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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Protein phosphorylation can regulate metabolite concentrations rather than control flux: The example of glycogen synthase
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Protein phosphorylation can regulate metabolite concentrations rather than control flux: The example of glycogen synthase

机译：蛋白质磷酸化可以调节代谢物浓度，而不是控制通量：糖原合酶的例子

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摘要

Despite dramatic increases in glucose influx during the transition from fasting to fed states, plasma glucose concentration remains tightly controlled. This constancy is in large part due to the capacity of skeletal muscle to absorb excess glucose and store it as glycogen. The magnitude of this capacity is controlled by insulin by way of regulated insertion of glucose transporters into the muscle cell membrane. Here, we examine the mechanism by which muscle cells are able to tolerate large flux increases across their transporters without significantly changing their own metabolite pools. MCA was used to probe data sets that measured the effects of changing plasma glucose and/or insulin concentrations on the rates of glycogen synthesis and the concentrations of metabolites, particularly glucose-6-phosphate. We find that homeostasis is achieved by insulin-dependent phosphorylation changes in GSase sensitivity to the upstream metabolite glucose-6-phosphate. The centrality of GSase to homeostasis resolves the paradox of its sensitivity to allosteric and covalent regulation despite its minimal role in flux control. The importance of this role for enzymatic phosphorylation to diabetes pathology is discussed, and its general applicability is suggested.
机译：尽管从禁食状态转变为进食状态期间葡萄糖流入量急剧增加，但血浆葡萄糖浓度仍受到严格控制。这种恒定性在很大程度上是由于骨骼肌吸收过量葡萄糖并将其存储为糖原的能力。胰岛素通过调节葡萄糖转运蛋白插入肌肉细胞膜的方式来控制这种能力的大小。在这里，我们研究了肌肉细胞能够耐受跨转运蛋白的通量增加而不会显着改变其自身代谢产物库的机制。 MCA用于探测数据集，这些数据集测量了血浆葡萄糖和/或胰岛素浓度的变化对糖原合成速率和代谢产物（尤其是6磷酸葡萄糖）浓度的影响。我们发现通过GSase对上游代谢物葡萄糖6-磷酸的胰岛素依赖性磷酸化变化实现了稳态。 GSase在体内稳态中的中心地位解决了其对变构和共价调节敏感性的悖论，尽管它在通量控制中的作用很小。讨论了这种作用对于糖尿病病理的酶促磷酸化的重要性，并提出了其普遍适用性。

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