STRUCTURE/FUNCTION OF PHOSPHOFRUCTOKINASE

描述：这项提议的长期目标是澄清 碳水化合物代谢的调节机制不同 哺乳动物组织。最初对监管的兴趣 作为糖酵解的关键调节酶之一，磷酸果糖激酶导致了 1980年发现了一种非常有效的天然存在的激活剂 肝脏中的磷酸果糖激酶，果糖2，6-P2。随后，Fru2，6-P2被 发现于所有哺乳动物组织、植物和酵母中，从而刺激一种新的 果糖2，6-P2在调控中的作用及调控研究 碳水化合物代谢。有强有力的证据表明，这种化合物在 在饮食和激素调节葡萄糖动态平衡中的重要作用 在肝脏中，也在心脏糖酵解的刺激中起重要作用 在肾上腺素和胰岛素刺激下的肌肉。有一个很强的医疗保健 了解Fru2，6-P2调控的药学意义 糖尿病患者。FRU2，6-P2的合成及其双官能团降解 果糖6-P，2-激酶/果糖2，6-二磷酸酶 变构控制的时尚。几种组织特异性同工酶形式 激酶/磷酸酶(分子量55-60kD)，包括睾丸、肝脏和 心脏已经被分离出来，显示出不同的调节控制 机械装置。最近从大鼠睾丸中提取的这种酶的结构是 用数据解决到2.0A，并揭示了关于 酶的功能结构和特定的氨基酸残基 它们定义了酶的结合和催化部位。这个结构 是一项重要的成就，并将作为帮助指导 并解释了专注于解剖两者关系的实验 结构和功能与激酶之间的变构通讯 以及这种双功能酶的磷酸酶亚基。

DESCRIPTION: The long term objective of this proposal is to elucidate regulatory mechanisms involved in carbohydrate metabolism in various mammalian tissues. Interest initially in the regulation of phosphofructokinase, one of the key regulatory enzymes of glycolysis, led in 1980 to the discovery of a very potent naturally occurring activator of phosphofructokinase in liver, fructose 2,6-P2. Subsequently, Fru2,6-P2 was found in all mammalian tissues, in plants, and yeast, thus stimulating a new investigation into the roles and regulation of Fru 2,6-P2 in controlling carbohydrate metabolism. There is strong evidence that this compound plays an important role in dietary and hormonal regulation of glucose homeostasis in liver and is also important in the stimulation of glycolysis in heart muscle under epinephrine and insulin stimulation. There is a strong medical and pharmaceutical importance of understanding the regulation of Fru2,6-P2 in diabetes. Fru 2,6-P2 is synthesized and degraded by a bi functional enzyme, fructose 6-P,2-kinase/fructose 2,6-bisphosphatase in an allosterically controlled fashion. Several tissue-specific isozymic forms of the kinase/phosphatase enzyme (M.W. 55-60 kD) including testes, liver and heart have been isolated that demonstrate different regulatory control mechanisms. The structure of the enzyme from rat testis has recently been solved with data to 2.0 A and has revealed a wealth of information as to the functional architecture of the enzyme and the specific amino acid residues that define the binding and catalytic sites of the enzyme. This structure is an important accomplishment and will serve as a foundation to help guide and interpret experiments focused on dissecting the relationship between structure and function and the allosteric communication between the kinase and phosphatase subunits of this bifunctional enzyme.