Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.99.5 (NADH dehydrogenase)
 2,135 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The product of the spontaneous dimerization and decarboxylation of aminoethylcysteine ketimine (simply named the dimer in this note) has been investigated for a possible biochemical activity. It has been found that the dimer inhibits the ADP-dependent oxidation of NAD(+)-linked substrates in rat liver mitochondria and electron transport from NADH to O2 in bovine heart submitochondrial particles (SMP). Oxidation of succinate by SMP is not impaired by concentrations of the dimer inhibiting almost totally NADH oxidation. Furthermore, the dimer did not affect the rotenone-insensitive electron transfer from NADH to menadione. These results give a preliminary indication suggesting that the dimer inhibits electron flow from NADH dehydrogenase to ubiquinone at or near the rotenone binding site(s). The dimer inhibition falls in the same range exhibited by some neurotoxins which are known to interact with the rotenone binding site.
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PMID:Aminoethylcysteine ketimine decarboxylated dimer inhibits mitochondrial respiration by impairing electron transport at complex I level. 813 20

We isolated and characterized mutants defective in nuo, encoding NADH dehydrogenase I, the multisubunit complex homologous to eucaryotic mitochondrial complex I. By Southern hybridization and/or sequence analysis, we characterized three distinct mutations: a polar insertion designated nuoG::Tn10-1, a nonpolar insertion designated nuoF::Km-1, and a large deletion designated delta(nuoFGHIJKL)-1. Cells carrying any of these three mutations exhibited identical phenotypes. Each mutant exhibited reduced NADH oxidase activity, grew poorly on minimal salts medium containing acetate as the sole carbon source, and failed to produce the inner, L-aspartate chemotactic band on tryptone swarm plates. During exponential growth in tryptone broth, nuo mutants grew as rapidly as wild-type cells and excreted similar amounts of acetate into the medium. As they began the transition to stationary phase, in contrast to wild-type cells, the mutant cells abruptly slowed their growth and continued to excrete acetate. The growth defect was entirely suppressed by L-serine or D-pyruvate, partially suppressed by alpha-ketoglutarate or acetate, and not suppressed by L-aspartate or L-glutamate. We extended these studies, analyzing the sequential consumption of amino acids by both wild-type and nuo mutant cells growing in tryptone broth. During the lag and exponential phases, both wild-type and mutant cells consumed, in order, L-serine and L-aspartate. As they began the transition to stationary phase, both cell types consumed L-tryptophan. Whereas wild-type cells then consumed L-glutamate, glycine, L-threonine, and L-alanine, mutant cells utilized these amino acids poorly. We propose that cells defective for NADH dehydrogenase I exhibit all these phenotypes, because large NADH/NAD+ ratios inhibit certain tricarboxylic acid cycle enzymes, e.g., citrate synthase and malate dehydrogenase.
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PMID:Mutations in NADH:ubiquinone oxidoreductase of Escherichia coli affect growth on mixed amino acids. 815 82

The existence of an organo-specific (heart) external NADH dehydrogenase located on the outer face of the inner mitochondrial membrane has been recently proposed. We have studied the respiration on external NADH in rat and beef heart mitochondrial fractions: (i) by using different mitochondrial isolation procedures on the rat, we observed that the higher the criteria of quality toward classical substrate respiration of mitochondrial fractions, the lower the external NADH-linked respiration; (ii) by using an especially loosely fitting glass-Teflon homogenizer, we obtained rat heart mitochondrial fractions practically free from external NADH linked respiration and with the highest respiratory control ratio on glutamate plus malate respiration. In rat and beef heart mitochondrial fractions containing an external NADH respiration: (i) ethoxyformic anhydride used previously to distinguish internal and external NADH oxidation was shown not to be specific; (ii) external NADH-linked respiration (although associated to the normally functioning respiratory chain as was shown by the effects of classic respiratory inhibitors) did not lead to ADP phosphorylation while glutamate plus malate did; (iii) respiratory activity on glutamate plus malate and external NADH was totally additive and the oxidation corresponded to two separate cytochrome oxidase pools, indicating a total functional separation between the two respiratory systems; (iv) NAD+ addition stimulated states 3 and 4 glutamate plus malate respiration to the same extent, indicating the presence of an appreciable number of internal dehydrogenases accessible to external cofactors. These results show that external NADH-linked dehydrogenase activity, which is usually detectable in mammal heart mitochondrial fractions, is of artefactual origin.
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PMID:The organo-specific external NADH dehydrogenase of mammal heart mitochondria has an artefactual origin. 839 14

It was found that the activities of prooxidant enzymes (NAD(P)H oxidases and NAD(P)H:cytochrome c reductases) in bovine leukemia virus-transformed calf and lamb embryo kidney fibroblasts (lines Mi-18 and FLK) were by 1.25-18 times higher when compared to corresponding nontransformed calf cells. The activity of DT-diaphorase was also increased by about one order of magnitude in transformed cells. The activities of antioxidant enzymes were almost unchanged (superoxide dismutase), decreased by 13% or 53% (catalase) or increased by 25% or 90% (glutathione reductase) in Mi-18 or FLK cells, respectively. These changes of enzyme activity increased the toxicity of simple redox-cycling quinones (duroquinone, naphthazarin) towards transformed cells, but did not affect the toxicity of daunorubicin. The latter was most probably related to the inhibition of plasma membrane NADH dehydrogenase.
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PMID:The changes of prooxidant and antioxidant enzyme activities in bovine leukemia virus-transformed cells. Their influence on quinone cytotoxicity. 839 4

The steady-state kinetics of the NADH dehydrogenase activities of the mitochondrial NADH-ubiquinone oxidoreductase in the presence of one-electron acceptors, ferricyanide and hexammineruthenium(III), were studied. Similar to ferricyanide, hexammineruthenium was found to be an efficient electron acceptor for the enzyme in inside-out submitochondrial particles and isolated Complex I, but not in intact mitochondria. Qualitatively the same results were obtained using submitochondrial particles or isolated Complex I. Both hexammineruthenium(III) and ferricyanide reduction was rotenone-insensitive and showed no stimulation by the uncouplers in tightly coupled submitochondrial particles. In contrast to the NADH-ferricyanide oxidoreductase reaction which exhibits a double substrate inhibition behaviour, no inhibition of the reaction by either NADH or the electron acceptor was revealed in the NADH-hexammineruthenium(III) reductase reaction. The double-reciprocal plots 1/v vs. 1/[NADH] at various hexammineruthenium(III) concentrations gave a series of straight lines intercepting in the third quadrant, thus supporting the mechanism of the overall reaction in which the reduced enzyme-NAD+ complex is oxidized by the electron acceptor before NAD+ dissociation. The apparent KsNADH values equal to 1 x 10(-5) and 4 x 10(-5) M for submitochondrial particles and Complex I, respectively (27 degrees C, pH 8.0), were determined from the secondary KmNADH vs. V (at different acceptor concentrations) plot. The Ki values for the competitive inhibition of NADH oxidation by NAD+ were 1 x 10(-3) M and 2 x 10(-3) M for the respective enzyme preparations. The results obtained suggest that hexammineruthenium(III) interacts with the NADH-ubiquinone oxidoreductase at a single reaction site different from that for fericyanide.
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PMID:Kinetics of the mitochondrial NADH-ubiquinone oxidoreductase interaction with hexammineruthenium(III). 844 12

It has been reported that N-methyl-beta-carbolinium analogues of the neurotoxic N-methyl-4-phenylpyridinium cation (MPP+) inhibit NADH-linked mitochondrial oxidations, as well as mitochondrial respiration on succinate nearly to the same extent [Fields, Albores, Neafsey and Collins (1992) Arch. Biochem. Biophys. 294, 539-544]. Those authors further claimed that MPP+ itself also blocks respiration through succinate dehydrogenase, in addition to its well-known effect on NADH dehydrogenase (Complex I), and concluded that both effects may contribute to the development of Parkinsonian symptoms. Since N-methyl-beta-carboliniums are thought to be endogenous metabolites, these findings, if verified, would have important implications on the etiology of idiopathic Parkinsonism. We have re-examined these observations, using mitochondria after full activation of succinate dehydrogenase, as well as submitochondrial particles, in which complexities due to membrane transport are not present. We report the following observations. (1) N-Methyl-beta-carboliniums inhibit mitochondrial respiration on NAD(+)-linked substrates in a time-dependent manner, and the inhibition is potentiated by the presence of tetraphenylboron anion (TPB-), as expected for positively charged compounds. (2) Unlike MPP+ itself, however, these compounds are uncouplers at higher concentrations, so that the effects seen in State 3 cannot be assigned exclusively to inhibition of NADH oxidation. (3) The effects on succinate oxidation in mitochondria, in which the full activity of the enzyme is expressed, are 1-1.5 orders of magnitude lower than on respiration via Complex I and are thus unlikely to contribute significantly to the neurotoxicity. (4) The effect of MPP+ on mitochondrial respiration via succinate dehydrogenase is trivial, in accord with previous reports from several laboratories, but contradicting the findings of Fields et al. (cited above). (5) In submitochondrial particles the inhibition of NADH oxidation (via the complete respiratory chain) has been confirmed, but it differs markedly from the action of MPP+ in two respects. First, the enhancement by TPB- is very small; secondly, the inhibition of NADH oxidation measured using ubiquinone (Q) analogues is far lower, suggesting that Complex I is not the only target. (6) In submitochondrial particles the inhibition of succinate oxidation by either O2 or Q analogues is incomplete, trivial or absent. (7) We thus conclude that we find no basis for assigning any potential biological effect of N-methyl-beta-carboliniums to the blockade of succinate oxidation.
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PMID:Is complex II involved in the inhibition of mitochondrial respiration by N-methyl-4-phenylpyridinium cation (MMP+) and N-methyl-beta-carbolines? 848 93

Effect of the polycation on oxidative phosphorylation in the rat liver mitochondria has been studied. Both oxygen uptake and coupled phosphorylation were progressively inhibited by increasing concentration of the polycation, as observed with NAD-linked substrates, succinate and ascorbate+TMPD which activates the terminal part of the respiratory chain. NADH oxidase, NADH dehydrogenase and cytochrome oxidase were strongly inhibited by the polycation, 80-90% of the activity being lost at an inhibitor concentration of 100 microM. Succinate oxidase and succinate dehydrogenase were inhibited 60-66% at 100 microM concentration of the polycation. The polycation inhibited the uncoupler 2,4-dinitrophenol stimulated ATPase activity both in presence and absence of Mg2+ ions. The polycation also inhibited salt-induced volume change.
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PMID:Inhibition of mitochondrial oxidative phosphorylation and its electron transport pathway by a polycation in vitro. 850 25

Studies were undertaken to investigate the principal actions underlying mercury-induced oxidative stress in the kidney. Mitochondria from kidneys of rats treated with HgCl2 (1.5 mg/kg i.p.) demonstrated a 2-fold increase in hydrogen peroxide (H2O2) formation for up to 6 hr following Hg(II) treatment using succinate as the electron transport chain substrate. No increase in H2O2 formation was observed when NAD-linked substrates (malate/glutamate) were used, suggesting that Hg(II) affects H2O2 formation principally at the ubiquinone-cytochrome b region of the mitochondrial respiratory chain in vivo. Together with increased H2O2 formation, mitochondrial glutathione (GSH) content was depleted by more than 50% following Hg(II) treatment, whereas formation of thiobarbiturate reactive substances (TBARS), indicative of mitochondrial lipid peroxidation, was increased by 68%. Studies in vivo revealed a significant concentration-related depolarization of the inner mitochondrial membrane following the addition of Hg(II) to mitochondria isolated from kidneys of untreated rats. This effect was accompanied by significantly increased H2O2 formation, GSH depletion and TBARS formation linked to both NADH dehydrogenase (rotenone-inhibited) and ubiquinone-cytochrome b (antimycin-inhibited) regions of the electron transport chain. Oxidation of pyridine nucleotides (NAD[P]H) was also observed in mitochondria incubated with Hg(II) in vitro. In further studies in vitro, the potential role of Ca2+ in Hg(II)-induced mitochondrial oxidative stress was investigated. Ca2+ alone (30-400 nmol/mg protein) produced no increase in H2O2 and only a slight increase in TBARS formation when incubated with kidney mitochondria isolated from untreated rats. However, Ca2+ significantly increased H2O2 and TBARS formation elicited by Hg(II) at the ubiquinone-cytochrome b region of the mitochondrial electron transport chain, whereas TBARS formation was decreased significantly when the Ca2+ uptake inhibitors, ruthenium red or [ethylenebis(oxyethylenenitrilo)]tetraacetic acid (EGTA), were included with Hg(II) in the reaction mixtures. These findings support the view that Hg(II) causes depolarization of the mitochondrial inner membrane with consequent increased H2O2 formation. These events, coupled with Hg(II)-mediated GSH depletion and pyridine nucleotide oxidation, create an oxidant stress condition characterized by increased susceptibility of mitochondrial membranes to iron-dependent lipid peroxidation (TBARS formation). Since increased H2O2 formation, GSH depletion and lipid peroxidation were also observed in vivo following Hg(II) treatment, these events may underlie oxidative tissue damage caused by mercury compounds. Moreover, Hg(II)-induced alterations in mitochondrial Ca2+ homeostasis may exacerbate Hg(II)-induced oxidative stress in kidney cells.
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PMID:Studies on Hg(II)-induced H2O2 formation and oxidative stress in vivo and in vitro in rat kidney mitochondria. 851 85

There are multiple routes of NAD(P)H oxidation associated with the inner membrane of plant mitochondria. These are the phosphorylating NADH dehydrogenase, otherwise known as Complex I, and at least four other nonphosphorylating NAD(P)H dehydrogenases. Complex I has been isolated from beetroot, broad bean, and potato mitochondria. It has at least 32 polypeptides associated with it, contains FMN as its prosthetic group, and the purified enzyme is sensitive to inhibition by rotenone. In terms of subunit complexity it appears similar to the mammalian and fungal enzymes. Some polypeptides display antigenic similarity to subunits from Neurospora crassa but little cross-reactivity to antisera raised against some beef heart complex I subunits. Plant complex I contains eight mitochondrial encoded subunits with the remainder being nuclear-encoded. Two of these mitochondrial-encoded subunits, nad7 and nad9, show homology to corresponding nuclear-encoded subunits in Neurospora crassa (49 and 30 kDa, respectively) and beef heart CI (49 and 31 kDa, respectively), suggesting a marked difference between the assembly of CI from plants and the fungal and mammalian enzymes. As well as complex I, plant mitochondria contain several type-II NAD(P)H dehydrogenases which mediate rotenone-insensitive oxidation of cytosolic and matrix NADH. We have isolated three of these dehydrogenases from beetroot mitochondria which are similar to enzymes isolated from potato mitochondria. Two of these enzymes are single polypeptides (32 and 55 kDa) and appear similar to those found in maize mitochondria, which have been localized to the outside of the inner membrane. The third enzyme appears to be a dimer comprised of two identical 43-kDa subunits. It is this enzyme that we believe contributes to rotenone-insensitive oxidation of matrix NADH. In addition to this type-II dehydrogenases, several observations suggest the presence of a smaller form of CI present in plant mitochondria which is insensitive to rotenone inhibition. We propose that this represents the peripheral arm of CI in plant mitochondria and may participate in nonphosphorylating matrix NADH oxidation.
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PMID:Functional molecular aspects of the NADH dehydrogenases of plant mitochondria. 859 75

Studies on the effect of various Cd2+ concentrations on substrate oxidation by whole cells of cadmium-sensitive Staphylococcus aureus 17810S showed that oxidation of glutamate or pyruvate was highly sensitive to low Cd2+ concentrations (5 microM), whereas L-lactate oxidation was insensitive even to high Cd2+ concentrations (100 microM). Location of the cadmium-sensitive targets in the enzyme systems involved in oxidation of these substrates was studied in subcellular fractions prepared from cells pretreated with 5 or 100 microM Cd2+. Activities of the cytoplasmic 2-oxoglutarate dehydrogenase complex (ODHC)') and pyruvate dehydrogenase complex (PDHC) were strongly inhibited with 5 microM Cd2+, while with 100 microM Cd2+ the inhibition was almost complete. In contrast, activities of the cytoplasmic NAD-dependent glutamate dehydrogenase (NAD-GDH), the membrane-bound NADH dehydrogenase (NDH) and HQNO-sensitive NADH oxidase were not sensitive to 100 microM Cd2+. These data indicate that the accessible, cadmium-sensitive targets are located only in the cytoplasmic ODHC and PDHC. It is postulated that two vicinal dithiols present in ODHC and PDHC may be regarded as the primary cadmium-sensitive targets in the systems oxidizing glutamate or pyruvate. Since activities of the membrane-bound NAD-independent L-lactate dehydrogenase (iLDH) and HQNO-sensitive L-lactate oxidase were not affected by 100 microM Cd2+, this indicates that the L-lactate oxidizing system lacks the accessible, cadmium-sensitive targets. The mechanism of Cd2+ toxicity to energy conservation with glutamate, pyruvate or L-lactate in S. aureus is discussed.
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PMID:Cadmium-sensitive targets in the aerobic respiratory metabolism of Staphylococcus aureus. 895 92


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