Pilkis S J, El-Maghrabi M R, McGrane M, Pilkis J, Claus T H
Fed Proc. 1982 Aug;41(10):2623-8.
Glucagon stimulates gluconeogenesis in part by decreasing the rate of phosphoenolpyruvate disposal by pyruvate kinase. Glucagon, via cyclic AMP (cAMP) and the cAMP-dependent protein kinase, enhances phosphorylation of pyruvate kinase, phosphofructokinase, and fructose-1,6-bisphosphatase. Phosphorylation of pyruvate kinase results in enzyme inhibition and decreased recycling of phosphoenolpyruvate to pyruvate and enhanced glucose synthesis. Although phosphorylation of 6-phosphofructo 1-kinase and fructose-1,6-bisphosphatase is catalyzed in vitro by the cAMP-dependent protein kinase, the role of phosphorylation in regulating the activity of and flux through these enzymes in intact cells is uncertain. Glucagon regulation of these two enzyme activities is brought about primarily by changes in the level of a novel sugar diphosphate, fructose 2,6-bisphosphate. This compound is an activator of phosphofructokinase and an inhibitor of fructose-1,6-bisphosphatase; it also potentiates the effect of AMP on both enzymes. Glucagon addition to isolated liver systems results in a greater than 90% decrease in the level of this compound. This effect explains in large part the effect of glucagon to enhance flux through fructose-1,6-bisphosphatase and to suppress flux through phosphofructokinase. The discovery of fructose 2,6-bisphosphate has greatly furthered our understanding of regulation at the fructose 6-phosphate/fructose 1,6-bisphosphate substrate cycle.
胰高血糖素部分通过降低丙酮酸激酶对磷酸烯醇丙酮酸的处理速率来刺激糖异生作用。胰高血糖素通过环磷酸腺苷（cAMP）和cAMP依赖性蛋白激酶，增强丙酮酸激酶、磷酸果糖激酶和果糖-1,6-二磷酸酶的磷酸化。丙酮酸激酶的磷酸化导致酶活性受到抑制，磷酸烯醇丙酮酸向丙酮酸的循环减少，从而增强葡萄糖的合成。虽然在体外cAMP依赖性蛋白激酶可催化6-磷酸果糖-1-激酶和果糖-1,6-二磷酸酶的磷酸化，但在完整细胞中，磷酸化在调节这些酶的活性及通量方面的作用尚不确定。胰高血糖素对这两种酶活性的调节主要是通过一种新型二磷酸糖——果糖2,6-二磷酸水平的变化来实现的。这种化合物是磷酸果糖激酶的激活剂和果糖-1,6-二磷酸酶的抑制剂；它还能增强AMP对这两种酶的作用。向分离的肝脏系统中添加胰高血糖素会导致这种化合物的水平下降90%以上。这一效应在很大程度上解释了胰高血糖素增强通过果糖-1,6-二磷酸酶的通量并抑制通过磷酸果糖激酶的通量的作用。果糖2,6-二磷酸的发现极大地推动了我们对磷酸果糖/果糖-1,6-二磷酸底物循环调节的理解。
