Liphardt, Kerstin: Characterization of VKORC1L1 with respect to VKORC1. - Bonn, 2019. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc:
author = {{Kerstin Liphardt}},
title = {Characterization of VKORC1L1 with respect to VKORC1},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2019,
month = jul,

note = {Vitamin K reduction is essential and catalyzed by two enzymes in vitro. Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) reduces vitamin K to sustain γ-carboxylation of vitamin K dependent (VKD) proteins. This modification is important to physiologically activate all VKD proteins, which are involved in blood coagulation, bone and glucose metabolism. Inhibition of VKORC1 by oral anticoagulants (OACs) is clini-cally used in therapy and prevention of thrombosis. However, OACs also inhibit the isozyme VKORC1-like1 (VKORC1L1), which may have antioxidative properties and is suspected to reduce vitamin K to scavenge reactive oxygen species.
Specific inhibition data for various OACs were examined by means genetically engi-neered VKOR deficient HEK 293T cells. Inhibition profile differed in terms of therapeutic OACs with 4-hydroxycoumarin and 1,3-indandione backbone. In contrast, rodenti-cides investigated showed similar susceptibility for both enzymes. To explain the distinct inhibition pattern in silico and in vitro analysis was performed which identified a warfarin binding site in VKORC1L1 other than VKORC1 binding site.
The function of VKORC1L1 in vivo is still unclear. In order to check the effect of the absence of the enzyme, we generated Vkorc1l1-/- mouse by CRISPR/Cas9 gene edit-ing. Those mice were viable in homozygous state, in contrast to Vkorc1-/- mice, and showed normal fertility. However, they were slender and smaller in size and showed reduced cholesterol and glucose levels in plasma compared to their wild type littermates. Further phenotyping is needed to describe those mice in more detail.},

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