STRUCTURE/FUNCTION OF PHOSPHOFRUCTOKINASE

描述：本提案的长期目标是阐明 参与各种碳水化合物代谢的调节机制 哺乳动物组织 最初对监管的兴趣 磷酸果糖激酶是糖酵解的关键调节酶之一， 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，Fru 2，6-P2被 在所有哺乳动物组织中发现，在植物和酵母中，从而刺激新的 Fru 2，6-P2在控制水稻枯萎病中的作用及其调控 碳水化合物代谢 有强有力的证据表明这种化合物 在葡萄糖稳态的饮食和激素调节中起重要作用 在肝脏中，在刺激心脏糖酵解中也很重要 肾上腺素和胰岛素刺激下的肌肉。 有一个强大的医疗 了解Fru 2，6-P2的调节和药学重要性 在糖尿病中。 Fru 2，6-P2的合成和降解由双功能 酶，果糖6-P，2-激酶/果糖2，6-二磷酸酶， 变构控制的方式 几种组织特异性同工酶 激酶/磷酸酶（M.W. 55-60 kD），包括睾丸、肝脏和 已经分离出显示出不同调节控制心脏 机制等 最近，来自大鼠睾丸的酶的结构被 用数据解决了2.0 A，并揭示了大量关于 酶的功能结构和特定的氨基酸残基 定义了酶的结合和催化位点。 这种结构 是一项重要的成就，将作为一个基础，帮助指导 并解释了一些实验， 结构和功能以及激酶之间的变构通讯 和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.