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:1.9.3.1 (cytochrome oxidase)
8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progressive exercise intolerance was associated with a decreased maximal rate of ubiquinol cytochrome c reductase (complex III) activity in the muscle mitochondria of the studied patient and with a thirty five-fold increase in the I50 for antimycin A. In contrast, myxothiazol sensitivity was not altered. Complex III activity was stable at 37 degrees C, but progressively decreased at 4 degrees C. An heteroplasmic G to A mutation at position 15615 of the mitochondrial DNA, resulting in the replacement of the highly conserved Gly290 in cytochrome b by Asp, was identified. Histochemical studies showed increased cytochrome oxidase and succinate dehydrogenase activities under the sarcolemma of type I fibres. After partial extraction of mitochondria from the muscle, the residual pellet contained a lower percentage of the mutation than did whole muscle, suggesting that the percentage of mutation is higher in the most readily extracted mitochondria, most probably present under the sarcolemma. In the current 8 transmembrane helix model of cytochrome b, Gly290 lies at the end of the sixth transmembrane helix, facing the intermembrane space and close to the presumed sites of interaction between cytochrome b, the iron-sulfur protein and the 9.5 kDa protein. Since immunoblotting experiments showed a relative decrease in the proportions of these three subunits in the patient's mitochondria compared with the other complex III subunits, it is probable that the complex III instability and the relative decrease in these subunits are related to the mutation. The relationship between the decrease in the apparent affinity for antimycin A and the instability of complex III are discussed.
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PMID:Antimycin resistance and ubiquinol cytochrome c reductase instability associated with a human cytochrome b mutation. 898 36

The nuclear ABC1 gene was isolated as a multicopy suppressor of a cytochrome b mRNA translation defect. Its inactivation leads to a respiratory deficiency suggesting a block in the bc1 segment of the respiratory chain [Bousquet, I., Dujardin, G. & Slonimski, P. P. (1991) EMBO J. 10, 2023-2031]. In the present study, we established that deleting the ABC1 chromosomal gene from Saccharomyces cerevisiae does not prevent the assembly of the bc1 complex (complex III) but markedly impairs the kinetics of its high-potential electron transfer pathway occurring on the positive, outer, side of the membrane, which results in reduced activity of the bc1 complex. In addition, the activity of complex II and its cytochrome b560 decrease drastically and complex IV activity is halved. It is also observed that the binding of the quinol to the bc1 complex ubiquinol oxidation site is affected and that adding exogenous quinones partially compensates for the respiratory deficiency in vitro, although the quinone content of mutant and wild-type mitochondria are similar. Lastly, complexes II, III and IV are found to be thermosensitive and the bc1 complex exhibits greater sensitivity than the wild-type strain to center N and P inhibitors, suggesting that the three multisubunit complexes have undergone structural modifications. The data suggest that the ABC1 gene product acts as a chaperone-like protein essential for the proper conformation and efficient functioning of the bc1 complex and the effects of the Abc1 protein on the complexes II and IV might result from interactions with the modified bc1 complex.
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PMID:The nuclear ABC1 gene is essential for the correct conformation and functioning of the cytochrome bc1 complex and the neighbouring complexes II and IV in the mitochondrial respiratory chain. 921 Apr 71

Spectral, inhibitor, and O2-consumption studies on membranes from free-living and bacteroid forms of Bradyrhizobium japonicum have revealed the existence of a number of terminal oxidases, and four terminal oxidase gene clusters within the heme-copper cytochrome family have been cloned. Here the complexes encoded by coxMNOP and coxWXYZ, genes with homology to CuA-containing cytochrome c oxidases and b-type ubiquinol oxidases respectively, are studied by analysis of mutants in each of the two oxidases and a double mutant in both of the terminal oxidase genes. Membranes from microaerobically incubated strain JHK12 (which contains an insertion in coxWXYZ) were deficient in levels of CO-reactive heme b, and both strains JHK12 and Bj3430 (the latter lacks coxMNOP) were deficient in CN--reactive cytochrome b. Membranes of the double mutant (strain JHKS4) retained less than 7% of the cytochrome b3 and 25% of the total CN--reactive cytochrome b of the wild type. Cyanide inhibition curves of oxygen uptake by wild-type membranes were triphasic, and only the phases inhibited by the highest (at about 50 &mgr;M CN-, attributed to cytochrome aa3) and the lowest (at approximately 0.1 &mgr;M) CN- were identifiable in the membranes from the two individual oxidase mutants. Membrane respiratory activity of the double mutant was resistant to CN- over a broad inhibitor concentration in the micromolar range. Consistent with our findings that these oxidases are expressed when cells are incubated in a low O2 environment, the double mutant was severely deficient in H2-dependent chemolithotrophic growth. The latter growth condition requires prolonged incubation in an atmosphere of H2, CO2, and a low (1% or less) partial pressure of oxygen. The double mutant was also deficient in whole cell O2 dependent H2 oxidation, with H2 uptake rates 31% of the wild type. Copyright 1998 Elsevier Science B.V.
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PMID:Roles of the bradyrhizobium japonicum terminal oxidase complexes in microaerobic H2-dependent growth 955 44

Our previous studies in iron-loaded rat heart cells showed that in vitro iron loading results in peroxidative injury, manifested in a marked decrease in rate and amplitude of heart cell contractility and rhythmicity, which is correctable by treatment with deferoxamine (DF). In the present studies we explored the role of mitochondrial damage in myocardial iron toxicity. Iron loading by 24-hour incubation with 0.36 mmol/L ferric ammonium citrate resulted in a decrease in the activity of nicotinamide adenine dinucleotide (NADH)-cytochrome c oxidoreductase (complex I+III) to 35.3%+/-11.2% of the value in untreated controls; of succinate-cytochrome c oxidoreductase (complex II+III) to 57.4%+/-3.1%; and of succinate dehydrogenase to 63.5%+/-12.6% (p < 0.001 in all cases). The decrease in activity of other mitochondrial enzymes, including NADH-ferricyanide reductase, succinate ubiquinone oxidoreductase (complex II), cytochrome c oxidase (complex IV), and ubiquinol cytochrome c oxidoreductase (complex III), was less impressive and ranged from 71.5%+/-15.8% to 91.5%+/-14.6% of controls. That the observed loss of respiratory enzyme activity was a specific effect of iron toxicity was clearly demonstrated by the complete restoration of enzyme activities by in vitro iron chelation therapy. Sequential treatment with iron and doxorubicin caused a loss of complex I+III and complex II+III activity that was greater than that seen with either agent alone but was only partially correctable by DF treatment. Alterations in cellular adenosine triphosphate measurements paralleled very closely the changes observed in respiratory complex activity. These findings demonstrate for the first time the impairment of cardiac mitochondrial respiratory enzyme activity caused by iron loading at conditions formerly shown to produce severe abnormalities in contractility and rhythmicity.
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PMID:Mitochondrial respiratory enzymes are a major target of iron toxicity in rat heart cells. 960 12

The preparation of pure and homogeneous membrane proteins or membrane protein complexes is time consuming, and the yields are frequently insufficient for structural studies. To circumvent these problems we established an indirect immunoaffinity chromatography method based on engineered Fv fragments. cDNAs encoding the variable domains of hybridoma-derived antibodies raised against various membrane proteins were cloned and expressed in Escherichia coli. The Fv fragments were engineered to serve as bifunctional adaptor molecules. The Fv fragment binds to the epitope of the membrane protein, while the Strep tag affinity peptide, which was fused to the carboxy-terminus of the VH chain, immobilizes the antigen-Fv complex on a streptavidin sepharose column. The usefulness of this technique is illustrated with membrane protein complexes from Paracoccus denitrificans, namely, the cytochrome c oxidase (EC 1.9.3.1), the ubiquinol:cytochrome c oxidoreductase (EC 1.10.2.2), and subcomplexes or individual subunits thereof. These membrane proteins were purified simply by combining the crude P. denitrificans membrane preparation with the E. coli periplasmic cell fraction containing the corresponding Fv fragment, followed by solubilization and streptavidin affinity chromatography. Pure and highly active membrane protein complexes were eluted in the Fv-bound form using diaminobiotin for mild competitive displacement of the Strep tag. The affinity column could thus be reused under continuous operation for several months. Five to 10 mg of membrane protein complexes could be obtained without any detectable impurities within five hours.
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PMID:Engineered Fv fragments as a tool for the one-step purification of integral multisubunit membrane protein complexes. 963 56

Free radicals are chemical species with an unpaired electron in the outer valence orbitals. The unpaired electron makes them paramagnetic (physics) and relatively reactive (chemistry). The free radicals that are normal metabolites in aerobic biological systems have varied reactivities, ranging from the high reactivity of hydroxyl radical (t1/2 = 10(-9) s) to the low reactivity of melanins (t1/2 = days). The univalent reduction of oxygen that takes place in mammalian organs produces superoxide radicals at a rate of about 2% of the total oxygen uptake. The primary production of superoxide radicals sustains a free radical chain reaction involving a series of reactive oxygen species (hydrogen peroxide, hydroxyl and peroxyl radical and singlet oxygen). Nitric oxide is almost unreactive as free radical except for its termination reaction with superoxide radical to yield the strong oxidant peroxynitrite. Nitric oxide also reacts with ubiquinol in a redox reaction, with cytochrome oxidase competitively with oxygen, and oxymyoglobin and oxyhemoglobin displacing oxygen. Septic shock and endotoxemia produce muscle dysfunction and oxidative stress due to increased steady state concentrations of reactive oxygen and nitrogen species.
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PMID:Biochemistry of free radicals: from electrons to tissues. 981 95

Age-associated alterations in the mitochondrial electron transport system (ETS) may lead to free radical generation and contribute to aging. The complexes of the ETS were screened spectrophotometrically in gastrocnemius of young (10 month) as well as older (20 and 26 month) B6C3F1 female mice fed an ad libitum (AL) diet or a restricted (DR) in total calories diet (40% less food than AL mice). The activities of complexes I, III, and IV decreased significantly by 62%, 54%, and 74%, respectively, in old AL mice (AL20) compared to young AL mice (AL10). Complexes I, III, and IV from DR10 mice had activities that were significantly lower than those seen in AL10 mice (suggesting a lower total respiratory rate or improved efficiency). By contrast, complex II activity did not decrease with age (actually increased, but not significantly) in AL20 mice. Complex II was decreased across age in DR mice. K(m) for ubiquinol-2 of complex III was significantly increased in AL10 animals (0.33 mM vs. 0.26 mM in DR10 mice) and was further increased with aging (0.44 mM in AL20 vs. 0.17 mM in DR20 mice). This suggests obstruction of binding, inhibition of electron flow in aging, which could yield premature product release as a free radical. Total complex IV by Vmax was highest in AL10 mice, but the proportion of complex as high-affinity sites was lower (69%) than in either DR10 (80%) or DR20 (80%). The percentage of high-affinity sites decreased to only 45% in AL20 mice, and Vmax was reduced by 75 percent. In AL26 mice high-affinity sites decreased to 33 percent. At physiologic concentration of reduced cytochrome c, significant dysfunction of complex IV in AL20 or AL26 mice would be expected with obstruction of overall electron transport. The age-associated loss of activity and function of complexes I, III, and IV may contribute to increased free radical production. Lack of sufficient DNA repair in mitochondria and juxtaposition to the ETS adds to susceptibility and accumulation of mtDNA and other mitochondrial macromolecular damage. DR seems to retard this deterioration of mitochondrial respiratory function by preserving enzymatic activities and function.
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PMID:The effects of dietary restriction on mitochondrial dysfunction in aging. 992 30

The aim of this work was to investigate the possible effects of resveratrol on the mitochondrial respiratory chain in rat brains. Isolation of mitochondria was performed at 4 degrees C using differential centrifugation. Mitochondrial respiration rate (0.4 mg of protein/ml) was determined by measuring mitochondrial oxygen consumption with a Clark electrode at 37 degrees C. Respiratory control ratio (RCR) was evaluated as the state 3/state 4 ratio of oxidative phosphorylation with substrates adenosine 5'-diphosphate (ADP) and malate plus glutamate, respectively in the presence and in the absence of resveratrol. The rate of oxygen consumption by the different complexes was checked using rotenone (2 microM), malonate (10 mM), antimycin A (1 microM), potassium cyanide (KCN) (0.3 mM) and oligomycin (10 microM) to inhibit complexes II, III, IV, V and I, respectively. Moreover, enzyme activity determinations were checked as follows: the activities of complexes II-III were measured as the rate of cytochrome c reduction at 550 nm (37 degrees C) successively triggered either by succinate (complexes II and III) or by decylubiquinol (DUQH2) (complex III), in the presence and in the absence of resveratrol. Adenosine 5'-triphosphate (ATP) synthase activity was checked as ATP hydrolysis (ATPase) at 37 degrees C for 10 min from purified mitochondria on Percoll gradient. The inorganic phosphate (Pi) concentration was measured by the Fiske and Subbarow method. When complexes I to V were activated by glutamate plus malate, resveratrol (10(-11) - 10(-4) M) significantly decreased RC (p < 0.001) following a biphasic curve with two EC50 values, 0.162 +/- 0.072 microM and 24.5 +/- 4.0 microM, representing about 56% of total oxygen consumption inhibition. We also observed a concentration-dependent effect on state 3 with two EC50 values, 2.28 +/- 0.87 nM and 27 +/- 5 microM respectively. On the other hand, resveratrol inhibited state 4 following a concentration-dependent curve with an EC50 of 37 +/- 11 microM. When complex IV operated alone, resveratrol (100 microM) did not modify oxygen consumption compared with control, indicating that this molecule did not inhibit complex IV. Thus resveratrol inhibits the mitochondrial respiratory chain through complexes I to III. In order to confirm these data, we measured the enzymatic activity of ubiquinol cytochrome c reductase alone and in the presence of resveratrol. In the presence of disrupted mitochondria, after freeze thawing cycles (three times), resveratrol inhibited about 20% of complex III activity. These results suggest that resveratrol and DUQH2 could be competitive on complex III. Resveratrol significantly inhibited ATPase activity (p < 0.001) following a biphasic curve with two EC50 values, 0.39 +/- 0.15 nM and 23.1 +/- 6.4 microM, both representing about 80% of oligomycin-dependent ATPase total activity. Resveratrol was effective as a protecting agent on the three models of oxidation. On lipid peroxidation of brain synaptosomes induced by the Fenton reaction, it was three times more potent than DUQH2. Its effectiveness in reducing 1,1-diphenyl-2-picryl hydrazyl radical (DPPH degrees) showed a stoichiometry of two, indicating that two hydrogen atoms of resveratrol were abstracted by the process. Resveratrol was also able to scavenge the superoxide anion (O2 degrees) generated from rat forebrain mitochondria in a concentration dependent manner. In conclusion, resveratrol can decrease complex III activity by competition with coenzyme Q. This property is especially interesting as this complex is the site where reactive oxygen substances (ROS) are generated. By decreasing the activity of complex III, resveratrol cannot only oppose the production of ROS but can also scavenge them.
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PMID:Effects of resveratrol on the rat brain respiratory chain. 1037 Aug 69

The reversible inhibitory effects of nitric oxide (.NO) on mitochondrial cytochrome oxidase and O(2) uptake are dependent on intramitochondrial.NO utilization. This study was aimed at establishing the mitochondrial pathways for.NO utilization that regulate O-(2) generation via reductive and oxidative reactions involving ubiquinol oxidation and peroxynitrite (ONOO(-)) formation. For this purpose, experimental models consisting of intact mitochondria, ubiquinone-depleted/reconstituted submitochondrial particles, and ONOO(-)-supplemented mitochondrial membranes were used. The results obtained from these experimental approaches strongly suggest the occurrence of independent pathways for.NO utilization in mitochondria, which effectively compete with the binding of.NO to cytochrome oxidase, thereby releasing this inhibition and restoring O(2) uptake. The pathways for.NO utilization are discussed in terms of the steady-state levels of.NO and O-(2) and estimated as a function of O(2) tension. These calculations indicate that mitochondrial.NO decays primarily by pathways involving ONOO(-) formation and ubiquinol oxidation and, secondarily, by reversible binding to cytochrome oxidase.
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PMID:The regulation of mitochondrial oxygen uptake by redox reactions involving nitric oxide and ubiquinol. 1060 29

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease affecting approximately1% of the population older than 50 years. There is a worldwide increase in disease prevalence due to the increasing age of human populations. A definitive neuropathological diagnosis of Parkinson's disease requires loss of dopaminergic neurons in the substantia nigra and related brain stem nuclei, and the presence of Lewy bodies in remaining nerve cells. The contribution of genetic factors to the pathogenesis of Parkinson's disease is increasingly being recognized. A point mutation which is sufficient to cause a rare autosomal dominant form of the disorder has been recently identified in the alpha-synuclein gene on chromosome 4 in the much more common sporadic, or 'idiopathic' form of Parkinson's disease, and a defect of complex I of the mitochondrial respiratory chain was confirmed at the biochemical level. Disease specificity of this defect has been demonstrated for the parkinsonian substantia nigra. These findings and the observation that the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which causes a Parkinson-like syndrome in humans, acts via inhibition of complex I have triggered research interest in the mitochondrial genetics of Parkinson's disease. Oxidative phosphorylation consists of five protein-lipid enzyme complexes located in the mitochondrial inner membrane that contain flavins (FMN, FAD), quinoid compounds (coenzyme Q10, CoQ10) and transition metal compounds (iron-sulfur clusters, hemes, protein-bound copper). These enzymes are designated complex I (NADH:ubiquinone oxidoreductase, EC 1.6. 5.3), complex II (succinate:ubiquinone oxidoreductase, EC 1.3.5.1), complex III (ubiquinol:ferrocytochrome c oxidoreductase, EC 1.10.2.2), complex IV (ferrocytochrome c:oxygen oxidoreductase or cytochrome c oxidase, EC 1.9.3.1), and complex V (ATP synthase, EC 3.6.1.34). A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with Parkinson's disease. The reduction in the activity of complex I is found in the substantia nigra, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP(+)) destroys dopaminergic neurons in the substantia nigra. Although the serum levels of CoQ10 is normal in patients with Parkinson's disease, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons.
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PMID:Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of parkinson's disease. 1135 Nov 30


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