甘油醛-3-磷酸脱氢酶（GAPDH）潜在有害突变集的结构、功能与稳定性分析，用于早期检测LUAD
Structure, function and stability analysis on potential deleterious mutation ensemble in glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for early detection of LUAD
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影响因子:5.1
分区:医学3区 / 药学2区 医学：研究与实验3区
发表日期:2024 Dec 01
作者:
Pearl John, C Sudandiradoss
DOI:
10.1016/j.lfs.2024.123127
摘要
肺腺癌（LUAD）是肺癌中最主要的组织学亚型，也是癌症死亡率的主要原因之一。突变率和糖酵解率的升高是肺癌中报道的主要变化。本研究旨在阐明关键糖酵解酶甘油醛-3-磷酸脱氢酶（GAPDH）及其相关SNPs在LUAD进展中的结构和功能作用。我们的基因表达分析显示，LUAD中GAPDH的表达水平较高。利用计算工具对有害SNPs进行了鉴定和特征分析。分子对接和动力学模拟（MDS）研究揭示了优先筛选的有害突变的结构后果。基于序列的分析发现，GAPDH中的28个有害SNPs，其中6个表现出有害和损伤作用。结构分析显示，两个稳定性SNPs为rs编号rs11549328（D39Y）和rs200102749（S51Y），它们位于保守域内。GAPDH序列的无序区（IDR）和翻译后修饰（PTM）分析显示，IDR区域位于191至194位置，IDR评分分别为0.511、0.520、0.517和0.503，伴有PTM修饰。被鉴定为有害的SNPs（D39Y和S51Y）位于GAPDH的功能性和保守域内。此外，GAPDH的IDR区域内存在的PTMs可能促进其在LUAD中的糖酵解活性增强。我们的研究结果为GAPDH在LUAD进展中的潜在致病突变提供了基础。
Abstract
Lung adenocarcinoma (LUAD) is the most prominent histological subtype among the lung cancer which is a leading cause in the cancer mortality rate. High mutational and glycolytic rates are the major reported alterations in the lung cancer. Here in our study we are elucidating the structural and functional role of key glycolytic enzyme Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and associated SNPs in LUAD progression.Our gene expression analysis reveals high expression of GAPDH in the LUAD. In silico tools and analysis were used for the identification and characterization of the deleterious SNPs. Molecular Docking and dynamics simulations (MDS) studies characterized the structural consequences of prioritized deleterious mutations.The sequence based analysis to identify SNPs in GAPDH resulted in 28 deleterious SNPs and 6 SNPs among them showed deleterious and damaging effect. The structural based analysis resulted in 2 stabilizing SNPs of rs ids rs11549328 (D39Y) and rs200102749 (S51Y) in the conserved domain. The IDR and PTM analysis of the GAPDH sequence resulted an IDR region from 191 to 194 positions with an IDR score of 0.511, 0.520, 0.517 and 0.503 with the PTM modifications.The identified deleterious SNPs (D39Y and S51Y) fall in the functional and conserved domain of GAPDH. In addition, the existence of PTMs within the IDR region of the GAPDH may contribute to its enhanced glycolytic activity in LUAD. The results of our study provide potential background deleterious mutants the pathological aspect of GAPDH in LUAD progression.