Proteomics

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In-cell isotope-coded labeling and LC-MS/MS analysis probe warfarin inhibition mechanism


ABSTRACT: Warfarin targets human vitamin K epoxide reductase (hVKOR), a redox enzyme in the membrane of endoplasmic reticulum (ER), to prevent the formation of blood clots. Although warfarin has been a popular medication since 1954, its mechanism of action is still unclear. A fundamental issue is the controversial orientation of transmembrane helices (TM) in hVKOR. Stable isotope-coded reagents were usedto label VKOR in free, mutated, and warfarin-binding states directly in the cellular environment, followed by LC-MS/MS bottom-up approach to investigate the warfarin binding mechanism.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Early Embryonic Cell

SUBMITTER: Weidong Cui  

LAB HEAD: Michael L. Gross

PROVIDER: PXD003774 | Pride | 2017-03-30

REPOSITORIES: Pride

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Publications

Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer.

Shen Guomin G   Cui Weidong W   Zhang Hao H   Zhou Fengbo F   Huang Wei W   Liu Qian Q   Yang Yihu Y   Li Shuang S   Bowman Gregory R GR   Sadler J Evan JE   Gross Michael L ML   Li Weikai W  

Nature structural & molecular biology 20161205 1


Although warfarin is the most widely used anticoagulant worldwide, the mechanism by which warfarin inhibits its target, human vitamin K epoxide reductase (hVKOR), remains unclear. Here we show that warfarin blocks a dynamic electron-transfer process in hVKOR. A major fraction of cellular hVKOR is in an intermediate redox state containing a Cys51-Cys132 disulfide, a characteristic accommodated by a four-transmembrane-helix structure of hVKOR. Warfarin selectively inhibits this major cellular form  ...[more]

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