NEW FAMILY OF PROTEIN KINASES

丙酮酸脱氢酶复合物提供了一个重要的代谢联系之间 糖酵解和葡萄糖的完全氧化。 青春痘使丙酮酸 通过乙酰辅酶A和克雷布斯循环氧化，因为没有生物化学 乙酰辅酶A可以转化回丙酮酸的方法。 活动 丙酮酸脱氢酶复合物的控制是可逆的 磷酸化 最近获得的证据表明， 负责丙酮酸脱氢酶共价修饰的是 以一种比以前所认为的更复杂的方式组织起来。 似乎 哺乳动物的丙酮酸脱氢酶激酶 丙酮酸脱氢酶的磷酸化和失活i）属于 一个新的真核丝氨酸特异性蛋白激酶家族，ii）以两种形式存在 同工酶类型在初级结构和组织方面不同 分布，和iii）可以是通过磷酸化调节的对象- 去磷酸化 目前的建议旨在继续 丙酮酸脱氢酶的调节方向的研究， 根据这些新数据。 它的目标是表征催化 丙酮酸脱氢酶激酶的作用机制， 激酶的两种亚型的调节特性，以及 第一种同种型自身磷酸化的作用的阐明 丙酮酸脱氢酶激酶调节其活性。 的详细 该建议的具体目标是：1）鉴定氨基酸残基 在丙酮酸脱氢酶激酶的催化结构域中， 激酶功能：2）表征两者的调节特性 丙酮酸脱氢酶激酶的亚型;和3）表征作用 丝氨酸残基自磷酸化在丙酮酸调节中的作用 脱氢酶激酶活性。 这些目标的实现不会 只会让我们更深入地了解 丙酮酸脱氢酶复合物，但也将使研究人员， 进一步研究分子机制 负责i）哺乳动物在哺乳期间选择呼吸燃料 饥饿，ii）有氧调节的组织特异性差异 葡萄糖的氧化，和iii）丙酮酸的异常调节 脱氢酶复合物在糖尿病、癌症、败血症 心肌病和肥胖症。

Pyruvate dehydrogenase complex provides an important metabolic link between glycolysis nd the complete oxidation of glucose. zit commits pyruvate to oxidation via acetyl-CoA and Krebs Cycle since there is no biochemical means by which acetyl-CoA can be converted back to pyruvate. The activity of pyruvate dehydrogenase complex is controlled by reversible phosphorylation. Evidence obtained just recently indicates that the system responsible for covalent modification of pyruvate dehydrogenase is organized in a much more complex way than was believed before. It appears that mammalian pyruvate dehydrogenase kinase responsible for phosphorylation and inactivation of pyruvate dehydrogenase i) belongs to a new family of eukaryotic serine-specific protein kinases, ii) exists as two isoenzymic forms different in terms of primary structure and tissue distribution, and iii) may be a subject of regulation by phosphorylation- dephosphorylation itself. The current proposal is designed to continue the studies on the regulation of pyruvate dehydrogenase in directions that follow form these new data. It targets characterization of the catalytic mechanism of pyruvate dehydrogenase kinase, the determination of the regulatory properties of the two isoforms of the kinase, and the elucidation of the role of autophosphorylation of the first isoform of pyruvate dehydrogenase kinase in regulation of its activity. The detailed specific aims of this proposal are; 1) to identify the amino acid residues within the catalytic domain of pyruvate dehydrogenase kinase important for kinase function: 2) to characterize the regulatory properties of the two isoforms of pyruvate dehydrogenase kinase; and 3) to characterize the role of autophosphorylation of serine residues in the regulation of pyruvate dehydrogenase kinase activity. The accomplishment of these goals will not only bring nre insight into our understanding of the structure and function of pyruvate dehydrogenase complex, but will also allow investigators to move further toward characterization of the molecular mechanisms responsible for i) selection respiratory fuels in mammals during starvation, ii) tissue specific differences in regulation of aerobic oxidation of glucose, and iii) abnormal regulation of pyruvate dehydrogenase complex in pathogenesis of diabetes, cancer, sepsis, cardiomyopathy and obesity.