Syed Nida Ali, Bhatti Attya, John Peter
Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan.
J Biomol Struct Dyn. 2023;41(23):13707-13717. doi: 10.1080/07391102.2023.2181654. Epub 2023 Feb 22.
Glyoxalase-1 (Glo-1) is a key member of the Glyoxalase system, the primary line of defense against dicarbonyl stress which, in tandem, with reduced levels of expression or activity of Glyoxalase-1 enzyme, has been implicated in various human diseases like type 2 diabetes mellitus (T2DM) and its vascular complications. The association of Glo-1 single nucleotide polymorphisms with genetic susceptibility to T2DM and its vascular complications is yet to be explored. Therefore, in this study, we have employed a computational approach to identify the most damaging missense or nonsynonymous SNPs (nsSNPs) in Glo-1 gene. Initially, we characterized missense SNPs that are damaging to the structural and functional integrity of Glo-1 using various bioinformatic tools. These tools included SIFT, PolyPhen-2, SNAP, PANTHER, PROVEAN, PhD-SNP, SNPs&GO, I-Mutant, MUpro and MutPred2. One of these missense SNPs (rs1038747749; corresponding to amino acid change Arginine to Glutamine at position 38) was found to be highly conserved in evolution and is an important part of the enzyme's active site, glutathione binding site, as well as the dimeric interface based on the results obtained from ConSurf and NCBI Conserved Domain Search tools. Project HOPE reported that this mutation replaces a positively charged polar amino acid (Arginine) with a small, neutrally charged amino acid (Glutamine). Comparative modelling of wildtype and mutant (R38Q) Glo-1 proteins was performed in the run up to molecular dynamics simulation analysis which showed that rs1038747749 adversely impacts Glo-1 protein's stability, rigidity, compactness, hydrogen bonds/interactions as demonstrated by the results of various parameters computed during the analysis.Communicated by Ramaswamy H. Sarma.
乙二醛酶-1（Glo-1）是乙二醛酶系统的关键成员，是抵御二羰基应激的主要防线。乙二醛酶-1酶表达水平或活性降低与二羰基应激共同作用，已被认为与多种人类疾病有关，如2型糖尿病（T2DM）及其血管并发症。Glo-1单核苷酸多态性与T2DM及其血管并发症遗传易感性的关联尚待探索。因此，在本研究中，我们采用了一种计算方法来识别Glo-1基因中最具破坏性的错义或非同义单核苷酸多态性（nsSNPs）。首先，我们使用各种生物信息学工具对损害Glo-1结构和功能完整性的错义单核苷酸多态性进行了表征。这些工具包括SIFT、PolyPhen-2、SNAP、PANTHER、PROVEAN、PhD-SNP、SNPs&GO、I-Mutant、MUpro和MutPred2。根据从ConSurf和NCBI保守结构域搜索工具获得的结果，发现其中一个错义单核苷酸多态性（rs1038747749；对应于第38位氨基酸从精氨酸变为谷氨酰胺）在进化过程中高度保守，是该酶活性位点、谷胱甘肽结合位点以及二聚体界面的重要组成部分。HOPE项目报告称，这种突变将带正电荷的极性氨基酸（精氨酸）替换为小的、带中性电荷的氨基酸（谷氨酰胺）。在进行分子动力学模拟分析之前，对野生型和突变型（R38Q）Glo-1蛋白进行了比较建模，结果表明，rs1038747749对Glo-1蛋白的稳定性、刚性、紧凑性、氢键/相互作用产生了不利影响，分析过程中计算的各种参数结果证明了这一点。由拉马斯瓦米·H·萨尔马传达。
