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首页> 外文期刊>Advances in enzyme regulation >Roles for fructose-2,6-bisphosphate in the control of fuel metabolism: beyond its allosteric effects on glycolytic and gluconeogenic enzymes.
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Roles for fructose-2,6-bisphosphate in the control of fuel metabolism: beyond its allosteric effects on glycolytic and gluconeogenic enzymes.

机译：2,6-二磷酸果糖在燃料代谢控制中的作用：其对糖酵解和糖异生酶的变构作用。

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摘要

Fructose-2,6-bisphosphate (F26P2) was identified as a regulator of glucose metabolism over 25 years ago. A truly bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PFK2/FBP2), with two active sites synthesizes F26P2 from fructose-6-phosphate (F6P) and ATP or degrades F26P2 to F6P and Pi. In the classic view, F26P2 regulates glucose metabolism by allosteric effects on 6-phosphofructo-1-kinase (6PFK1, activation) and fructose-1,6-bisphosphatase (FBPase, inhibition). When levels of F26P2 are high, glycolysis is enhanced and gluconeogenesis is inhibited. In this regard, altering levels of F26P2 via 6PFK2/FBP2 overexpression has been used for metabolic modulation, and has been shown capable of restoring euglycemia in rodent models of diabetes. Recently, a number of novel observations have suggested that F26P2 has much broader effects on the enzymes of glucose metabolism. This is evidenced by the effects of F26P2 on the gene expression of two key glucose metabolic enzymes, glucokinase (GK) and glucose-6-phosphatase (G6Pase). When levels of F26P2 are elevated in the liver, the gene expression and protein amount of GK is increased whereas G6Pase is decreased. These coordinated changes in GK and G6Pase protein illustrate how F26P2 regulates glucose metabolism. F26P2 also affects the gene expression of enzymes related to lipid metabolism. When F26P2 levels are elevated in liver, the expression of two key lipogenic enzymes, acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) is reduced, contributing to a unique coordinated decrease in lipogenesis. When combined, F26P2 effects on glucose and lipid metabolism provide cooperative regulation of fuel metabolism. The regulatory roles for F26P2 have also expanded to transcription factors, as well as certain key proteins (enzymes) of signaling and/or energy sensoring. Although some effects may be secondary to changes in metabolite levels, high levels of F26P2 have been shown to regulate protein amount and/or phosphorylation state of hepatic nuclear factor 1-alpha (HNF1alpha), carbohydrate response element binding protein (ChREBP), peroxisome proliferators-activated receptor alpha (PPARalpha), and peroxisome proliferators-activated receptor gamma co-activator 1beta (PGC1beta), as well as Akt and AMP-activated protein kinase (AMPK). Importantly, changes in these transcription factors, signaling proteins, and sensor proteins are produced in a way that appropriately coordinates whole body fuel metabolism.
机译：25年前，果糖2,6-双磷酸酯（F26P2）被确定为葡萄糖代谢的调节剂。真正的双功能酶，6-磷酸果糖-2-激酶/果糖-2,6-双磷酸酶（6PFK2 / FBP2），具有两个活性位点，可以从果糖-6-磷酸酯（F6P）和ATP合成F26P2，或将F26P2降解为F6P和Pi 。在经典观点中，F26P2通过对6-磷酸果糖-1-激酶（6PFK1，激活）和果糖-1,6-双磷酸酶（FBPase，抑制）的变构作用来调节葡萄糖代谢。当F26P2的水平高时，糖酵解作用增强，糖异生被抑制。在这方面，通过6PFK2 / FBP2过表达改变F26P2的水平已被用于代谢调节，并且已显示能够在糖尿病的啮齿动物模型中恢复正常血糖。最近，许多新颖的观察表明，F26P2对葡萄糖代谢酶具有更广泛的作用。 F26P2对两种关键的葡萄糖代谢酶（葡萄糖激酶（GK）和葡萄糖-6-磷酸酶（G6Pase））的基因表达证明了这一点。当肝脏中F26P2的水平升高时，GK的基因表达和蛋白质量增加，而G6Pase降低。 GK和G6Pase蛋白的这些协调变化说明F26P2如何调节葡萄糖代谢。 F26P2还影响与脂质代谢有关的酶的基因表达。当肝脏中的F26P2水平升高时，两种关键的脂肪生成酶（乙酰辅酶A羧化酶1（ACC1）和脂肪酸合酶（FAS））的表达降低，从而导致脂肪生成的独特协调性降低。组合使用时，F26P2对葡萄糖和脂质代谢的作用可协同调节燃料代谢。 F26P2的调节作用也已扩展到转录因子，以及信号传导和/或能量感应的某些关键蛋白质（酶）。尽管某些影响可能是代谢物水平的改变所致，但高水平的F26P2已被证明可调节肝核因子1-alpha（HNF1alpha），碳水化合物反应元件结合蛋白（ChREBP），过氧化物酶体增殖物的蛋白量和/或磷酸化状态激活受体α（PPARalpha）和过氧化物酶体增殖物激活受体γ共激活因子1beta（PGC1beta），以及Akt和AMP激活的蛋白激酶（AMPK）。重要的是，这些转录因子，信号蛋白和传感器蛋白的变化以适当协调全身燃料代谢的方式产生。

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