1）解剖变构 L2结构域和合成配体调节PDK 3和PDK 1活性的机制; 2）提供 PDK 4高反应性的生物化学和结构基础，并鉴定E1 p底物结合位点 3）阐明PDK介导的PDC失活的分子机制， E1 p底物的磷酸化。标准方法包括X射线晶体学和 等温滴定量热法和激酶活性测定，已建立在这个实验室将是 为实现这些具体目标。了解这些的结构和生化机制 PDK异构体将为开发新的PDK抑制剂以改善人类疾病引起的疾病提供范例 葡萄糖代谢异常

The prominent mitochondrial protein kinases (mPKs) comprising pyruvate dehydrogenase kinases (PDKs), and branched-chain !-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) are tethered to the E2p/E3BP core of the mammalian pyruvate dehydrogenase complex (PDC). These mPKs down-regulate activity of the mitochondrial PDC 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 impaired glucose oxidation. Toward understanding the structure and function of these PDKs, The P.I.¿s laboratory has determined the crystal structures for isoforms 1, 2, and 3, and various PDKinhibitor/ activator complexes. Based on these advances, the P.I. proposes to continue our investigation into the structure, function and regulation of mammalian PDKs. The Specific Aims are: 1) To dissect the allosteric mechanisms by which the L2 domain and synthetic ligands modulate PDK3 and PDK1 activities; 2) To offer biochemical and structural basis for the hyper-reactivity of PDK4 and to identify the E1p substrate-binding site in this kinase isoform; 3) To decipher the molecular mechanisms underlying the inactivation of PDC by PDKmediated phosphorylation of the E1p substrate. Standard methods including X-ray crystallography and isothermal titration calorimetry and kinase activity assays that have been established in this laboratory will be employed to achieve these Specific Aims. Understanding the structural and biochemical mechanisms for these PDK isoforms will provide a paradigm for developing new PDK inhibitors to ameliorate human disease caused by aberrant glucose catabolism.