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)

Measurement of the effect of drugs on the in vivo rates of synthesis of rabbit liver organelle bound proteins were measured following individual treatments with the inducers phenobarbital, 3-methylcholanthrene and PCB (a mixture of polychlorinated biphenyls) and the inhibitors, cycloheximide, aflatoxin B1, chloramphenicol and actinomycin D. Following their isolation from a homogenate containing the combined livers of 14C-leucine injected experimental animals and 3H-leucine injected control animals, purified fractions of the following proteins were prepared: microsomal cytochrome b5, cytochrome P-450, NADH-cytochrome b5 reductase, NADPH-cytochrome P-450 reductase and proteolipids, outer mitochondrial membrane cytochrome b5, NADH-cytochrome b5 reductase and proteolipids, inner mitochondrial membrane cytochrome c, NADH dehydrogenase and proteolipids, intermitochondrial membrane cytochrome b5 and circulating serum albumin. The effect of a drug was examined by measuring the 14C/3H ratio of leucine incorporation of each fraction; ratios which differed markedly from a control value of 1 represented actual changes in the relative rates of protein synthesis. Increased rates of synthesis of cytochrome P-450 and its reductase, intermitochondrial membrane cytochrome b5 and all three proteolipid fractions resulted from each inducer treatment. Treatments with 3-methylcholanthrene and PCB also increased the rate of synthesis of cytochrome b5 and its reductase in both the microsome and outer mitochondrial membrane. In addition, the PCB treatment increased the rates of synthesis of cytochrome c and NADH-dehydrogenase. The rates of synthesis of cytochromes, reductases and of circulating serum albumin were inhibited following treatments with cycloheximide, aflatoxin B1 and actinomycin D. Actinomycin D appeared to inhibit the release of newly synthesized albumin into the bloodstream while chloramphenicol treatment appeared to inhibit the incorporation of cytochrome c into the mitochondria. After 20 hours of treatment with inhibitors, the inhibitory effect of actinomycin D and cycloheximide were still apparent while the rates of protein synt;esis in chloramphenicol and aflatoxin B1 treated animals increased to levels above the controls. The incorporation of radioactively labeled leucine into the proteolipids of the microsomal, and the outer and inner mitochondrial membranes were inhibited following the treatment with actinomycin D and stimulated following the treatment with cycloheximide.
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PMID:Effect of a single dose of inducers and inhibitors on the rate of synthesis of cytochromes and reductases in liver organelles. 11 59

The NADH-ubiquinone reductase activity of the respiratory chains of several organisms was inhibited by capsaicin and dihydrocapsaicin, which are the pungent principles of red pepper. This inhibition was correlated with the presence of an energy transducing site in this segment of the respiratory chain. Where the NADH-quinone oxidoreductase segment involved an energy coupling site (e.g., in Paracoccus denitrificans, Escherichia coli, and Thermus thermophilus HB-8 membranes and bovine heart mitochondria), capsaicin acted as an inhibitor of ubiquinone reduction by NADH. In contrast, where this energy coupling site was absent (e.g., in Saccharomyces cerevisiae mitochondria and Bacillus subtilis membranes), there was no inhibition of NADH-ubiquinone reductase activity by capsaicin. The capsaicin inhibition of Paracoccus membranes was reversed by washing the membranes with medium containing bovine serum albumin. In the E. coli and Paracoccus membranes and bovine submitochondrial particles, capsaicin acted as a noncompetitive inhibitor for ubiquinone-1 at lower concentrations of ubiquinone-1 (less than 20 microM) and as a competitive inhibitor at higher concentrations of ubiquinone-1 (greater than 50 microM). In addition, the concentrations of capsaicin required for 50% inhibition of NADH oxidase activity of bovine submitochondrial particles were increased when ubiquinone-10 was added to the particles. The mechanism by which capsaicin inhibits the energy-transducing NADH-quinone oxidoreductase is discussed.
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PMID:Inhibition by capsaicin of NADH-quinone oxidoreductases is correlated with the presence of energy-coupling site 1 in various organisms. 211 34

The binding of porcine heart mitochondrial malate dehydrogenase and beta-hydroxyacyl-CoA dehydrogenase to bovine heart NADH:ubiquinone oxidoreductase (complex I), but not that of bovine heart alpha-ketoglutarate dehydrogenase complex, is virtually abolished by 0.1 mM NADH. The malate dehydrogenase and beta-hydroxyacyl-CoA enzymes compete in part for the same binding site(s) on complex I as do the malate dehydrogenase and alpha-ketoglutarate dehydrogenase complex enzymes. Associations between mitochondrial malate dehydrogenase and bovine serum albumin were observed. Subtle convection artifacts in short-time centrifugation tests of enzyme association with the Beckman Airfuge are described. Substrate channeling of NADH from both the mitochondrial and cytoplasmic malate dehydrogenase isozymes to complex I and reduction of ubiquinone-1 were shown to occur in vitro by transient enzyme-enzyme complex formation. Excess apoenzyme causes little inhibition of the substrate channeling reaction with both malate dehydrogenase isozymes in spite of tighter equilibrium binding than the holoenzyme to complex I. This substrate channeling could, in principle, provide a dynamic microcompartmentation of mitochondrial NADH.
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PMID:Substrate channeling of NADH and binding of dehydrogenases to complex I. 250 78

The interactions of long chain (greater than C7), alkyl compounds with tightly coupled, beef heart submitochondrial particles (SMP) have been investigated with respect to their effects upon respiratory chain-linked electron transfer and energy coupling capacity. Long chain alkyl alcohols, amines, free fatty acids, and methyl esters exhibit a general uncoupling effect, with stimulation of the succinate oxidase activity but inhibition of the NADH oxidase, in SMP. The degree of effectiveness is dependent on the nature of the functional group and the length of the alkyl chain. Submitochondrial particles depleted of F1 and the F1-inhibitor protein are similarly affected. Subsequent treatment with bovine serum albumin reverses the effects of free fatty acids and results in partial recovery of activity with alkyl amines, alcohols, and methyl esters. Differences between the effects of these alkyl compounds and those of sodium dodecyl sulfate, deoxycholate, palmitoyl carnitine, and palmitoyl CoA rule out detergent-like action as the explanation for these observations. These data suggest that specific lipophilic interactions with the membrane, modulated by the nature of the functional group, are responsible for the effects of these compounds on the energy transducing system of SMP. Analyses of the reduction kinetics of the cytochromes indicate that the sites of interaction of these compounds with the inner mitochondrial membrane are associated with the primary dehydrogenase of complex I and energy coupling site 2; alkyl amines possess an additional site of interaction in the region of complex III.
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PMID:The modes of action of long chain alkyl compounds on the respiratory chain-linked energy transducing system in submitochondrial particles. 287 39

The binding of ganglioside GM1 to bovine serum albumin has been studied by using absorption and fluorescence properties of the protein chromophores. Differences in the ultraviolet absorption spectrum and in fluorescence quenching, as well as a marked shift of the wavelength at the fluorescence maximum provide information about the binding of this ganglioside to albumin. Ultracentrifugal studies showed that there are two forms of the GM1-protein complexes which differ markedly in their molecular weight. These two forms have been separated on this basis, by a chromatographic sieving procedure, and designated as complexes I and II. Both complexes are characterized by a GM1: protein ratio of one ganglioside micelle per albumin polypeptide chain. Complex II polymerizes slowly and irreversibly to a dimer, complex I. These results have been correlated with the optical studies in order to draw limited inferences as to the environment of the binding sites on the native protein. The interaction between GM1 micelles and albumin is mostly hydrophobic and the two complexes are actually mixed ganglioside-protein micelles. At submicellar concentrations of ganglioside a binding of ganglioside GM1 to albumin also occurs. This process is due, however, to an aspecific, reversible adhesion of GM1 molecules on the albumin surface with no apparent perturbation of the albumin structure.
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PMID:Interaction of GMI ganglioside with bovine serum albumin: formation and isolation of multiple complexes. 746 Aug 98

The measurement of individual respiratory chain complexes is an important component of the investigation of diseases due to mitochondrial dysfunction. We have evaluated assays which measure complexes I to IV in human skeletal muscle mitochondria and in addition optimized these assays to provide sensitive and reliable diagnostic techniques, particularly in situations where a partial interruption at a single complex needs to identified. Using several established methods of membrane disruption we have found that optimal activities of complexes I and II are obtained by freeze-thawing the mitochondria in hypotonic potassium phosphate buffer, whereas complex III and IV activities are markedly increased by the addition of the detergent n-dodecyl-beta-D-maltoside. Complex I activity is measured in the presence of 2.5 mg.ml-1 bovine serum albumin, which increases rotenone sensitivity, and we have shown that NADH-cytochrome b5 reductase makes an important contribution to the rotenone-insensitive NADH-ubiquinone oxidoreductase activity. Complex II activity is measured after preincubation of the mitochondrial fraction with succinate to fully activate the complex. Complex I and III activities are dependent upon the length of the isoprenoid chain of the ubiquinone and ubiquinol, respectively. These assays have been used to establish a control range.
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PMID:An evaluation of the measurement of the activities of complexes I-IV in the respiratory chain of human skeletal muscle mitochondria. 819 14

Excessive free fatty acid (FFA) exposure represents a potentially important diabetogenic condition that can impair insulin secretion from pancreatic beta-cells. Because mitochondrial oxidative phosphorylation is a main link between glucose metabolism and insulin secretion, in the present work we investigated the effects of the FFA oleate (OE) on mitochondrial function in the clonal pancreatic beta-cell line, MIN6. Both the long term (72 h) and short term (immediately after application) impact of OE exposure on beta-cells was investigated. After 72 h of exposure to OE (0.4 mm, 0.5% bovine serum albumin) cells were washed and permeabilized, and mitochondrial function (respiration, phosphorylation, membrane potential formation, production of reactive oxygen species) was measured in the absence or presence of OE. MIN6 cells exposed to OE for 72 h showed impaired glucose-stimulated insulin secretion and decreased cellular ATP. Mitochondria in OE-exposed cells retained normal functional characteristics in FFA-free medium; however, they were significantly more sensitive to the acute uncoupling effect of OE treatment. The mitochondria of OE-exposed cells displayed increased depolarization caused by acute OE treatment, which is attributable to the elevation in the FFA-transporting function of uncoupling protein 2 and the dicarboxylate carrier. These cells also had an increased production of reactive oxygen species in complex I of the mitochondrial respiratory chain that could be activated by FFA. A high level of reduction of respiratory complex I augmented acute FFA-induced uncoupling in a way compatible with activation of mitochondrial uncoupling protein by intramitochondrial superoxide. A stronger augmentation was observed in OE-exposed cells. Together, these events may underlie FFA-induced depression of the ATP/ADP ratio in beta-cells, which accounts for the defective glucose-stimulated insulin secretion associated with lipotoxicity.
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PMID:Mitochondrial functional state in clonal pancreatic beta-cells exposed to free fatty acids. 1264 85

Aspergillus fumigatus is an unusual pathogen in immunocompetent individuals; its incidence has increased in the last decades in patients immunocompromised, like those with chronic granulomatosis disease and AIDS. The aim of this study was to identify differences between the respiratory chain of host and the fungus planning to use the later as a pharmacological target. We evaluated respiration, membrane potential and oxidative phosphorylation of mitochondria of the spheroplasts of A. fumigatus in situ, after permeabilization with digitonin. Firstly, a functional respiratory chain (complex I-V) was demonstrated: adenosine 5'-diphosphate (ADP) induced an oligomycin-sensitive transition from resting to phophorylating respiration in the presence of the oxidizable substrates malate, glutamate, alpha-ketoglutarate, pyruvate, dihydroorotate, succinate, N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) and exogenous NADH. In addition, the ability of the fungus to oxidize exogenous NADH, as well as the insensitivity of its respiration to rotenone, in association with the sensitivity to flavone, indicate the presence of an alternative NADH-ubiquinone oxidoreductase; the partial sensitivity of respiration to antimycin A and cyanide, in association with the sensitivity to benzohydroxamic acid, indicates the presence of an alternative oxidase. The fatty acid-uncoupled respiration was partly reversed by bovine serum albumin (BSA) and guanosine 5'-triphosphate (GTP) and was insensitive to either carboxyatractyloside or ADP. These results, together with evidences obtained using antibodies raised against uncoupling protein (UCP) from potato, indicate in addition, the presence of an uncoupling protein in the respiratory chain of A. fumigatus.
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PMID:In situ evidence of an alternative oxidase and an uncoupling protein in the respiratory chain of Aspergillus fumigatus. 1459 41

Derivatives of benzazolo[3,2-a]quinolium salts (QSDs) are reductively activated by the enzymatic reducing agents hypoxanthine (or xanthine)/xanthine oxidase and NADH dehydrogenase as evidenced by the increase in rates of ferricytochrome c (Cyt(III)c) reduction and oxygen consumption, respectively. No correlation between Michaelis-Menten parameters and QSDs redox potentials was found regarding anaerobic or aerobic Cyt(III)c reduction, although maximum rates were observed for nitro-containing QSDs. However, oxygen consumption rates correlate with QSDs redox potentials when NADH dehydrogenase is used as reducing agent. QSDs bind covalently to bovine serum albumin (BSA) under anaerobic conditions, in the presence, and less in the absence, of HX/XO and only if the nitro group is present at the QSD. QSDs react with glutathione (GSH) in the presence of HX/XO but not in its absence, under anaerobic conditions. The amount of reacted GSH increases, and the relative amount of GSSG formed decreases, with an increase in the QSD reduction potential, thus indicating that GSH reacts with reduced nitro-containing QSDs mainly in a manner which does not involve the production of GSSG, presumably, through the formation of the nitroso-QSD-GSH conjugate. QSDs are, thus, novel nitro-containing heterocyclic compounds which could be bioreductively activated to react with oxygen and thiols.
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PMID:Reductive activation and thiol reactivity of benzazolo[3,2-a]quinolinium salts. 1514 83

In this work we studied permeability transition by incubating mitochondria in the presence of 50 muM Ca(2+) and malate/glutamate as substrates. This condition, besides inducing the release of pyridine nucleotides, promotes the generation of reactive oxygen-derived species by the complex I of the respiratory chain. The latter leads to the opening of the mitochondrial permeability transition pore. Ca(2+) release, mitochondrial swelling and collapse of the transmembrane electric potential, were analyzed to assess this process. We propose that the mechanism for pore opening, in addition to the oxidative stress, involves the uncoupling effect of fatty acids providing activation of phospholipase A2, lipid peroxidation, and the oxidation of membrane thiols. This proposal emerges from the data indicating the protective effect of bovine serum albumin and N-ethylmaleimide. The key role of reactive oxygen species was implied based on the fact that the scavenger alpha-phenyl-tert-butyl nitrone inhibited pore opening.
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PMID:On the role of the respiratory complex I on membrane permeability transition. 1590 45


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