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

Takeda, Kazuki; Ikenaka, Yoshinori; Fourches, Denis; Tanaka, Kazuyuki D.; Nakayama, Shouta M. M.; Triki, Dhoha; Li, Xinhao; Igarashi, Manabu; Tanikawa, Tsutomu; Ishizuka, Mayumi

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

Takeda, Kazuki; Ikenaka, Yoshinori; Fourches, Denis et al.

Pesticide biochemistry and physiology, 2021, 173, 104774

Permalink : https://hdl.handle.net/2115/84268

このアイテムのアクセス数:395件（2026-03-06 00:03 集計）

閲覧可能ファイル

ファイル	フォーマット	サイズ	閲覧回数	説明
Non-marked 201210	pdf	230 KB	326

論文情報

ファイル出力 EndNote Basic出力 Mendeley出力

アクセス権	open access
URI	https://hdl.handle.net/2115/84268
タイトル	The VKORC1 ER-luminal loop mutation (Leu76Pro) leads to a significant resistance to warfarin in black rats (Rattus rattus)
著者	Takeda, Kazuki ; Ikenaka, Yoshinori ; Fourches, Denis ; Tanaka, Kazuyuki D. ; Nakayama, Shouta M. M. ; Triki, Dhoha ; Li, Xinhao ; Igarashi, Manabu ; Tanikawa, Tsutomu ; Ishizuka, Mayumi
著者名 Takeda, Kazuki
e-Rad_Researcher 40543509 著者名 Ikenaka, Yoshinori
著者名 Fourches, Denis
著者名 Tanaka, Kazuyuki D.
e-Rad_Researcher 90647629 著者名 Nakayama, Shouta M. M.
著者名 Triki, Dhoha
著者名 Li, Xinhao
e-Rad_Researcher 10374240 著者名 Igarashi, Manabu
著者名 Tanikawa, Tsutomu
e-Rad_Researcher 50332474 著者名 Ishizuka, Mayumi
言語	英語
キーワード	Vitamin K epoxide reductase
	Warfarin
	Rodenticide-resistance
	Molecular docking
	Molecular dynamics simulations
発行日	2021-03-01
出版者	Elsevier
収録物名	Pesticide biochemistry and physiology
巻(号)	173
ページ	104774
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
権利情報	Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
権利情報	© <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/
PISSN	0048-3575
関連情報 (isVersionOf)	出版社版DOI https://doi.org/10.1016/j.pestbp.2021.104774