NEW FAMILY OF PROTEIN KINASES

丙酮酸脱氢酶复合体在 糖酵解和葡萄糖的完全氧化。青春痘致丙酮酸 通过乙酰-CoA和Krebs循环进行氧化，因为没有生化反应 乙酰辅酶A可被转化回丙酮酸的方法。活动 丙酮酸脱氢酶复合体受可逆性控制 磷酸化。最近获得的证据表明，该系统 负责丙酮酸脱氢酶的共价修饰 组织的方式比人们之前认为的要复杂得多。它看起来 哺乳动物丙酮酸脱氢酶激酶负责 丙酮酸脱氢酶的磷酸化和失活)属于一种 新的真核丝氨酸特异性蛋白激酶家族，II)以两种形式存在 同工酶的一级结构和组织形式不同 分布，以及iii)可能是通过磷酸化调节的对象- 去磷酸化本身。目前的提案旨在延续 丙酮酸脱氢酶调控方向的研究 根据这些新的数据。它的目标是表征催化剂 丙酮酸脱氢酶的作用机制、酶活性测定 这两种亚型的调节特性，以及 肌动蛋白第一亚型自身磷酸化作用的阐明 丙酮酸脱氢酶在其活性调节中的作用。详细的 这项建议的具体目标是：1)确定氨基酸残基 在丙酮酸脱氢酶的催化结构域内，对 激酶功能：2)表征两者的调节特性 丙酮酸脱氢酶激酶的异构体；以及3)表征其作用 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 只对我们对结构和功能的理解有新的见解 丙酮酸脱氢酶复合体，但也将允许调查人员 进一步研究分子机制 负责i)选择哺乳动物的呼吸燃料 饥饿，II)有氧调节的组织特异性差异 葡萄糖的氧化，以及III)丙酮酸的异常调节 脱氢酶复合体在糖尿病、癌症、脓毒症、 心肌病和肥胖。

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.