Impacts of 119 missense variants at functionally important sites of drug-metabolizing human cytosolic sulfotransferase SULT1A1: An in silico study

Ahsan, Tamim; Shoily, Sabrina Samad; Fatema, Kaniz; Sajib, Abu Ashfaqur

doi:10.1016/j.imu.2021.100836

Cited by 2 publications

(2 citation statements)

References 80 publications

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“…From the results illustrated in Table 2 , the CYP4F2*3 (V433M) variant exhibited reduced protein stability. Destabilization of a protein structure can change its biological function and disrupt the signaling cascades and normal pathways of the protein [ 53 ].…”

Section: Resultsmentioning

confidence: 99%

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

Farajzadeh-Dehkordi

Mafakher

Samiee-Rad

et al. 2023

BMC Mol and Cell Biol

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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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Section: Resultsmentioning

confidence: 99%

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

Farajzadeh-Dehkordi

Mafakher

Samiee-Rad

et al. 2023

BMC Mol and Cell Biol

View full text Add to dashboard Cite

show abstract

“…From the results illustrated in Table2, the CYP4F2*3 (V433M) variant showed reduced protein stability. Destabilization of a protein structure can change its biological function and disrupt the signal cascades and the normal pathways of the protein[50].…”

mentioning

confidence: 99%

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

Dehkordi

Mafakher

Samiee-Rad

et al. 2022

Preprint

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Background Cytochrome P450 4F2 (CYP4F2) enzyme is one 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 missense variant CYP4F2*3 (V433M) cause decreased activity of CYP4F2 and inter-individual variations in warfarin dose in different ethnic groups. However, the molecular pathogenicity mechanism of missense V433M on the CYP4F2 protein at the atomic level has not yet been completely elucidated. Methods and results In the current study, we evaluate the effect of V433M substitution on the CYP4F2 enzyme through 11 different bioinformatics tools. Further molecular dynamics (MD) simulation was applied to assess the impact of V433M mutation on CYP4F2 protein structure, stability, and dynamics. Also, the molecular docking method was performed to illustrate the effect of V433M on its interaction with vitamin K. Based on our results, the CYP4F2*3 variant is a damaging polymorphism with destabilizing nature. Simulation results presented that missense V433M affects the dynamics and stability of CYP4F2 by reducing its compactness and stability, which means its tendency to change the overall structural conformation and flexibility of CYP4F2. The docking result showed that the CYP4F2*3 variant decreased binding affinity between vitamin K1 and CYP4F2 enzyme, which caused less activity of CYP4F2*3 compared to native CYP4F2. Conclusions This investigation determined the molecular pathogenicity mechanism of the CYP4F2*3 variant on the human CYP4F2 protein and supplied new information for comprehending the structure-function relationship in CYP4F2 and other CYP4 enzymes. These findings will help to develop effective drugs and individual treatment options.

show abstract

Impacts of 119 missense variants at functionally important sites of drug-metabolizing human cytosolic sulfotransferase SULT1A1: An in silico study

Cited by 2 publications

References 80 publications

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

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