REGULATION OF KETO ACID DEHYDROGENSES IN THE HEART

心脏中酮酸脱氢的调节

• 批准号: 3337792
• 负责人: MERLE S OLSON
• 金额: $ 14.51万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/3337792
• 关键词: acylation; adrenergic agents; alpha ketoglutarate; bioenergetics; coenzyme A; enzyme complex; enzyme substrate; heart; heart metabolism; hormone regulation /control mechanism; insulin; kidney; liver; mitochondria; oxidoreductase inhibitor; perfusion; phosphorylation; protein kinase; pyruvate dehydrogenase; radiotracer

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.

提出的研究计划的主要目的是阐明