A quantum chemical study of the mechanism of action of Vitamin K epoxide reductase (VKOR)

Davis, Charles H.; Deerfield, David W.; Wymore, Troy; Stafford, Darrel W.; Pedersen, Lee G.

doi:10.1016/j.jmgm.2006.10.005

Cited by 22 publications

(25 citation statements)

References 26 publications

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“…The procedure in the appendix of the preceding paper was employed to locate the transition states [1]. The program GaussView [12] was used to visually examine structures at all steps throughout the calculations; this proved essential for staying on course.…”

Section: Methodsmentioning

confidence: 99%

“…The program GaussView [12] was used to visually examine structures at all steps throughout the calculations; this proved essential for staying on course. The method/basis set employed has proven to be useful previously [13,14] for exploring reactive intermediates and was useful in our work on the reductase [1]. As in the reductase study [1], the long hydrophobic side chain of Vitamin K was truncated after the first double bond for practical computer time considerations.…”

Section: Methodsmentioning

confidence: 99%

“…In the preceding paper, we considered the pathway of action for Vitamin K epoxide reductase (VKOR) [1]. In the Vitamin K cycle (Fig.…”

Section: Introductionmentioning

confidence: 99%

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A quantum chemical study of the mechanism of action of Vitamin K carboxylase (VKC)

Davis

Deerfield

Wymore

et al. 2007

Journal of Molecular Graphics and Modelling

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A quantum chemical study of the mechanism of action of Vitamin K carboxylase (VKC)

Davis

Deerfield

Wymore

et al. 2007

Journal of Molecular Graphics and Modelling

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“…Mechanism of action of vitamin K (see [7] and references therein, and [8][9][10][11]) and its photophysical and photobiological properties [12][13][14][15][16][17][18] have been studied extensively. Structure and vibrational spectra of the model molecule of both vitamin K 1 and K 2 having an allyl group instead of a phytyl side chain (designated further as model 1, see Fig.…”

Section: Introductionmentioning

confidence: 99%

Conformational analysis of vitamin K1 model molecule: a theoretical study

Захаров

Vogt

2010

Struct Chem

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Isomerism, conformations, and molecular structure of a model molecule of vitamin K 1 with a truncated side chain have been studied by the density functional theory calculations using B3LYP method and double-and triple-f correlation consistent basis sets. The conformations of two possible (E and Z) isomers, formed by the rotations around three single C-C bonds closest to the naphthoquinone ring, have been studied. The lowest energy conformers are stabilized by additional hydrogen bonds between hydrogen atoms of the side chain and an oxygen atom in the naphthoquinone subunit. It is interesting to note that the structure of the energetically preferred conformer of the E-isomer (3c) has been found to be similar to the solid state structures of phylloquinones in the photosystem I of cyanobacterium Synechococcus elongatus. The excited electronic states of two lowest energy conformers have also been investigated.

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“…The initial step most likely requires the protonation of the epoxide oxygen by one of the two cysteine residues followed by the formation of a covalent enzyme-substrate complex mediated by the second cysteine residue. This carbon-sulphur bond is subsequently broken when a sulphur-sulphur bond between two cysteine residues in VKOR is formed [54]. These two cysteine residues must be re-reduced to regenerate active enzyme; it is assumed that this reduction is catalysed by a second protein, but the identity of this is not known.…”

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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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A quantum chemical study of the mechanism of action of Vitamin K epoxide reductase (VKOR)

Cited by 22 publications

References 26 publications

A quantum chemical study of the mechanism of action of Vitamin K carboxylase (VKC)

A quantum chemical study of the mechanism of action of Vitamin K carboxylase (VKC)

Conformational analysis of vitamin K1 model molecule: a theoretical study

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

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