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: UNIPROT:Q16795 (ubiquinone)
5,455 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ethanol non-drinker (UChA) and drinker (UChB) rat lines derived from an original Wistar colony have been selectively bred at the University of Chile for over 70 generations. Two main differences between these lines are clear. (1) Drinker rats display a markedly faster acute tolerance than non-drinker rats. In F2 UChA x UChB rats (in which all genes are 'shuffled'), a high acute tolerance of the offspring predicts higher drinking than a low acute tolerance. It is further shown that high-drinker animals 'learn' to drink, starting from consumption levels that are one half of the maximum consumptions reached after 1 month of unrestricted access to 10% ethanol and water. It is likely that acquired tolerance is at the basis of the increases in ethanol consumption over time. (2) Non-drinker rats carry a previously unreported allele of aldehyde dehydrogenase-2 (Aldh2) that encodes an enzyme with a low affinity for Nicotinamide-adenine-dinuclectide (NAD+) (Aldh2(2)), while drinker rats present two Aldh2 alleles (Aldh2(1) and Aldh2(3)) with four- to fivefold higher affinities for NAD+. Further, the ALDH2 encoded by Aldh2(1) also shows a 33% higher Vmax than those encoded by Aldh2(2) and Aldh2(3). Maximal voluntary ethanol intakes are the following: UChA Aldh2(2)/Aldh2(2) = 0.3-0.6 g/kg/day; UChB Aldh2(3)/Aldh2(3) = 4.5-5.0 g/kg/day; UChB Aldh2(1)/Aldh2(1) = 7.0-7.5 g/kg/day. In F2 offspring of UChA x UChB, the Aldh2(2)/Aldh2(2) genotype predicts a 40-60% of the alcohol consumption. Studies also show that the low alcohol consumption phenotype of Aldh2(2)/Aldh2(2) animals depends on the existence of a maternally derived low-activity mitochondrial reduced form of nicotinamide-adenine-dinucleotide (NADH)-ubiquinone complex I. The latter does not influence ethanol consumption of animals exhibiting an ALDH2 with a higher affinity for NAD+. An illuminating finding is the existence of an 'acetaldehyde burst' in animals with a low capacity to oxidize acetaldehyde, being fivefold higher in UChA than in UChB animals. We propose that such a burst results from a great generation of acetaldehyde by alcohol dehydrogenase in pre-steady-state conditions that is not met by the high rate of acetaldehyde oxidation in mitochondria. The acetaldehyde burst is seen despite the lack of differences between UChA and UChB rats in acetaldehyde levels or rates of alcohol metabolism in steady state. Inferences are drawn as to how these studies might explain the protection against alcoholism seen in humans that carry the high-activity alcohol dehydrogenase but metabolize ethanol at about normal rates.
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PMID:The UChA and UChB rat lines: metabolic and genetic differences influencing ethanol intake. 1696 61

Mammalian mitochondrial dihydrolipoamide dehydrogenase (DLDH, EC 1.8.1.4) catalyzes NAD(+)-dependent oxidation of dihydrolipoamide in vivo and can also act as a diaphorase catalyzing in vitro nicotinamide adenine dinucleotide (reduced form) (NADH)-dependent reduction of electron-accepting molecules such as ubiquinone and nitroblue tetrazolium (NBT). In this paper, we report a gel-based method for histochemical staining and quantification of DLDH diaphorase activity using blue native PAGE (BN-PAGE). Rat brain mitochondrial extracts, used as the source of DLDH, were resolved by nongradient BN-PAGE (9%), which was followed by diaphorase activity staining using NADH as the electron donor and NBT as the electron acceptor. It was shown that activity staining of DLDH diaphorase was both protein amount- and time-dependent. Moreover, this in-gel activity-staining method was demonstrated to be in good agreement with the conventional spectrophotometric method that measures DLDH dehydrogenase activity using dihydrolipoamide as the substrate. The method was applied to determine levels of DLDH diaphorase activity in several rat tissues other than the brain, and the results indicated a similar level of DLDH diaphorase activity for all the tissues examined. Finally, the effects of thiol-reactive reagents such as N-ethylmaleimide (NEM) and nitric oxide donors on DLDH diaphorase activity were evaluated, demonstrating that, with this method, DLDH diaphorase activity can be determined without having to remove these thiol-reactive reagents that may otherwise interfere with spectrophotometric measurement of DLDH dehydrogenase activity. The gel-based method can also be used as a means to isolate mitochondrial DLDH that is to be analyzed by mass spectral techniques in studying DLDH post-translational modifications.
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PMID:Histochemical staining and quantification of dihydrolipoamide dehydrogenase diaphorase activity using blue native PAGE. 1731 58

We present here the sequence of the mitochondrial DNA of the pathogenic thermodimorphic fungus Paracoccidioides brasiliensis, agent of an endemic disease in most South American countries. The sequenced genome has 71 334 bp and is organized as a circular molecule with two gaps of unknown size flanking the middle exon of the nad5 gene. We located genes coding for the three subunits of the ATP synthase (atp6, atp8 and atp9), the apocytochrome b (cob), three subunits of the cytochrome c oxidase enzyme complex (cox1, cox2 and cox3), seven subunits of the reduced nicotinamide adenine dinucleotide ubiquinone oxidoreductase (nad1, nad2, nad3, nad4, nad5, nad6 and nad4L) and the large (rnl) and small (rns) subunits of ribosomal RNA. Two maturases and a ribosomal protein (rms5) are located inside introns. Twenty-five tRNAs were identified with acceptors for all 20 amino acids. Seven polypurine/polypyrimidine tracts (140-240 bp) have been found in this genome. All genes are in the same orientation over the genome, while their order is closest to the mitochondrial genomes from Penicillium marneffei and Aspergillus nidulans.
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PMID:The mitochondrial genome from the thermal dimorphic fungus Paracoccidioides brasiliensis. 1749 1

Human cytomegalovirus infection perturbs multiple cellular processes that could promote the release of proapoptotic stimuli. Consequently, it encodes mechanisms to prevent cell death during infection. Using rotenone, a potent inhibitor of the mitochondrial enzyme complex I (reduced nicotinamide adenine dinucleotide-ubiquinone oxido-reductase), we found that human cytomegalovirus infection protected cells from rotenone-induced apoptosis, a protection mediated by a 2.7-kilobase virally encoded RNA (beta2.7). During infection, beta2.7 RNA interacted with complex I and prevented the relocalization of the essential subunit genes associated with retinoid/interferon-induced mortality-19, in response to apoptotic stimuli. This interaction, which is important for stabilizing the mitochondrial membrane potential, resulted in continued adenosine triphosphate production, which is critical for the successful completion of the virus' life cycle. Complex I targeting by a viral RNA represents a refined strategy to modulate the metabolic viability of the infected host cell.
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PMID:Complex I binding by a virally encoded RNA regulates mitochondria-induced cell death. 1764 Nov 88

NADH-ubiquinone oxidoreductase (complex I) is the first enzyme of the respiratory electron transport chain in mitochondria. It conserves the energy from NADH oxidation, coupled to ubiquinone reduction, as a proton motive force across the inner membrane. Complex I catalyzes NADPH oxidation, NAD+ reduction, and hydride transfers from reduced to oxidized nicotinamide nucleotides also. Here, we investigate the transhydrogenation reactions of complex I, using four different nucleotide pairs to encompass a range of reaction rates. Our experimental data are described accurately by a ping-pong mechanism with double substrate inhibition. Thus, we contend that complex I contains only one functional nucleotide binding site, in agreement with recent structural information, but in disagreement with previous mechanistic models which have suggested that two different binding sites are employed to catalyze the two half reactions. We apply the Michaelis-Menten equation to describe the productive states formed when the nucleotide and the active-site flavin mononucleotide have complementary oxidation states, and dissociation constants to describe the nonproductive states formed when they have the same oxidation state. Consequently, we derive kinetic and thermodynamic information about nucleotide binding and interconversion in complex I, relevant to understanding the mechanisms of coupled NADH oxidation and NAD+ reduction, and to understanding how superoxide formation by the reduced flavin is controlled. Finally, we discuss whether NADPH oxidation and/or transhydrogenation by complex I are physiologically relevant processes.
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PMID:Transhydrogenation reactions catalyzed by mitochondrial NADH-ubiquinone oxidoreductase (Complex I). 1800 Nov 42

Proton pump inhibitors exert their preventive and healing effects on gastropathy induced by nonsteroidal anti-inflammatory drug (NSAIDs) by a dual action: the antisecretory and the antioxidant effect. The latter was investigated by using esomeprazole against indomethacin-induced gastric mucosa lesions in rats and assessed by a histomorphometric analysis. Treatment by intragastric gavage were 1% methocel as vehicle; esomeprazole 10, 30, or 60 micromol/kg; indomethacin 100 micromol/kg; and esomeprazole 10, 30, or 60 micromol/kg plus indomethacin 100 micromol/kg. The evaluation of glutathione (GSH) levels and respiratory chain complex activities [nicotinamide adenine dinucleotide, reduced (NADH)-ubiquinone oxidoreductase, succinate dehydrogenase, cytochrome C reductase, cytochrome oxidase] was performed in the isolated gastric mucosa. Esomeprazole (10-60 micromol/kg) dose dependently reversed, up to complete recovery, the inhibitory effect of indomethacin on GSH levels (approximately 60% inhibition) and mitochondrial enzyme activities (inhibition ranging from 60% to 75%). Indomethacin-induced mucosal injuries were reduced by esomeprazole. Thus, in addition to inhibiting acid secretion, the gastroprotective effect of esomeprazole can be ascribed to a reduction in gastric oxidative injury.
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PMID:Effects of esomeprazole on glutathione levels and mitochondrial oxidative phosphorylation in the gastric mucosa of rats treated with indomethacin. 1854 84

Reduced activity of CLK-1/MCLK1 (also known as COQ7), a mitochondrial enzyme that is necessary for ubiquinone biosynthesis, prolongs the lifespan of nematodes and mice by a mechanism that is distinct from that of the insulin signaling pathway. Here we show that 2-fold reduction of MCLK1 expression in mice reveals an additional function for the protein, as this level of reduction does not affect ubiquinone levels yet affects mitochondrial function substantially. Indeed, we observe that the phenotype of young Mclk1(+/-) mutants includes a severe reduction of mitochondrial electron transport, ATP synthesis, and total nicotinamide adenine dinucleotide (NAD(tot)) pool size as well as an alteration in the activity of key enzymes of the tricarboxylic acid cycle. Surprisingly, we also find that Mclk1 heterozygosity leads to a dramatic increase in mitochondrial oxidative stress by a variety of measures. Furthermore, we find that the mitochondrial dysfunction is accompanied by a decrease in oxidative damage to cytosolic proteins as well as by a decrease in plasma isoprostanes, a systemic biomarker of oxidative stress and aging. We propose a mechanism for the conjunction of low ATP levels, high mitochondrial oxidative stress, and low non-mitochondrial oxidative damage in a long-lived mutant. Our model helps to clarify the relationship between energy metabolism and the aging process and suggests the need for a reformulation of the mitochondrial oxidative stress theory of aging.
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PMID:Early mitochondrial dysfunction in long-lived Mclk1+/- mice. 1863 41

Complex I or reduced nicotinamide adenine dinucleotide (NADH): ubiquinone oxydoreductase deficiency is the most common cause of respiratory chain defects. Molecular bases of complex I deficiencies are rarely identified because of the dual genetic origin of this multi-enzymatic complex (nuclear DNA and mitochondrial DNA) and the lack of phenotype-genotype correlation. We used a rapid method to screen patients with isolated complex I deficiencies for nuclear genes mutations by Surveyor nuclease digestion of cDNAs. Eight complex I nuclear genes, among the most frequently mutated (NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1 and NDUFV2), were studied in 22 cDNA fragments spanning their coding sequences in 8 patients with a biochemically proved complex I deficiency. Single nucleotide polymorphisms and missense mutations were detected in 18.7% of the cDNA fragments by Surveyor nuclease treatment. Molecular defects were detected in 3 patients. Surveyor nuclease screening is a reliable method for genotyping nuclear complex I deficiencies, easy to interpret, and limits the number of sequence reactions. Its use will enhance the possibility of prenatal diagnosis and help us for a better understanding of complex I molecular defects.
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PMID:Rapid screening for nuclear genes mutations in isolated respiratory chain complex I defects. 1916 55

NADH:ubiquinone oxidoreductase (complex I) is a complicated respiratory chain enzyme that conserves the energy from NADH oxidation, coupled to ubiquinone reduction, as a proton motive force across the mitochondrial inner membrane. Alternatively, NADH oxidation, by the flavin mononucleotide in complex I, can be coupled to the reduction of hydrophilic electron acceptors, in non-energy-transducing reactions. The reduction of molecular oxygen and hydrophilic quinones leads to the production of reactive oxygen species, the reduction of nicotinamide nucleotides leads to transhydrogenation, and "artificial" electron acceptors are widely used to study the mechanism of NADH oxidation. Here, we use a combined modeling strategy to accurately describe data from three flavin-linked electron acceptors (molecular oxygen, APAD(+), and ferricyanide), in the presence and absence of a competitive inhibitor, ADP-ribose. Our combined ping-pong (or ping-pong-pong) mechanism comprises the Michaelis-Menten equation for the reactions of NADH and APAD(+), simple dissociation constants for nonproductive nucleotide-enzyme complexes (defined for specific flavin oxidation states), and second-order rate constants for the reactions of ferricyanide and oxygen. The NADH-dependent parameters are independent of the identity of the electron acceptor. In contrast, a further flavin-linked acceptor, hexaammineruthenium(III), does not obey ping-pong-pong kinetics, and alternative sites for its reaction are discussed. Our analysis provides kinetic and thermodynamic information about the reactions of the flavin active site in complex I that is relevant to understanding the physiologically relevant mechanisms of NADH oxidation and superoxide formation.
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PMID:Reactions of the flavin mononucleotide in complex I: a combined mechanism describes NADH oxidation coupled to the reduction of APAD+, ferricyanide, or molecular oxygen. 1989 8

The mitochondrial (mt) genomes of two soybean rust pathogens, Phakopsora pachyrhizi and P. meibomiae, have been sequenced. The mt genome of P. pachyrhizi is a circular 31 825-bp molecule with a mean GC content of 34.6%, while P. meibomiae possesses a 32 520-bp circular molecule with a mean GC content of 34.9%. Both mt genomes contain the genes encoding ATP synthase subunits 6, 8 and 9 (atp6, atp8 and atp9), cytochrome oxidase subunits I, II and III (cox1, cox2 and cox3), apocytochrome b (cob), reduced nicotinamide adenine dinucleotide ubiquinone oxidoreductase subunits (nad1, nad2, nad3, nad4, nad4L, nad5 and nad6), the large and small mt ribosomal RNA genes, one ORF coding for a ribosomal protein (rps3), and a set of 24 tRNA genes that recognize codons for all amino acids. The order of the protein-coding genes and tRNA is identical in the two Phakopsora species, and all genes are transcribed from the same DNA strand clockwise. Introns were identified in the cox1, cob and mnl genes of both species, with three of the introns having ORFs with motifs similar to the LAGLIDADG endonucleases of other fungi. Phylogenetic analysis of the 14 shared protein-coding genes agrees with commonly accepted fungal taxonomy.
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PMID:Analysis of the complete mitochondrial genome sequences of the soybean rust pathogens phakopsora pachyrhizi and p. meibomiae. 2064 55


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