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The VKORC1 ER-luminal loop mutation (Leu76Pro) leads to a significant resistance to warfarin in black rats (Rattus rattus)

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Title: The VKORC1 ER-luminal loop mutation (Leu76Pro) leads to a significant resistance to warfarin in black rats (Rattus rattus)
Authors: Takeda, Kazuki Browse this author
Ikenaka, Yoshinori Browse this author →KAKEN DB
Fourches, Denis Browse this author
Tanaka, Kazuyuki D. Browse this author
Nakayama, Shouta M. M. Browse this author →KAKEN DB
Triki, Dhoha Browse this author
Li, Xinhao Browse this author
Igarashi, Manabu Browse this author →KAKEN DB
Tanikawa, Tsutomu Browse this author
Ishizuka, Mayumi Browse this author →KAKEN DB
Keywords: Vitamin K epoxide reductase
Molecular docking
Molecular dynamics simulations
Issue Date: 1-Mar-2021
Publisher: Elsevier
Journal Title: Pesticide biochemistry and physiology
Volume: 173
Start Page: 104774
Publisher DOI: 10.1016/j.pestbp.2021.104774
Abstract: Well-known 4-hydroxycoumarin derivatives, such as warfarin, act as inhibitors of the vitamin K epoxide reductase (VKOR) and are used as anticoagulants. Mutations of the VKOR enzyme can lead to resistance to those compounds. This has been a problem in using them as medicine or rodenticide. Most of these mutations lie in the vicinity of potential warfarin-binding sites within the ER-luminal loop structure (Lys30, Phe55) and the transmembrane helix (Tyr138). However, a VKOR mutation found in Tokyo in warfarin-resistant rats does not follow that pattern (Leu76Pro), and its effect on VKOR function and structure remains unclear. We conducted both in vitro kinetic analyses and in silico docking studies to characterize the VKOR mutant. On the one hand, resistant rats (R-rats) showed a 37.5-fold increased IC50 value to warfarin when compared to susceptible rats (S-rats); on the other hand, R-rats showed a 16.5-fold lower basal VKOR activity (Vmax/Km). Docking calculations exhibited that the mutated VKOR of R-rats has a decreased affinity for warfarin. Molecular dynamics simulations further revealed that VKOR-associated warfarin was more exposed to solvents in R-rats and key interactions between Lys30, Phe55, and warfarin were less favored. This study concludes that a single mutation of VKOR at position 76 leads to a significant resistance to warfarin by modifying the types and numbers of intermolecular interactions between the two.
Rights: © <2021>. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
Type: article (author version)
Appears in Collections:獣医学院・獣医学研究院 (Graduate School of Veterinary Medicine / Faculty of Veterinary Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 石塚 真由美

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