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Identification of Key Functional Residues in the Active Site of Vitamin K Epoxide Reductase-like Protein (VKORC1L1)

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Matagrin, Benjamin | Hammed, Abdessalem | Michaux, Arnaud | Hodroge, Ahmed | Benoit, Etienne | Lattard, Virginie

Edité par CCSD ; Insight Medical Publishing -

International audience. Background/Purpose: Vitamin K is involved in the gamma-carboxylation of the vitamin K dependent proteins. Due to the limited intake of vitamin K, its regeneration is necessary and involves the vitamin K 2,3-epoxide reductase (VKOR) activity. This activity is catalyzed by VKORC1 and/or VKORC1L1 proteins. Warfarin is able to inhibit both enzymes, but VKORC1L1 appears to be 30-fold more resistant to warfarin than VKORC1.Methods: To predict functional peptide regions or amino acid residues important for VKOR activity or resistance to vitamin K antagonists (VKA) of human VKORC1L1, we conducted a multiple alignment of VKORC1L1 and VKORC1 sequences. The role of conserved amino acid residues between VKORC1 and VKORC1L1, but also the role of conserved amino-acid residues in VKORC1L1 but not in VKORC1 were challenged by systematic engineering of point mutations combined with in vitro functional assays.Findings: Interestingly, engineering mutants at position 130 allowed us to obtain a VKORC1L1 as susceptible to VKA as wild type VKORC1. Our results also suggested the involvement of Cys-43(+7), Cys-51(+7), Cys-132(+7) and Cys-135(+7), in the transfer of the redox power to vitamin K epoxide.Conclusion: Altogether, this study provides novel insight into VKORC1L1 active site functional domains. Glu-130 is a key residue governing the natural resistance of VKORC1L1 to VKAs.

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