Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
Department of Neuroscience Technology, College of Applied Medical Sciences, Imam Abdulrahman Bin Faisal University, Jubail, Saudi Arabia.
Adv Protein Chem Struct Biol. 2022;130:351-373. doi: 10.1016/bs.apcsb.2022.02.005. Epub 2022 Apr 8.
An increase in the fast blood glucose (FBG) levels has been linked to an increased risk of developing a chronic condition, type 2 diabetes (T2D). The mutation in the G6PC2 gene was identified to have a lead role in the modulation of FBG levels. The abnormal regulation of this enzyme influences glucose-stimulated insulin secretion (GSIS), which controls the insulin levels corresponding to the system's glucose level. This study focuses on the mutations at the G6PC2 gene, which cause the variation from normal expression levels and increase the risk of T2D. We examined the non-synonymous single nucleotide polymorphisms (nsSNPs) present in the G6PC2 and subjected them to pathogenicity, stability, residue conservation, and membrane simulation. The individual representation of surrounding amino acids in the mutant (I63T) model showed the loss of hydrophobic interactions compared to the native G6PC2. In addition, the trajectory results from the membrane simulation exhibited reduced stability, and the least compactness was identified for the I63T mutant model. Our study shed light on the structural and conformational changes at the transmembrane region due to the I63T mutation in G6PC2. Additionally, the Gibbs free energy landscape analysis against the two principal components showed structural differences and decreased the conformational stability of the I63T mutant model compared to the native. Like those presented in this study, dynamical simulations may indeed be crucial to comprehending the structural insights of G6PC2 mutations in cardiovascular-associated mortality and T2D.
血糖水平升高与慢性疾病、2 型糖尿病（T2D）风险增加有关。G6PC2 基因突变被认为在调节血糖水平方面起主要作用。这种酶的异常调节会影响葡萄糖刺激的胰岛素分泌（GSIS），从而控制与系统葡萄糖水平相对应的胰岛素水平。本研究关注 G6PC2 基因的突变，这些突变导致正常表达水平的变化，并增加 T2D 的风险。我们检查了 G6PC2 中存在的非同义单核苷酸多态性（nsSNP），并对其致病性、稳定性、残基保守性和膜模拟进行了分析。与天然 G6PC2 相比，突变体（I63T）模型中周围氨基酸的个体表示显示出疏水性相互作用的丧失。此外，膜模拟的轨迹结果表明稳定性降低，并且 I63T 突变体模型的紧凑性最低。我们的研究揭示了 G6PC2 中 I63T 突变导致跨膜区域的结构和构象变化。此外，针对两个主要成分的吉布斯自由能景观分析显示出结构差异，并降低了与天然相比，I63T 突变体模型的构象稳定性。像本研究中提出的那样，动力学模拟对于理解心血管相关死亡率和 T2D 中 G6PC2 突变的结构见解确实可能至关重要。
