CYP2C9常见及新变异体结构和功能的生物信息学分析  

Bioinformatics Analysis for Structure and Function of Common and Novel Cytochrome P4502C9 Variants

作　　者：兰秋月 蔡剑平[1] 戴大鹏[1] 周晓阳[1] LAN Qiuyue;CAI Jianping;DAI Dapeng(The Key Laboratory of Geriatrics,Beijing Institute of Geriatrics,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing Hospital/National Center of Gerontology of National Health Commission,Beijing 100730,China)

机构地区：[1]北京医院国家老年医学中心、国家卫生健康委北京老年医学研究所、国家卫生健康委老年医学重点实验室、中国医学科学院老年医学研究院,100730

出　　处：《医学研究杂志》2024年第10期67-73,共7页Journal of Medical Research

基　　金：国家科技重大专项项目(2017ZX09304026004);国家重点研发计划项目(2020YFC2008300)。

摘　　要：目的 利用生物信息学工具对我国人群中CYP2C9常见变异体(*3)及新变异体(*76~*85)进行预测分析,旨在阐述氨基酸变异对CYP2C9蛋白结构、特性和功能等多维度造成的影响。方法 应用多种分析工具,对各变异体的理化性质、糖基化和磷酸化修饰、重要结构域、空间结构及功能变化和与探针药物(甲苯磺丁脲)对接模式等方面进行了预测分析。结果与CYP2C9*1比较,各变异体从氨基酸序列、局部结构域、磷酸化位点、理化性质、空间结构及与底物对接模式等方面发生了不同程度和多层面的改变。*76和*84在局部结构、整体空间结构和功能等方面均有破坏,且与疾病爆发相关;*78~*79和*81~*82变异体在不同层面预测结果具有显著异质性;*85因移码突变致终止密码子提前出现,大部分重要结构域缺失,结果提示可能会影响蛋白质翻译及全酶的组装。虽然*3的理化性质、局部结构域和稳定性等预测结果与*1比较,均无明显变化,但与甲苯磺丁脲对接结果显示*3蛋白与甲苯磺丁脲在对接口袋形状、三维尺寸及接触模式发生明显改变。结论 本研究从蛋白一级结构、二级结构、三级结构、全酶与药物对接、理化特性和功能等多角度、多层面地分析了氨基酸变异对表型的影响,为将来CYP2C9变异体的结构解析、体内外药物代谢实验和个体化用药提供了重要参考和新的解读视角。Objective Bioinformatics tools were used to conduct a prediction analysis of common CYP2C9 variants(*3)and new variants(*76-*85)in our population,aiming to illustrate the impact of amino acid variants on the multidimensional aspects of CYP2C9 protein structure,properties,and functions.Methods The physicochemical properties,glycosylation and phosphorylation modification,important structural domains,spatial structure and functional changes,and docking mode with the probe drug,tolbutamide,were predicted for each variant by applying various analytical tools.Results Compared with CYP2C9*1,the variants showed different degrees and multiple levels of alterations in amino acid sequence,local structural domains,phosphorylation sites,physicochemical properties,tertiary structure,and docking patterns with substrates.*76 and*84 showed local structure,overall spatial structure,and function disruptions,and they were also correlated with disease outbreaks.*78-*79 and*81-*82 variants showed significant heterogeneity in the predicted results at different levels;*85 had an early termination codon and deletion of most critical structural domains due to a code-shift mutation,and the results suggested that it might affect the protein translation and the assembly of the whole enzyme.The predicted results of the physicochemical properties,local structural domains,and stability of*3 were all non-significantly altered in comparison with*1;however,docking results showed that*3 protein and tolbutamide were significantly changed in the shape,three-dimensional size,and contact pattern of the docking pocket.Conclusion This study analyzed the effects of amino acid variants on phenotypes from multiple perspectives and levels,including protein primary,secondary,and tertiary structures,holoenzyme-drug docking,physicochemical properties,and functions,which provides essential references and new interpretative perspectives for future structural elucidation,ex vivo and in vivo drug metabolism experiments,and individualized dosing of CYP2C9 variants.

关 键 词：细胞色素P4502C9 生物信息学 分子对接 蛋白结构和功能 

分 类 号：R394[医药卫生—医学遗传学]