葡萄糖激酶Y214C活性突变的理论研究

Theoretical Study of Abrupt Change of Activity via Y214C Mutation of Glucokinase

葡萄糖激酶(GK)催化葡萄糖转变为6-磷酸葡萄糖,这是糖代谢的第一步.正因为如此,GK活性异常在糖代谢紊乱的发生发展中起着重要作用.对青年型早发糖尿病(MODY2)和高胰岛素性低血糖症(PHHI)的深入研究证实GK活性改变与糖尿病的发生有关.为了研究GK活性改变的机理,利用分子动力学模拟和隐性溶剂的自由能计算对GK的单点突变Y214C(Tyr214→Cys)进行了理论研究.通过GK的Cα原子均方根浮动变化(RMSF)和动态相关性矩阵(DCCM)分析发现,Y214C突变导致处于活化状态的GK的构象更加稳定;通过包结自由能分析发现,Y214C突变可增加GK对葡萄糖的包结亲合性.相关研究结果有助于从原子水平理解Y214C活性突变的机制,并为糖尿病的治疗提供一定的理论参考.

Glucokinase（GK） is a glycolic enzyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate,the first step of glycolysis.This is why variation in activity of GK plays an important role in abnormal glycemia.Actually,numerous researches about maturity-onset diabetes of the young 2（MODY 2） and persistent hyperinsulinemic hypoglycemia of infancy（PHHI） have confirmed that varying activity of GK is related to occurrence of diabetes.Therefore,explicit molecular dynamics simulations and implicit solvent binding free-energy calculations were carried out to investigate the activation mechanism of GK point mutation Y214C（Tyr214 →Cys）.Based on root mean square fluctuation（RMSF） and dynamic cross-correlation matrices（DCCM） conformation analysis,it was found that GK Y214C mutation resulted in a more stable active conformation of GK.Analysis of binding free-energy demonstrated that the GK Y214C point mutation resulted in increased binding affinity of GK with glucose.Relevant findings are beneficial to understanding the activation mechanism of GK Y214C mutation at atomic level and contributing to treatment of diabetes.