Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To assess lucigenin, a chemilumigenic probe, as a detector of superoxide anion in microsomes, NADPH oxidation, lucigenin disappearance, and chemiluminescence in a system including purified NADPH-cytochrome P450 reductase were examined. NADPH oxidation was increased by adding lucigenin, and concurrently, its disappearance and oxygen consumption were also stimulated. Chemiluminescence, which is negligibly emitted in the presence of the reductase alone, was remarkably amplified with phospholipids and albumin. Menadione inhibited lucigenin disappearance resulting in suppression of chemiluminescence. Lucigenin chemiluminescence measured in microsomes appears not to reflect direct superoxide anion production from microsomal components and from quinones, such as menadione.
Biochem Mol Biol Int 1998 Jun
PMID:Lucigenin reduction by NADPH-cytochrome P450 reductase and the effect of phospholipids and albumin on chemiluminescence. 963 35

Quinones caused quenching of Chl a fluorescence in native and model systems. Menadione quenched twofold the fluorescence of Chl a and BChl a in pea chloroplasts, chromatophores of purple bacteria, and liposomes at concentrations of 50-80 microM. To obtain twofold quenching in Triton X-100 micelles and in ethanol, the addition of 1.3 mM and 11 mM menadione was required, respectively. A proportional decrease in the lifetime and yield of Chl a fluorescence in chloroplasts, observed as the menadione concentration increased, is indicative of the efficient excitation energy transfer from bulk Chl to menadione. The decrease in the lifetime and yield of fluorescence was close to proportional in liposomes, but not in detergent micelles. The insensitivity of the menadione quenching effect to DCMU in chloroplasts, and similarity of its action in chloroplasts and liposomes indicate that menadione in chloroplasts interacts with antenna Chl, i.e., nonphotochemical quenching of fluorescence occurs.
Biochem Mol Biol Int 1998 Oct
PMID:Quenching of chlorophyll fluorescence by quinones. 980 1

Mitochondrial (mt) DNA is damaged by free radicals. Recent data also show that there are cell type-dependent differences in mtDNA repair capacity. In this study, we explored the effects of xanthine oxidase (XO), which generates superoxide anion directly, and menadione, which enhances superoxide production within mitochondria, on mtDNA in pulmonary arterial (PA), microvascular (MV), and pulmonary venous (PV) endothelial cells (ECs). Both XO and menadione damaged mtDNA in the EC phenotypes, with a rank order of sensitivity of (from most to least) PV > PA > MV for XO and MV = PV > PA for menadione. Dimethylthiourea and deferoxamine blunted menadione- and XO-induced mtDNA damage, thus supporting a role for the iron-catalyzed formation of hydroxyl radical. Damage to the nuclear vascular endothelial growth factor gene was not detected with either XO or menadione. PAECs and MVECs, but not PVECs, repaired XO-induced mtDNA damage quickly. Menadione-induced mtDNA damage was avidly repaired in MVECs and PVECs, whereas repair in PAECs was slower. Analysis of mtDNA lesions at nucleotide resolution showed that damage patterns were similar between EC phenotypes, but there were disparities between XO and menadione in terms of the specific nucleotides damaged. These findings indicate that mtDNA in lung vascular ECs is damaged by XO- and menadione-derived free radicals and suggest that mtDNA damage and repair capacities differ between EC phenotypes.
Am J Physiol Lung Cell Mol Physiol 2001 Jun
PMID:Oxygen radical-induced mitochondrial DNA damage and repair in pulmonary vascular endothelial cell phenotypes. 1135 Aug 11

Long-term complications of diabetes mellitus have been ascribed to both the effects of prolonged hyperglycemia and to increased oxidative stress. In an attempt to identify the mechanisms underlying the acute effects of hyperglycemia on oxidative stress, we investigated the hypothesis that high glucose might lead to an insufficiency in reducing equivalents (such as NADPH) and thus to a disruption in the glutathione-dependent antioxidant defences and to an incapacity to deal with oxidant attack. For this purpose, erythrocytes from diabetic patients were incubated for 0-90 min in 5.55 or 33.3 mM D-glucose containing tertbutyl hydroperoxide 0.5 and 1 mM, Menadione 100 microM, or glucose oxidase. The time course of the changes in non-protein bound glutathione (reduced and oxidised), lactate and pyruvate, alanine and fluorescent products of oxidative proteolysis, hemolysis and methemoglobin was monitored. The results show that although glucose utilisation was unaffected, all oxidants caused a persistent decrease in total non-protein-bound glutathione suggesting binding to proteins. However, changes in glutathione and redox status differed between the various oxidants and were not directly related to the extent of oxidative cellular damage. In these experimental conditions, with short incubations and using the erythrocyte as the simplest cellular model of glucose metabolism, neither high glucose nor the diabetic condition worsened the susceptibility of erythrocytes to acute in vitro oxidative damage.
Mol Cell Biochem 2001 Sep
PMID:Divergent effects of different oxidants on glutathione homeostasis and protein damage in erythrocytes from diabetic patients: effects of high glucose. 1171 65

Vitamin K-dependent gamma-carboxylation is an essential posttranslational modification required for the functional activity of coagulation proteins such as factors VII, IX, X, and prothrombin. Warfarin, an inhibitor of vitamin K-dependent gamma-carboxylation, was used in earlier work on adult zebrafish to provide evidence for the presence of vitamin K-dependent carboxylase in zebrafish. Here we demonstrate the presence of vitamin K-dependent carboxylase activity in zebrafish by directly assaying the microsomal fraction prepared from adult, unfertilized eggs, and embryos from different developmental stages. Gamma-carboxylase activity was detected both before and after fertilization of embryos and the activity levels remained relatively constant from 6 h postfertilization (hpf) through other advanced stages of development. The expression of activity in the early embryos (0-6 hpf) may be due to the presence of maternal protein since the activity was detected even in the unfertilized eggs. Gamma-carboxylase activity in the eggs as well as early embryos suggested that vitamin K-dependent carboxylase is important throughout development. The detection of vitamin K-dependent carboxylase mRNA by RT-PCR and inhibitor studies using warfarin confirmed these activity results. Further, these studies provide a basis for selecting warfarin-resistant zebrafish mutants in order to find genes regulating gamma-carboxylase activity including the yet unidentified vitamin K-epoxide reductase.
Blood Cells Mol Dis
PMID:Developmental expression of vitamin K-dependent gamma-carboxylase activity in zebrafish embryos: effect of warfarin. 1183 65

The inclusion interaction of the complexes between Vitamin K(3) (VK(3)) and beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and sulfobutylether-beta-cyclodextrin (SBE-beta-CD) were studied by using steady-state fluorescence measurements. The various factors affecting the inclusion process were examined in detail. The formation constants and inclusion stoichiometry for VK(3)-CDs were determined. The results showed that the inclusion ability of beta-CD and its derivatives was the order: SBE-beta-CD>HP-beta-CD>beta-CD. The related inclusion mechanism is proposed to explain the inclusion process. A method of determining VK(3) was established with the linear range was 2.5 x 10(-6)-5.0 x 10(-4) M, and was used to determine the VK(3) tablets. The recoveries were in the range of 97.52-103.5%. The results were satisfactory.
Spectrochim Acta A Mol Biomol Spectrosc 2003 Jul
PMID:Study on vitamin K3-cyclodextrin inclusion complex and analytical application. 1278 60

Menadione (vitamin K(3)) has been shown to form charge transfer complexes with N,N-dimethyl aniline, N,N-dimethyl p-toluidine and N,N-dimethyl m-toluidine in CCl(4) medium. The CT transition energies are well correlated with the ionisation potentials of the anilines. The formation constants of the complexes have been determined at a number of temperatures from which the enthalpies and entropies of formation have been obtained. The formation constants exhibit a very good linear free energy relationship (Hammett) at all the temperatures studied.
Spectrochim Acta A Mol Biomol Spectrosc 2004 Jan
PMID:Study of charge transfer complexes of menadione (vitamin K3) with a series of anilines. 1467 Apr 74

Mitochondrial disorder is characteristic of many myocardial injuries such as endotoxemia, shock, acidosis, ischemia/reperfusion, and others. The goal of possible therapy is to increase ATP production. Derivatives of vitamins K may be a potent electron carrier between various mitochondrial electron-donating and electron-accepting enzyme complexes. We aimed to test the possibility that menadione or its water-soluble derivative AK-135, the newly synthesized analogues of vitamin K1--N-derivatives of 2-methyl-3-aminomethyl 1.4-naphthoquinone, would reduce cardiomyocyte damage after hypoxia or mitochondrial respiratory chain inhibition in culture. Menadione, and more effectively, AK-135, restored the electron flow in defective respiratory chain (hypoxia or rotenone) systems. As was shown in this study, 3 microM of AK-135 restored ATP production after blockade of electron flow through mitochondrial complex I with 5 microM rotenone up to 13.18+/-1.56 vs. 3.21+/-1.12 nmol/mg protein in cells treated with rotenone only. In cultures pretreated with 4 microM dicumarol (DT-diaphorase inhibitor), the protective effect of AK-135 and menadione was abolished completely (1.67+/-1.43 and 2.97+/-0.57 nmol/mg protein, respectively). Inhibition of mitochondrial oxidative phosphorylation caused an increase in intracellular Ca(2+) levels. Here we have demonstrated restoration of calcium oscillations and cardiomyocyte contractility by menadione and its derivative after blockade of NADH: ubiquinone oxidoreductase with rotenone, and decrease of Ca(2+) overloading during hypoxia.
J Mol Cell Cardiol 2005 Jul
PMID:Effects of menadione and its derivative on cultured cardiomyocytes with mitochondrial disorders. 1589 62

A reaction path including transition states is generated for the Dowd mechanism [P. Dowd, R. Hershlne, S.W. Ham, S. Naganathan. Vitamin K and energy transduction: a base strength amplification mechanism. Science 269 (2005) 1684-1691] of action for Vitamin K carboxylase (VKC) using quantum chemical methods (B3LYP/6-311G**). VKC, an essential enzyme in mammalian systems, catalyzes the conversion of hydroquinone form of Vitamin K to the epoxide form in the presence of oxygen. An intermediate species of the oxidation of Vitamin K, an alkoxide, acts apparently to abstract the gamma hydrogen from specifically located glutamate residues. We are able to follow the Dowd proposed path to generate this alkoxide species. The geometries of the proposed model intermediates and transition states in the mechanism are energy optimized. We find that the most energetic step in the mechanism is the uni-deprotonation of the hydroquinone - once this occurs, there is only a small barrier of 3.5kcal/mol for the interaction of oxygen with the carbon to be attacked - and then the reaction proceeds downhill in free energy to form the critical alkoxide species. The results are consistent with the idea that the enzyme probably acts to facilitate the formation of the epoxide by reducing the energy required to deprotonate the hydroquinone form.
J Mol Graph Model 2007 Sep
PMID:A quantum chemical study of the mechanism of action of Vitamin K carboxylase (VKC) III. Intermediates and transition states. 1718 65

A reaction path including transition states is generated for the Silverman mechanism [R.B. Silverman, Chemical model studies for the mechanism of Vitamin K epoxide reductase, J. Am. Chem. Soc. 103 (1981) 5939-5941] of action for Vitamin K epoxide reductase (VKOR) using quantum mechanical methods (B3LYP/6-311G**). VKOR, an essential enzyme in mammalian systems, acts to convert Vitamin K epoxide, formed by Vitamin K carboxylase, to its (initial) quinone form for cellular reuse. This study elaborates on a prior work that focused on the thermodynamics of VKOR [D.W. Deerfield II, C.H. Davis, T. Wymore, D.W. Stafford, L.G. Pedersen, Int. J. Quant. Chem. 106 (2006) 2944-2952]. The geometries of proposed model intermediates and transition states in the mechanism are energy optimized. We find that once a key disulfide bond is broken, the reaction proceeds largely downhill. An important step in the conversion of the epoxide back to the quinone form involves initial protonation of the epoxide oxygen. We find that the source of this proton is likely a free mercapto group rather than a water molecule. The results are consistent with the current view that the widely used drug Warfarin likely acts by blocking binding of Vitamin K at the VKOR active site and thereby effectively blocking the initiating step. These results will be useful for designing more complete QM/MM studies of the enzymatic pathway once three-dimensional structural data is determined and available for VKOR.
J Mol Graph Model 2007 Sep
PMID:A quantum chemical study of the mechanism of action of Vitamin K epoxide reductase (VKOR) II. Transition states. 1718 66


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