The Vitamin K Oxidoreductase Is a Multimer That Efficiently Reduces Vitamin K Epoxide to Hydroquinone to Allow Vitamin K-dependent Protein Carboxylation

Rishavy, Mark A.; Hallgren, Kevin W.; Wilson, Lee A; Usubalieva, Aisulu; Runge, Kurt W.; Berkner, Kathleen L.

doi:10.1074/jbc.m113.497297

Cited by 37 publications

(52 citation statements)

References 36 publications

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“…KO is then recycled by VKORC1, a vitamin K oxidoreductase (VKOR) (2,3) that is evolutionarily conserved (4). VKORC1 recycles KO to KH 2 in 2 steps, wherein KO is first converted to vitamin K quinone (K) and then to KH 2 (5). Together, the enzymatic activities of GGCX and VKORC1 form the vitamin K cycle (1).…”

Section: Introductionmentioning

confidence: 99%

VKOR paralog VKORC1L1 supports vitamin K–dependent protein carboxylation in vivo

et al. 2018

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Section: Introductionmentioning

confidence: 99%

VKOR paralog VKORC1L1 supports vitamin K–dependent protein carboxylation in vivo

et al. 2018

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“…The compound with the highest experimentally determined IC 50 , NSC645827 (CAS# 128113-19-9; Scheme 5) shares some structural features with coumarins, as do many of the other compounds identified in this process [114]. A further study mined the NCI database specifically for compounds with the coumarin scaffold.…”

Section: Dicoumarol Also Inhibits Nqo1mentioning

confidence: 99%

“…Despite its relatively small size (18.2 kDa), mammalian VKOR is capable of catalysing two reactions: the conversion of vitamin K epoxide to vitamin K and the reduction of vitamin K to the hydroxy form [49]. The functionally active form of the enzyme is a multimer, most likely a dimer [50].…”

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confidence: 99%

Dicoumarol: A Drug which Hits at Least Two Very Different Targets in Vitamin K Metabolism

Timson

2017

CDT

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Dicoumarol, a symmetrical biscoumarin can be considered as the "parent" of the widely used anticoagulant drug, warfarin. The discovery of dicoumarol's bioactive properties resulted from an investigation into a mysterious cattle disease in the 1940s. It was then developed as a pharmaceutical, but was superseded in the 1950s by warfarin. Both dicoumarol and warfarin antagonise the blood clotting process through inhibition of vitamin K epoxide reductase (VKOR). This blocks the recycling of vitamin K and prevents the γ-carboxylation of glutamate residues in clotting factors.VKOR is an integral membrane protein and our understanding of the molecular mechanism of action of dicoumarol and warfarin is hampered by the lack of a three dimensional structure. There is consequent controversy about the membrane topology of VKOR, the location of the binding site for coumarin inhibitors and the mechanism of inhibition by these compounds. Dicoumarol (and warfarin) also inhibit a second enzyme, NAD(P)H quinone oxidoreductase 1 (NQO1). This soluble, cytoplasmic enzyme may also play a minor role in the recycling of vitamin K. However, its main cellular roles as an enzyme appear to be detoxification and the prevention of the build-up of reactive oxygen species. NQO1 is well characterised biochemically and structurally. Consequently, structurebased drug design has identified NQO1 inhibitors which have potential for the development of anticancer drugs. Many of these compounds are structurally related to dicoumarol and some have reduced "off target" effects. Therefore, it is possible that dicoumarol will become the "parent" of a second group of drugs.

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“…While controversy over VKORC1 membrane topology remains it is agreed that VKORC1L1 has a 4TM topology similar to the bacterial enzyme [11]. Finally it should be noted that there is evidence to suggest that VKORC1 can form multimeric structures though there is no evidence for a heterooligomeric complexes between VKORC1 and VKORC1L1 [21,22].…”

Section: Introductionmentioning

confidence: 99%

The membrane topology of vitamin K epoxide reductase is conserved between human isoforms and the bacterial enzyme

Cao

Lith

Mitchell

et al. 2016

Biochemical Journal

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The membrane topology of vitamin K epoxide reductase is conserved between human isoforms and the bacterial enzyme. Biochemical Journal, 473(7), pp. 851-858. (doi:10.1042/bj20151223) This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/120748/ ABSTRACTThe membrane topology of vitamin K epoxide hydrolase (VKOR) is controversial with data supporting both a three transmembrane and a four transmembrane model. The positioning of the transmembrane domains and the loops between these domains is critical if we are to understand the mechanism of vitamin K oxidation and it's recycling by members of the thioredoxin family of proteins and the mechanism of action of warfarin, an inhibitor of VKOR. Here we show that both mammalian VKOR isoforms adopt the same topology, with the large loop between transmembrane one and two facing the lumen of the endoplasmic reticulum (ER). We used a redox sensitive GFP fused to the N-or C-terminus to show that these regions face the cytosol, and introduction of glycosylation sites along with mixed disulfide formation with thioredoxin like transmembrane protein (TMX) to demonstrate ER localisation of the major loop. The topology is identical to the bacterial homologue from Synechococcus sp., for which the structure and mechanism of recycling has been characterized. Our results provide a resolution to the membrane topology controversy and support previous results suggesting a role for members of the ER protein disulfide isomerase family in recycling VKOR.

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The Vitamin K Oxidoreductase Is a Multimer That Efficiently Reduces Vitamin K Epoxide to Hydroquinone to Allow Vitamin K-dependent Protein Carboxylation

Cited by 37 publications

References 36 publications

VKOR paralog VKORC1L1 supports vitamin K–dependent protein carboxylation in vivo

VKOR paralog VKORC1L1 supports vitamin K–dependent protein carboxylation in vivo

Dicoumarol: A Drug which Hits at Least Two Very Different Targets in Vitamin K Metabolism

The membrane topology of vitamin K epoxide reductase is conserved between human isoforms and the bacterial enzyme

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