HORMONAL CONTROL OF HEPATIC GLUCONEOGENESIS/GLYCOLYSIS

描述：双功能酶，6-磷酸-2- 激酶/果糖-2，6-二磷酸酶是唯一负责 高效果糖2，6-二磷酸的合成及降解 肝碳流调节剂。F2，6-P是一种变构激活剂 糖酵解酶6-磷酸果糖激酶及其抑制物 葡萄糖异生酶果糖1，6-二磷酸酶。低密度脂蛋白的代谢效应 胰高血糖素通过cAMP依赖的蛋白激酶对肝脏碳流量的影响是 由胞内F2，6-P浓度介导。在糖尿病方面， 肝脏过度产生葡萄糖是导致 高血糖，这导致与高血压相关的主要问题 疾病。F2，6-P在肝脏血糖控制中的中枢作用 生产和使用表明，药物治疗针对的是 提高F2，6-P水平对糖尿病患者有利。这个 拟议的研究将调查针对 因此双功能酶的双磷酸酶结构域具有抑制作用。 利用两种策略提高F2，6-P水平：1)生产 表达突变酶或携带敲除酶的转基因小鼠 基因，分别建立长期高或低的F2，6-P水平和 2)用核磁共振波谱对反应进行物理研究 双磷酸酶结构域的作用机制，并确定其功能作用 活性部位氨基酸残基。这应该为 双磷酸酶活性特异性抑制剂的合理设计 肝脏6-phosphofructo-2-kinase/fructose-2，6-bisphosphatase.

DESCRIPTION: The bifunctional enzyme, 6-phospho-2- kinase/fructose-2,6-bisphosphatase is the sole enzyme responsible for the synthesis and degradations of fructose 2,6-bisphosphate (F2,6-P) a potent modulator of hepatic carbon flux. F2,6-P is an allosteric activator of the glycolytic enzyme 6-phosphofructokinase and an inhibitor of the gluconeogenic enzyme fructose 1,6-bisphosphatase. The metabolic effects of glucagon, via cAMP-dependent protein kinase, on hepatic carbon flux are mediated by the intracellular concentration of F2,6-P. In diabetes, excessive production of glucose by the liver is a major contributor to hyperglycemia, which leads to the major problems associated with the disease. The central role of F2,6-P in control of hepatic glucose production and utilization suggests that drug therapies directed towards increasing F2,6-P levels will be beneficial to the diabetic patient. The proposed studies will investigate the efficacy of targeting the bisphosphatase domain of the bifunctional enzyme for inhibition therefore increasing the levels of F2,6-P using two strategies: 1) production of transgenic mice that express a mutant enzyme or carry a knockout enzyme gene, to establish chronically high or low F2,6-P levels, respectively, and 2) physical studies using NMR spectroscopy to characterize the reaction mechanism of the bisphosphatase domain and define the functional role of active site amino acid residues. This should provide the basis for the rational design of specific inhibitors of the bisphosphatase activity of hepatic 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.