Family of likely enzymes that includes the catalytic subunit of vitamin K epoxide reductase. Bacterial homologues are fused to members of the thioredoxin family of oxidoreductases.
Vitamin K epoxide reductase (VKOR) recycles vitamin K 2,3-epoxide to vitamin K hydroquinone, a co-factor that is essential for the posttranslational gamma-carboxylation of several blood coagulation factors [ (PUBMED:14765194) ]. VKORC1, the catalytic subunit of the VKOR complex, is a member of a large family of predicted enzymes that are present in vertebrates, Drosophila, plants, bacteria and archaea [ (PUBMED:15276181) ]. Bacterial VKOR homologues catalyse disulphide bridge formation in secreted proteins by cooperating with a periplasmic, Trx-like redox partner [ (PUBMED:18413314) (PUBMED:18695247) ]. In fact, in some plant and bacterial homologues the VKORC1 homologous domain is fused with domains of the thioredoxin family of oxidoreductases [ (PUBMED:15276181) ]. VKOR is part of a disulphide bond formation pathway that uses electrons from cysteines of newly synthesized proteins to reduce a quinone [ (PUBMED:20110994) ].
Family alignment:
There are 5031 VKc domains in 5031 proteins in SMART's nrdb database.
Click on the following links for more information.
Evolution (species in which this domain is found)
Taxonomic distribution of proteins containing VKc domain.
This tree includes only several representative species. The complete taxonomic breakdown of all proteins with VKc domain is also avaliable.
Click on the protein counts, or double click on taxonomic names to display all proteins containing VKc domain in the selected taxonomic class.
Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
Identification of the gene for vitamin K epoxide reductase.
Nature. 2004; 427: 541-4
Display abstract
Vitamin K epoxide reductase (VKOR) is the target of warfarin, the most widely prescribed anticoagulant for thromboembolic disorders. Although estimated to prevent twenty strokes per induced bleeding episode, warfarin is under-used because of the difficulty of controlling dosage and the fear of inducing bleeding. Although identified in 1974 (ref. 2), the enzyme has yet to be purified or its gene identified. A positional cloning approach has become possible after the mapping of warfarin resistance to rat chromosome 1 (ref. 3) and of vitamin K-dependent protein deficiencies to the syntenic region of human chromosome 16 (ref. 4). Localization of VKOR to 190 genes within human chromosome 16p12-q21 narrowed the search to 13 genes encoding candidate transmembrane proteins, and we used short interfering RNA (siRNA) pools against individual genes to test their ability to inhibit VKOR activity in human cells. Here, we report the identification of the gene for VKOR based on specific inhibition of VKOR activity by a single siRNA pool. We confirmed that MGC11276 messenger RNA encodes VKOR through its expression in insect cells and sensitivity to warfarin. The expressed enzyme is 163 amino acids long, with at least one transmembrane domain. Identification of the VKOR gene extends our understanding of blood clotting, and should facilitate development of new anticoagulant drugs.
Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2.
Nature. 2004; 427: 537-41
Display abstract
Coumarin derivatives such as warfarin represent the therapy of choice for the long-term treatment and prevention of thromboembolic events. Coumarins target blood coagulation by inhibiting the vitamin K epoxide reductase multiprotein complex (VKOR). This complex recycles vitamin K 2,3-epoxide to vitamin K hydroquinone, a cofactor that is essential for the post-translational gamma-carboxylation of several blood coagulation factors. Despite extensive efforts, the components of the VKOR complex have not been identified. The complex has been proposed to be involved in two heritable human diseases: combined deficiency of vitamin-K-dependent clotting factors type 2 (VKCFD2; Online Mendelian Inheritance in Man (OMIM) 607473), and resistance to coumarin-type anticoagulant drugs (warfarin resistance, WR; OMIM 122700). Here we identify, by using linkage information from three species, the gene vitamin K epoxide reductase complex subunit 1 (VKORC1), which encodes a small transmembrane protein of the endoplasmic reticulum. VKORC1 contains missense mutations in both human disorders and in a warfarin-resistant rat strain. Overexpression of wild-type VKORC1, but not VKORC1 carrying the VKCFD2 mutation, leads to a marked increase in VKOR activity, which is sensitive to warfarin inhibition.
This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with VKc domain which could be assigned to a KEGG orthologous group, and not all proteins containing VKc domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.
