University of Dundee, Scotland, UK.
Cell Metab. 2010 Nov 3;12(5):456-66. doi: 10.1016/j.cmet.2010.10.006.
Glycogen synthase (GS), a key enzyme in glycogen synthesis, is activated by the allosteric stimulator glucose-6-phosphate (G6P) and by dephosphorylation through inactivation of GS kinase-3 with insulin. The relative importance of these two regulatory mechanisms in controlling GS is not established, mainly due to the complex interplay between multiple phosphorylation sites and allosteric effectors. Here we identify a residue that plays an important role in the allosteric activation of GS by G6P. We generated knockin mice in which wild-type muscle GS was replaced by a mutant that could not be activated by G6P but could still be activated normally by dephosphorylation. We demonstrate that knockin mice expressing the G6P-insensitive mutant display an ∼80% reduced muscle glycogen synthesis by insulin and markedly reduced glycogen levels. Our study provides genetic evidence that allosteric activation of GS is the primary mechanism by which insulin promotes muscle glycogen accumulation in vivo.
糖原合酶（GS）是糖原合成的关键酶，它可以通过别构激活剂葡萄糖-6-磷酸（G6P）和胰岛素介导的 GS 激酶-3 去磷酸化而被激活。这两种调节机制在控制 GS 中的相对重要性尚不清楚，主要是由于多个磷酸化位点和别构效应物之间的复杂相互作用。在这里，我们鉴定出一个在 G6P 别构激活 GS 中起重要作用的残基。我们生成了敲入小鼠，其中野生型肌肉 GS 被一种不能被 G6P 激活但仍能被去磷酸化正常激活的突变体所取代。我们证明，表达 G6P 不敏感突变体的敲入小鼠，其胰岛素诱导的肌肉糖原合成减少了约 80%，糖原水平也明显降低。我们的研究提供了遗传证据，表明 GS 的别构激活是胰岛素促进体内肌肉糖原积累的主要机制。
