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 果糖2，6-二磷酸（F2，6-P）的合成与降解 肝碳流量调节剂。 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剂 果糖1，6-二磷酸酶。 的代谢作用 胰高血糖素，通过cAMP依赖性蛋白激酶，对肝碳通量的影响， 由F2，6-P的细胞内浓度介导。在糖尿病中， 肝脏产生过多的葡萄糖是 高血糖症，这导致与糖尿病相关的主要问题。 疾病 F_（2，6-P）在控制肝葡萄糖中的中心作用 生产和利用表明，针对 增加F2，6-P水平将有益于糖尿病患者。 的 拟议的研究将调查针对 双功能酶的双磷酸酶结构域用于抑制， 使用两种策略增加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)物理研究，使用核磁共振光谱来表征反应 双磷酸酶结构域的作用机制，并定义 活性位点氨基酸残基。 这应该为 双磷酸酶活性特异性抑制剂的合理设计 肝6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶。

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.