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Computational Insight Into Vitamin K-1 omega-Hydroxylation by Cytochrome P450 4F2
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology. East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China.
East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China..
East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China..
East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai, Peoples R China..
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2018 (English)In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, article id 1065Article in journal (Refereed) Published
Abstract [en]

Vitamin K-1 (VK1) plays an important role in the modulation of bleeding disorders. It has been reported that omega-hydroxylation on the VK1 aliphatic chain is catalyzed by cytochrome P450 4F2 (CYP4F2), an enzyme responsible for the metabolism of eicosanoids. However, the mechanism of VK1 omega-hydroxylation by CYP4F2 has not been disclosed. In this study, we employed a combination of quantum mechanism (QM) calculations, homology modeling, molecular docking, molecular dynamics (MD) simulations, and combined quantum mechanism/molecular mechanism (QM/MM) calculations to investigate the metabolism profile of VK1 omega-hydroxylation. QM calculations based on the truncated VK1 model show that the energy barrier for omega-hydroxylation is about 6-25 kJ/mol higher than those at other potential sites of metabolism. However, results from the MD simulations indicate that hydroxylation at the omega-site is more favorable than at the other potential sites, which is in accordance with the experimental observation. The evaluation of MD simulations was further endorsed by the QM/MM calculation results. Our studies thus suggest that the active site residues of CYP4F2 play a determinant role in the omega-hydroxylation. Our results provide structural insights into the mechanism of VK1 omega-hydroxylation by CYP4F2 at the atomistic level and are helpful not only for characterizing the CYP4F2 functions but also for looking into the omega-hydroxylation mediated by other CYP4 enzymes.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018. Vol. 9, article id 1065
Keywords [en]
cytochrome P450, CYP4F2, omega-hydroxylation, molecular dynamics, QM/MM, homology modeling, vitamin K-1
National Category
Theoretical Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-235873DOI: 10.3389/fphar.2018.01065ISI: 000445589400001OAI: oai:DiVA.org:kth-235873DiVA, id: diva2:1254360
Note

QC 20181009

Available from: 2018-10-09 Created: 2018-10-09 Last updated: 2018-10-09Bibliographically approved

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Tu, Yaoquan

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