错义变异CYP4F2*3 (V433M)与人类CYP4F2功能障碍相关的计算分析:功能和结构影响

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS
Mahvash Farajzadeh-Dehkordi, Ladan Mafakher, Fatemeh Samiee-Rad, Babak Rahmani
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引用次数: 2

摘要

背景:细胞色素P450 4F2 (CYP4F2)酶是CYP4家族的一员,负责脂肪酸、治疗药物和信号分子(如花生四烯酸、生育酚和维生素k)的代谢。一些报道表明,错义变异CYP4F2*3 (V433M)导致不同种族人群中CYP4F2活性降低和华法林剂量的个体间差异。然而,错义V433M在CYP4F2中的分子致病机制在原子水平上尚未完全阐明。方法和结果:在目前的研究中,我们使用14种不同的生物信息学工具评估了V433M替代对CYP4F2的影响。进一步进行分子动力学(MD)模拟,以评估V433M突变对CYP4F2蛋白结构、稳定性和动力学的影响。此外,我们还利用分子对接来说明V433M对其与维生素K1相互作用的影响。根据我们的研究结果,CYP4F2*3变异是一个具有不稳定性质的破坏性氨基酸取代。仿真结果表明,错义V433M通过降低CYP4F2的致密性和稳定性来影响CYP4F2的动力学和稳定性,这意味着它倾向于改变CYP4F2的整体结构构象和柔韧性。对接结果显示,CYP4F2*3变异降低了维生素K1与CYP4F2的结合亲和力,与天然CYP4F2相比,CYP4F2*3的活性降低。结论:本研究明确了CYP4F2*3变异对人CYP4F2蛋白的分子致病性机制,为进一步了解CYP4F2与其他CYP4酶的结构-功能关系提供了新的信息。这些发现将有助于开发有效的药物和治疗方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Computational analysis of missense variant CYP4F2*3 (V433M) in association with human CYP4F2 dysfunction: a functional and structural impact.

Computational analysis of missense variant CYP4F2*3 (V433M) in association with human CYP4F2 dysfunction: a functional and structural impact.

Computational analysis of missense variant CYP4F2*3 (V433M) in association with human CYP4F2 dysfunction: a functional and structural impact.

Computational analysis of missense variant CYP4F2*3 (V433M) in association with human CYP4F2 dysfunction: a functional and structural impact.

Background: Cytochrome P450 4F2 (CYP4F2) enzyme is a member of the CYP4 family responsible for the metabolism of fatty acids, therapeutic drugs, and signaling molecules such as arachidonic acid, tocopherols, and vitamin K. Several reports have demonstrated that the missense variant CYP4F2*3 (V433M) causes decreased activity of CYP4F2 and inter-individual variations in warfarin dose in different ethnic groups. However, the molecular pathogenicity mechanism of missense V433M in CYP4F2 at the atomic level has not yet been completely elucidated.

Methods and results: In the current study, we evaluated the effect of the V433M substitution on CYP4F2 using 14 different bioinformatics tools. Further molecular dynamics (MD) simulations were performed to assess the impact of the V433M mutation on the CYP4F2 protein structure, stability, and dynamics. In addition, molecular docking was used to illustrate the effect of V433M on its interaction with vitamin K1. Based on our results, the CYP4F2*3 variant was a damaging amino acid substitution with a destabilizing nature. The simulation results showed that missense V433M affects the dynamics and stability of CYP4F2 by reducing its compactness and stability, which means that it tends to change the overall structural conformation and flexibility of CYP4F2. The docking results showed that the CYP4F2*3 variant decreased the binding affinity between vitamin K1 and CYP4F2, which reduced the activity of CYP4F2*3 compared to native CYP4F2.

Conclusions: This study determined the molecular pathogenicity mechanism of the CYP4F2*3 variant on the human CYP4F2 protein and provided new information for understanding the structure-function relationship of CYP4F2 and other CYP4 enzymes. These findings will aid in the development of effective drugs and treatment options.

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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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