Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.3 (complex I)
8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An NADH dehydrogenase possessing a specific activity 3-5 times that of membrane-bound enzyme was obtained by extraction of Acholeplasma laidlawii membranes with 9.0% ethanol at 43 degrees C. This dehydrogenase contained only trace amounts of iron (suggesting an uncoupled respiration), a flavin ratio of 1:2 FAD to FMN and 30-40% lipid. Its resistance to sedimentation is probably due to the high flotation density of the lipids. It efficiently utilized ferricyanide, menadione and dichlorophenol indophenol as electron acceptors, but not O2, ubiquinone Q10 or cytochrome c. Lineweaver-Burk plots of the dehydrogenase were altered to linear functions upon extraction with 9.0% ethanol. A secondary site of ferricyanide reduction could not be explained by the presence of cytochromes, which these membranes lack. In comparison to other respiratory chain-linked NADH dehydrogenases in cytochrome-containing respiratory chains, this dehydrogenase was characterized by similar Km's with ferricyanide, dichlorophenol indophenol, menadione as electron acceptors, but considerably smaller V's with ferricyanide, dichlorophenol indophenol, menadione as electron acceptors, and smaller specific activities. It was not stimulated or reactivated by the addition of FAD, FMN, Mg2+, cysteine or membrane lipids, and was less sensitive to respiratory inhibitors than unextracted enzyme. The ineffectiveness of ADP stimulation on O2 uptake, the insensitivity to oligomycin and the very low iron content of A. laidlawii membranes were considered in relation to conservation of energy by these cells. Some kinetic properties of the dehydrogenation, the uniquely high glycolipid content and apparently uncoupled respiration at Site I were noteworthy characteristics of this NADH dehydrogenase from the truncated respiratory chain of A. laidlawii.
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PMID:The reduced nicotinamide adenine dinucleotide "oxidase" of Acholeplasma laidlawii membranes. 17 76

Intact but fragile mitochondria were isolated from unsporulated oocysts of Eimeria tenella. The mitochondria respired in response to succinate, malate plus pyruvate, and L-ascorbate at rates of 1.00, 0.40, and 0.25 mu1 O2/min/mg protein, respectively. Spectrophotometric analyses of the cytochromes in mitochondria and whole oocysts revealed b-type and o-type cytochromes, at roughly similar levels, but no cytochrome c could be detected. The mitochondrial respiration was inhibited by cyanide, azide, carbon monoxide, antimycin A, and 2-heptyl-4-hydroxyquinoline-N-oxide, but was relatively resistant to rotenone and amytal. The quinolone coccidiostats buquinolate, amquinate, methyl benzoquate, and decoquinate were identified as very powerful inhibitiors of succinate and malate plus pyruvate supported respiration in E. tenella mitochondria. None of these four drugs exhibited any inhibitory effect on chicken liver mitochondria. Only 3 pmol of the quinolones per mg mitochondrial protein was needed to achieve 50% inhibition. The inhibition could not be reversed by coenzymes Q6 or Q10. Since the quinolones did not affect L-ascorbate-supported respiration or the activities of submitochondrial succinate dehydrogenase and NADH dehydrogenase, the site of action of the quinolone coccidiostats was tentatively identified as probably near cytochrome b in E. tenella mitochondria. Mitochondria isolated from an E. tenella amquinate-resistant mutant were much less susceptible to quinolone coccidiostats; 50% inhibition was attained by 300 pmol of the drugs/mg mitochondrial protein. The results suggest that the mechanisms of action of quinolone coccidiostats is by inhibiting the cytochrome-mediated electron transport in the mitochondria of coccidia. 2-Hydroxynaphthoquinone coccidiostats were identified as inhibitors of mitochondrial respiration of both E. tenella and chicken liver. They inhibited submitochondrial succinate dehydrogenase and NADH dehydrogenase of E. tenella, and remained equally active against the mitochondrial function of E. tenella amquinolate-resistant mutant.
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PMID:Studies of the mitochondria from Eimeria tenella and inhibition of the electron transport by quinolone coccidiostats. 117 97

The in vitro toxicity of multiple hydrophobic compounds was the focus of this study. A mitochondrial respiratory assay, sensitive to perturbations caused by hydrophobic chemicals, was utilized to measure the effects of individual aromatic hydrocarbon pollutants and their mixtures on mitochondrial respiratory function. Benzene, naphthalene, acenaphthene, and 1-chloronaphthalene, common industrial solvents shown to interact additively in vivo, were evaluated using this in vitro assay system. Mitochondrial respiration was inhibited 50% (EC50) by 525 ppm (6.7 mM) benzene, 15 ppm (117 microM) naphthalene, 3.9 ppm (25.5 microM) acenaphthene, or 3.8 ppm (23.4 microM) 1-chloronaphthalene. NADH:O2 oxidoreductase (NADH-->O2), NADH:ubiquinone oxidoreductase, and ubiquinol:O2 oxidoreductase activities were inhibited by all four compounds, whereas succinate:O2 oxidoreductase, cytochrome c oxidase, and duroquinol:O2 oxidoreductase activities were not inhibited. Inhibition of mitochondrial respiration occurred at the level of ubiquinone (coenzyme Q10) for all four aromatic hydrocarbons. The ultraviolet absorbance spectrum of isolated Q10 was also altered by naphthalene, acenaphthene, or 1-chloronaphthalene, suggesting a specific interaction between that component of the respiratory chain and these aromatic hydrocarbons. Inhibition by a mixture of 2, 3, or 4 of the compounds tested was additive, reflecting a summation effect of each compound present in the mixture. This additive nature is consistent with previously reported effects of these compounds in vivo and with compounds having similar modes of action. The similar mode of action in vitro is a specific interaction with coenzyme Q10, not a generalized membrane perturbation as speculated to occur in vivo, and is the likely mechanism for the observed additive toxicity.
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PMID:Additive effects and potential inhibitory mechanism of some common aromatic pollutants on in vitro mitochondrial respiration. 147 93

The inhibition of NADH dehydrogenase by 1-methyl-4-phenylpyridinium (MPP+) leading to ATP depletion has been proposed to explain cell death in the expression of the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Electron paramagnetic resonance studies show no effect of MPP+ on the reduction of the iron-sulfur clusters of NADH dehydrogenase. Mitochondria inhibited by MPP+ were sonicated and both the NADH oxidase and the NADH-Q reductase activities were measured. NADH oxidase activity was not fully restored to control levels, but NADH-Q reductase activity was the same as that of the control. Neither succinate-oxidase nor succinate-Q reductase activities were inhibited. These data indicate that MPP+ interaction with NADH dehydrogenase interferes with the passage of electrons from the iron-sulfur cluster of highest potential to endogenous Q10 but that the inhibition can be relieved by the addition of a small, water-soluble Q analog. Inhibition at this site is sufficient to explain the inhibition of respiration and no inhibition of other mitochondrial functions was observed.
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PMID:The inhibition site of MPP+, the neurotoxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is near the Q-binding site of NADH dehydrogenase. 282 83

It is widely believed that the nigrostriatal toxicity of MPTP is due to its oxidation by brain monoamine oxidase first to MPDP+, and eventually to MPP+. Following uptake by the synaptic dopamine reuptake system, it is concentrated in the matrix of striatal mitochondria by an energy-dependent carrier, energized by the electrical gradient of the membrane. At the very high intramitochondrial concentrations thus reached, MPP+ combines with NADH dehydrogenase at a point distal to its iron-sulfur clusters but prior to the Q10 combining site. This leads to cessation of oxidative phosphorylation, ATP depletion, and cell death. Other pyridine derivatives act similarly on NADH dehydrogenase but they are not acutely toxic unless concentrated by the MPP+ carrier.
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PMID:Mechanism of the neurotoxicity of 1-methyl-4-phenylpyridinium (MPP+), the toxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 328 90

A 34 kDa coenzyme Q reductase has been solubilized and purified from pig liver plasma membranes. The solubilized enzyme reduced coenzyme Q0 with NADH. Ubiquinones with longer isoprenoid side chain such as Q2 and Q10 were also reduced when the quinones and the enzyme were reconstituted into phospholipid liposomes. N-terminal sequencing of an internal peptide showed identity to bovine NADH-cytochrome b5 reductase. Biochemical characterization of the purified enzyme indicated that the coenzyme Q reductase corresponds to an unusual form of NADH-cytochrome b5 reductase.
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PMID:A phospholipid-dependent NADH-coenzyme Q reductase from liver plasma membrane. 761 97

The plasma membrane NADH oxidase activity partially purified from the surface of HeLa cells exhibited hydroquinone oxidase activity. The preparations completely lacked NADH:ubiquinone reductase activity. However, in the absence of NADH, reduced coenzyme Q10 (Q10H2=ubiquinol) was oxidized at a rate of 15+/-6 nmol min-1 mg protein-1 depending on degree of purification. The apparent Km for Q10H2 oxidation was 33 microM. Activities were inhibited competitively by the cancer cell-specific NADH oxidase inhibitors, capsaicin and the antitumor sulfonylurea N-(4-methylphenylsulfonyl)-N'-(4-chlorophenyl)urea (LY181984). With coenzyme Q0, where the preparations were unable to carry out either NADH:quinone reduction or reduced quinone oxidation, quinol oxidation was observed with an equal mixture of the Q0 and Q0H2 forms. With the mixture, a rate of Q0H2 oxidation of 8-17 nmol min-1 mg protein-1 was observed with an apparent Km of 0.22 mM. The rate of Q10H2 oxidation was not stimulated by addition of equal amounts of Q10 and Q10H2. However, addition of Q0 to the Q10H2 did stimulate. The oxidation of Q10H2 proceeded with what appeared to be a two-electron transfer. The oxidation of Q0H2 may involve Q0, but the mechanism was not clear. The findings suggest the potential participation of the plasma membrane NADH oxidase as a terminal oxidase of plasma membrane electron transport from cytosolic NAD(P)H via naturally occurring hydroquinones to acceptors at the cell surface.
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PMID:The plasma membrane NADH oxidase of HeLa cells has hydroquinone oxidase activity. 1035 95

The selenoprotein thioredoxin reductase (TrxR1) is an essential antioxidant enzyme known to reduce many compounds in addition to thioredoxin, its principle protein substrate. Here we found that TrxR1 reduced ubiquinone-10 and thereby regenerated the antioxidant ubiquinol-10 (Q10), which is important for protection against lipid and protein peroxidation. The reduction was time- and dose-dependent, with an apparent K(m) of 22 microm and a maximal rate of about 12 nmol of reduced Q10 per milligram of TrxR1 per minute. TrxR1 reduced ubiquinone maximally at a physiological pH of 7.5 at similar rates using either NADPH or NADH as cofactors. The reduction of Q10 by mammalian TrxR1 was selenium dependent as revealed by comparison with Escherichia coli TrxR or selenium-deprived mutant and truncated mammalian TrxR forms. In addition, the rate of reduction of ubiquinone was significantly higher in homogenates from human embryo kidney 293 cells stably overexpressing thioredoxin reductase and was induced along with increasing cytosolic TrxR activity after the addition of selenite to the culture medium. These data demonstrate that the selenoenzyme thioredoxin reductase is an important selenium-dependent ubiquinone reductase and can explain how selenium and ubiquinone, by a combined action, may protect the cell from oxidative damage.
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PMID:The mammalian cytosolic selenoenzyme thioredoxin reductase reduces ubiquinone. A novel mechanism for defense against oxidative stress. 1243 34

The effects of increasing mitochondrial oxidative phosphorylation (OXPHOS), by enhancing electron transport chain components, were evaluated on 1-methyl-4-phenylpyridinium (MPP+) toxicity in brain neuroblastoma cells. Although glucose is a direct energy source, ultimately nicotinamide and flavin reducing equivalents fuel ATP produced through OXPHOS. The findings indicate that cell respiration/mitochondrial O(2) consumption (MOC) (in cells not treated with MPP+) is not controlled by the supply of glucose, coenzyme Q(10) (Co-Q(10)), NADH+, NAD or nicotinic acid. In contrast, MOC in whole cells is highly regulated by the supply of flavins: riboflavin, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), where cell respiration reached up to 410% of controls. In isolated mitochondria, FAD and FMN drastically increased complex I rate of reaction (1300%) and (450%), respectively, having no effects on complex II or III. MPP+ reduced MOC in whole cells in a dose-dependent manner. In isolated mitochondria, MPP+ exerted mild inhibition at complex I, negligible effects on complexes II-III, and extensive inhibition of complex IV. Kinetic analysis of complex I revealed that MPP+ was competitive with NADH, and partially reversible by FAD and FMN. Co-Q(10) potentiated complex II ( approximately 200%), but not complex I or III. Despite positive influence of flavins and Co-Q(10) on complexes I-II function, neither protected against MPP+ toxicity, indicating inhibition of complex IV as the predominant target. The nicotinamides and glucose prevented MPP+ toxicity by fueling anaerobic glycolysis, evident by accumulation of lactate in the absence of MOC. The data also define a clear anomaly of neuroblastoma, indicating a preference for anaerobic conditions, and an adverse response to aerobic. An increase in CO(2), CO(2)/O(2) ratio, mitochondrial inhibition or O(2) deprivation was not directly toxic, but activated metabolism through glycolysis prompting depletion of glucose and starvation. In conclusion, the results of this study indicate that the mechanism of action for MPP+, involves the inhibition of complex I and and more specifically complex IV, leading to impaired OXPHOS and MOC. Moreover, flavin dervatives control the rate of complex I/cellular respiration and Co-Q10 augments complex II [corrected].
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PMID:Effects of enhancing mitochondrial oxidative phosphorylation with reducing equivalents and ubiquinone on 1-methyl-4-phenylpyridinium toxicity and complex I-IV damage in neuroblastoma cells. 1500 52

Current treatment options for parkinsonism as a neurodegenerative disease are limited and still mainly symptomatic and lack significant disease-modifying effect. Understanding its molecular pathology and finding the cause of dopaminergic cell loss will lead to exploring therapies that could prevent and cure the disease. Mitochondrial dysfunction was found to stimulate releasing of reactive oxygen species (ROS) with subsequent induction of apoptotic neuronal cell death. The aim of the present study was to throw the light on the role of coenzyme Q10 with or without L-dopa in an experimental model of parkinsonism induced by rotenone in rats. The present work showed that rotenone (2.5 mg/kg/day i.p. for 60 days) induced a model of parkinsonism (group II) resembling the basic findings in human characterized by bradykinesia and rigidity manifested as an increase in catalepsy score (detected after 20 days with bad prognosis after 60 days) with marked decrease in striatal dopamine levels. This model confirmed the implication of mitochondrial-apoptotic pathway in the pathogenesis of parkinsonism as there was a decrease in levels of striatal complex I activity and ATP as well as extreme overexpression of the antiapoptotic protein Bcl-2, and also exhibited the role of coenzyme Q10 where its plasma and striatal levels were found to be decreased in comparison to the normal control rats (group I). This proposed pathogenesis was evidenced by the significant correlation between catalepsy score and the neurochemical parameters obtained in the current work. The treated groups started to receive the drug(s) after 20 days from induction of parkinsonism and continued to complete for 60 days. Oral administration of Co Q10 in a low dose 200 mg/kg/day (group III) or a high dose 600 mg/kg/day (group IV), resulted in amelioration of the mitochondrial induced apoptosis by dose-dependent restoration of striatal complex I activity, ATP levels with temperate increase in expression of Bcl-2 as well as decrease in catalepsy score. Although both low and high doses of Co Q10 resulted in significant increase in its plasma and striatal levels, but only the high dose was shown to reach the recommended therapeutic levels. As a current replacement therapy, oral administration of levodopa 10 mg/kg/day (group V), caused symptomatic improvement in the form of reduction of catalepsy score with restoration of striatal dopamine levels, but it did not show any significant effects on either striatal complex I activity, ATP levels or the expression of Bcl-2, pointing to the lack of its disease-modifying role. On the other hand, its administration with high dose of coenzyme Q10 caused the most marked symptomatic improvement in catalepsy score when compared to its administration with low dose of coenzyme Q10, or when compared to either coenzyme Q10 high dose or L-dopa, respectively. Moreover, administration of high dose coenzyme Q10 with L-dopa provided a significant increase in striatal complex I activity, ATP levels and Bcl-2 expression in comparison to group administered coenzyme Q10 low dose with L-dopa, in addition to the significant restoration of striatal dopamine levels and both plasma and striatal Co Q10 levels. Regarding that L-dopa is viewed as a replacement therapy in parkinsonism, it could be concluded that addition of coenzyme Q10 in a high dose in early parkinson's disease could be recommended based on its proved disease-modifying role on several levels of the proposed mechanisms, including improvement of respiratory chain activity and intervention with neuronal apoptosis. A further research to investigate other apoptosis-targeted compounds will open a new era in the treatment of parkinsonism.
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PMID:Mechanism of the neuroprotective role of coenzyme Q10 with or without L-dopa in rotenone-induced parkinsonism. 1881 89


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