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

BMC Molecular and Cell Biology

Research

Babak Rahmani¹  Mahvash Farajzadeh-Dehkordi¹  Fatemeh Samiee-Rad²  Ladan Mafakher³ 

[1] Department of Molecular Medicine, Faculty of Medical School, Qazvin University of Medical Sciences, Qazvin, Iran;Department of Pathology, Faculty of Medical School, Qazvin University of Medical Sciences, Qazvin, Iran;Thalassemia & Hemoglobinopathy Research center, Health research institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran;Department of Pathology, Faculty of Medical School, Qazvin University of Medical Sciences, Qazvin, Iran;

关键词: Damaging variant;    CYP4F2*3;    V433M variation;    Warfarin;    Vitamin K1;    In silico;    Molecular modeling;    Molecular dynamics simulations;   

DOI  :  10.1186/s12860-023-00479-0

 received in 2022-10-11, accepted in 2023-05-02,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundCytochrome 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 resultsIn 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.ConclusionsThis 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.

【 授权许可】

CC BY   
© The Author(s) 2023

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