| 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 |
| Warfarin |
| Rodenticide-resistance |
| 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 http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/84268 |
| 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)
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