Search results for VKORC1

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Protein (2 results from a total of 2)

Identifier: R-HSA-159746
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane
Primary external reference: UniProt: VKORC1: Q9BQB6
Identifier: R-HSA-2980944
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane
Primary external reference: UniProt: VKORC1L1: Q8N0U8

Reaction (4 results from a total of 4)

Identifier: R-HSA-9026967
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane, cytosol
4-Hydroxycoumarins belong to a class of vitamin K antagonist anticoagulant drug molecules derived from coumarin, a bitter-tasting but sweet-smelling natural substance made by plants. It itself doesn't affect coagulation, but is transformed in mouldy feeds or silages by a number of fungi into active dicumarol, a substance that does have anticoagulant properties. Identified in 1940, dicumarol became the prototypical drug of the 4-hydroxycoumarin anticoagulant drug class but has been superceded by warfarin since the 1950's (Norn et al. 2014). Phenindione was introduced in the early 1950s and acts similarly to warfarin, but it has been associated with hypersensitivity reactions so is now rarely used (Naisbitt et al. 2005). Other coumarin-derivatives commonly prescribed in Europe and other regions are the long-acting phenprocoumon (half-life 140 hours) and short-acting acenocoumarol (half-life 11 hours) (Gadisseur et al. 2002). Warfarin, the more potent form of dicumarol and initially used as rat poison, was introduced as an oral anticoagulant in the 1950s and is currently the most widely used oral anticoagulant. Although the working mechanism of the 4-Hydroxycoumarin drugs is similar, there are some important differences in pharmacokinetics between them (Verhoef et al. 2014).

The reduction of vitamin K 2,3-epoxide (MK4 epoxide) by VKORC1 is essential to sustain gamma-carboxylation of vitamin K-dependent proteins such as the clotting factors II, VII, IX and X. The anticoagulant drug warfarin inhibits VKORC1 (Whitlon et al. 1978), thereby reducing clotting ability (Choonara et al. 1985, 1988), which is used as a treatment for thrombotic disorders such as deep vein thrombosis (DVT), pulmonary embolism and to prevent stroke (Ageno et al. 2012). A common side-effect of warfarin anticoagulation is bleeding which can be counteracted by vitamin K supplementation (Ageno et al. 2012). The exact mechanism by which warfarin inhibits VKORC1 remains elusive. Several recent mechanistic studies suggest competitive binding of a key residue in VKORC1 (Czogalla et al. 2017) or blockage of a dynamic electron-transfer process in VKORC1 (Shen et al. 2017). New oral anticoagulants (NOAC; rivaroxaban, dabigatran, apixaban) have become available as an alternative to warfarin anticoagulation. Unlike warfarin, they are fast-acting and don't require routine coagulation monitoring (Gomez-Outes et al. 2013).
Identifier: R-HSA-159790
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane, endoplasmic reticulum lumen, cytosol
The regeneration of reduced vitamin K (vitamin K hydroquinone) from vitamin K epoxide is catalyzed by vitamin K epoxide reductase (VKORC1) (Sadler 2004). Two important features of this reaction remain unclear. First, dithiothreitol functions efficiently as a reductant in vitro (Wallin & Martin 1985), but the in vivo reductant remains unknown. Second, while people homozygous for mutations in VKORC1 protein lack epoxide reductase activity (Rost et al. 2004) and cultured insect cells transfected with the cloned human VKORC1 gene express vitamin K epoxide reductase activity (Li et al. 2004), the possibility that the active form of the enzyme is a complex with other proteins cannot be formally excluded.
Identifier: R-HSA-6806647
Species: Homo sapiens
Compartment: endoplasmic reticulum lumen, endoplasmic reticulum membrane
VKORC1L1 (Vitamin K epoxide reductase complex subunit 1-like protein 1) in the endoplasmic reticulum catalyzes the reduction of MK4 epoxide to MK4, the active form of vitamin K. A physiological role for this reaction has not been established (Hammed et al. 2013; Tie et al. 2014; Westhofen et al. 2011).
Identifier: R-HSA-6807214
Species: Homo sapiens
Compartment: endoplasmic reticulum lumen, endoplasmic reticulum membrane
GGCX (gamma glutamyl carboxylase) in the endoplasmic reticulum gamma-carboxylates three glutamate residues on BGLAP(24-100) (pro-osteocalcin). MK4 (vitamin K hydroquinone) is oxidized to MK4 epoxide in the process (Berkner 2000; Ferron et al. 2015; Furie et al. 1999; Hauschka et al. 1989; Morris et al. 1995; oser et al. 1980; Stenina et al. 2001).

Set (1 results from a total of 1)

Identifier: R-HSA-9035082
Species: Homo sapiens
Compartment: cytosol

Complex (2 results from a total of 2)

Identifier: R-HSA-6806371
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane
Identifier: R-HSA-9035037
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane

Pathway (1 results from a total of 1)

Identifier: R-HSA-6806664
Species: Homo sapiens
Vitamin K is a required co-factor in a single metabolic reaction, the gamma-carboxylation of glutamate residues of proteins catalyzed by GGCX (gamma-carboxyglutamyl carboxylase). Substrates of GGCX include blood clotting factors, osteocalcin (OCN), and growth arrest-specific protein 6 (GAS6) (Brenner et al. 1998). Vitamin K is derived from green leafy vegetables as phylloquinone and is synthesized by gut flora as menaquinone-7. These molecules are taken up by intestinal enterocytes with other lipids, packaged into chylomicrons, and delivered via the lymphatic and blood circulation to tissues of the body, notably hepatocytes and osteoblasts, via processes of lipoprotein trafficking (Shearer & Newman 2014; Shearer et al. 2012) described elsewhere in Reactome.

In these tissues, menadiol (reduced vitamin K3) reacts with geranylgeranyl pyrophosphate to form MK4 (vitamin K hydroquinone), the form of the vitamin required as cofactor for gamma-carboxylation of protein glutamate residues (Hirota et al. 2013). The gamma-carboxylation reactions, annotated elsewhere in Reactome as a part of protein metabolism, convert MK4 to its epoxide form, which is inactive as a cofactor. Two related enzymes, VKORC1 and VKORCL1, can each catalyze the reduction of MK4 epoxide to active MK4. VKORC1 activity is essential for normal operation of the blood clotting cascade and for osteocalcin function (Ferron et al. 2015). A physiological function for VKORCL1 has not yet been definitively established (Hammed et al. 2013; Tie et al. 2014).

ChemicalDrug (3 results from a total of 3)

Identifier: R-ALL-9014945
Compartment: cytosol
The anticoagulant drug warfarin inhibits VKORC1 (Whitlon et al. 1978), thereby reducing clotting ability (Choonara et al. 1985, 1988), which is used as a treatment for thrombotic disorders such as deep vein thrombosis (DVT), pulmonary embolism and to prevent stroke (Ageno et al. 2012). A common side-effect of warfarin anticoagulation is bleeding which can be counteracted by vitamin K supplementation (Ageno et al. 2012). The exact mechanism by which warfarin inhibits VKORC1 remains elusive. Several recent mechanistic studies suggest competitive binding of a key residue in VKORC1 (Czogalla et al. 2017) or blockage of a dynamic electron-transfer process in VKORC1 (Shen et al. 2017).
Identifier: R-ALL-9035044
Compartment: cytosol
The oral anticoagulant drug phenindione binds to and inhibits VKORC1, acting in a similar way to warfarin (Field et al. 1952). However, phenindione can be associated with hypersensitivity reactions so is rarely used (Naisbitt et al. 2005).
Identifier: R-ALL-9035047
Compartment: cytosol
Dicumarol is a naturally-occurring anticoagulant that binds to and inhibits VKORC1 (Hollman 1991). It is a derivative of coumarin, a bitter, sweet smelling substance made by plants that can be transformed into dicumarol by fungi. It became the prototype of the 4-hydroxycoumarin anticoagulant drug class but has since (1950s) been replaced by its simpler derivative warfarin, and other 4-hydroxycoumarin drugs (Gomez-Outes et al. 2012).
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