REGULATION OF KETO ACID DEHYDROGENSES IN THE HEART

心脏中酮酸脱氢的调节

基本信息

批准号：
3337797
负责人：
MERLE S OLSON
金额：
$ 13.94万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-08-01 至 1990-06-30
项目状态：
已结题

项目摘要

The major objective of the proposed research program is to elucidate regulatory mechanisms for two multienzyme complexes involved in mirochondrial energy production in cardiac tissue. The regulation of the pyruvate and the branched chain Alpha-keto acid dehydrogenase enzyme complexes by two forms of covalent modification (e.g., phosphorylation and acylation) will be investigated using the purified enzyme complexes from bovine heart, isolated rat heart mitochondria and in the isolated perfused rat heart. Experimental support will be sought for our contention that these two enzyme complexes are activated by their respective natural substrates but inactivated by the substrates for the other complex, e.g., pyruvate activates pyruvate dehydrogenase but inactivate the branched chain complex while the branched chain Alpha-keto acids activate the branched chain complex but inactivate the pyruvate complex. Of particular interest will be our suggestion that the pyruvate dehydrogenase kinase may be regulated by acylation/acetylation by various Alpha-keto acid substrates or Coenzyme A derivatives. Finally, the effects of various metabolic and hormonal states on the regulation of the pyruvate and branched chain dehydrogenase complexes will be investigated in perfused heart preparations. Experiments are proposed to test a suggestion that insulin exerts its stimulatory effect on the pyruvate dehydrogenase complex through an effect of a (e.g., disulfide containing) mediator substance on a reactive thiol moiety on the pyruvate dehydrogenase kinase. It is anticipated that the proposed studies will provide a necessary and unique perception of how the regulation of these two very important enzyme complexes is crucial for the maintenance of an appropriate energy generating capability in my myocardium.

拟议研究计划的主要目标是阐明涉及两种多酶复合物的调控机制心脏组织中线粒体能量的产生。的监管丙酮酸和支链α-酮酸脱氢酶通过两种形式的共价修饰（例如磷酸化和酰化）将使用纯化的酶复合物进行研究牛心脏、分离的大鼠心脏线粒体和分离的灌注老鼠的心。我们的论点将寻求实验支持这两种酶复合物被各自的天然酶激活底物，但被其他复合物的底物灭活，例如，丙酮酸激活丙酮酸脱氢酶但使支链失活复合物，而支链α-酮酸激活支链链复合物但使丙酮酸复合物失活。特别感兴趣我们建议丙酮酸脱氢酶激酶可能是通过各种α-酮酸底物的酰化/乙酰化调节或辅酶A衍生物。最后，各种代谢的影响激素状态对丙酮酸和支链的调节将在灌注心脏中研究脱氢酶复合物准备工作。建议进行实验来测试胰岛素的建议通过以下方式对丙酮酸脱氢酶复合物发挥刺激作用（例如，含有二硫化物的）介体物质对丙酮酸脱氢酶激酶上的反应性硫醇部分。这是预计拟议的研究将提供必要且独特的了解如何调节这两种非常重要的酶复合物对于维持适当的能量至关重要我的心肌产生的能力。