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)

The plastid DNA of higher plants contains eleven reading frames that are homologous to subunits of the mitochondrial NADH-ubiquinone oxidoreductase (complex I). The genes are expressed, but a plastid NAD(P)H dehydrogenase has not yet been isolated and the function of the enzyme in plastid metabolism is unknown. Cyanobacteria also contain a NADH dehydrogenase that is homologous to the mitochondrial complex I. The enzyme is sensitive to rotenone and is located on the cytoplasmic and the thylakoid membrane. We report here the sequence of five subunits (ndhA, -I, G, -E and -D) of the NADH dehydrogenase from the unicellular cyanobacterium Synechocystis sp. PCC6803. As in plastid DNA, the genes ndh(A-I-G-E) are clustered and probably constitute an operon. The ndhD gene is associated with a gene encoding an iron-sulphur protein of photosystem I (psaC) as in plastid DNA. In contrast to the situation in plastids, psaC and ndhD are not cotranscribed but transcribed from opposite strands. The deduced amino acid sequence of the cyanobacterial polypeptides is more similar to the corresponding plastid (40-68% identity) than to the corresponding mitochondrial subunits (17-39% identity). Thus, the cyanobacterial NADH-dehydrogenase provides a prokaryotic model system which is more suitable to genetic analysis than the enzyme of plastids.
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PMID:Cloning and transcription analysis of the ndh(A-I-G-E) gene cluster and the ndhD gene of the cyanobacterium Synechocystis sp. PCC6803. 146 44

Previous work has shown that irrespective of the route of exposure methyl isocyanate (MIC) caused acute lactic acidosis in rats (Jeevaratnam et al., Arch. Environ. Contam. Toxicol. 19, 314-319, 1990) and the hypoxia was of stagnant type due to tissue hypoperfusion resulting from hypovolemic hypotension in rabbits administered MIC subcutaneously (Jeevarathinam et al., Toxicology 51, 223-240, 1988). The present study was designed to investigate whether MIC could induce histotoxic hyperoxia through its effects on mitochondrial respiration. Male Wistar rats were used for liver mitochondrial and submitochondrial particle (SMP) preparation. Addition of MIC to tightly coupled mitochondria in vitro resulted in stimulation of state 4 respiration, abolition of respiratory control, decrease in ADP/O ratio, and inhibition of state 3 oxidation. The oxidation of NAD(+)-linked substrates (glutamate + malate) was more sensitive (five- to sixfold) to the inhibitory action of MIC than succinate while cytochrome oxidase remained unaffected. MIC induced twofold delay in the onset of anerobiosis, and cytochrome b reduction in SMP with NADH in vitro confirms inhibition of electron transport at complex I region. MIC also stimulated the ATPase activity in tightly coupled mitochondria while lipid peroxidation remained unaffected. As its hydrolysis products, methylamine and N,N'-dimethylurea failed to elicit any change in vitro; these effects reveal that MIC per se acts as an inhibitor of electron transport and a weak uncoupler. Administration of MIC sc at lethal dose caused a similar change only with NAD(+)-linked substrates, reflecting impairment of mitochondrial respiration at complex I region and thereby induction of histotoxic hypoxia in vivo.
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PMID:In vitro and in vivo effect of methyl isocyanate on rat liver mitochondrial respiration. 147 Nov 48

There is increasing evidence that defective function of the mitochondrial enzyme NADH CoQ reductase (complex I) is involved not only in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, but also in idiopathic Parkinson's disease (PD). Complex I deficiency has been identified in PD substantia nigra and appears to be disease-specific and selective for the substantia nigra within the central nervous system. We describe a method for preparation of an enriched mitochondrial fraction from 60 mL blood. Using this technique, we analyzed respiratory chain function in 25 patients with PD and 15 matched control subjects. We confirm a previous report of a specific complex I deficiency in PD platelet mitochondria. Although there was a statistically significant decrease in complex I activity in the PD group compared with the control group (p = 0.005), the defect was mild (16%); it was not possible to distinguish PD from control values on an individual basis. This deficiency is not detectable in platelet whole-cell homogenates, presumably reflecting the relative insensitivity of this preparation and the limited decrease in complex I activity in PD. The presence of a mild complex I defect in platelets together with a more severe defect in substantia nigra suggests either that the pharmacological characteristics shared by these two tissues render them susceptible to a particular toxin or toxins, or that the defect is widely distributed and other biochemical events enhance the deficiency in substantia nigra.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelet mitochondrial function in Parkinson's disease. The Royal Kings and Queens Parkinson Disease Research Group. 147 69

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

A technique is described for the isolation and purification of intact, respiratory-competent mitochondria from Schizosaccharomyces pombe. The purified mitochondria are capable of oxidizing NADH and succinate as respiratory substrates, indicating the presence of succinate dehydrogenase and an NADH dehydrogenase located on the outer surface of the inner membrane. Mitochondria display good respiratory control with an ADP/O ratio of < 2. Respiratory activity is linearly dependent upon the redox poise of the quinone pool, suggesting the presence of an unbranched respiratory pathway to molecular oxygen. Immunogold labelling using antisera raised against mitochondrial HSP70 proteins (SSP1, SSC1 and PHSP1) from three different species, namely S. pombe, Saccharomyces cerevisiae and the plant Pisum sativum respectively, has been used to investigate the presence and ultrastructure of the mitochondria isolated by this procedure. The immunocytochemistry was carried out using cells containing wild-type levels of SSP1 protein and cells over-expressing the protein. These results also demonstrate the capacity of mitochondria to import increased levels of protein in vivo. In vitro import experiments using COXIV-DHFR indicate that purified S. pombe mitochondria can efficiently import this precursor, and that protein translocation is dependent upon an oxidizable substrate and a membrane potential.
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PMID:Schizosaccharomyces pombe mitochondria: morphological, respiratory and protein import characteristics. 148 70

The interaction of fungal quinone pigments bostricoidin, fusarubin, javanicin, and 2-oxyjuglone with mitochondrial NADH:ubiquinone reductase (complex I, EC 1.6.99.3) has been studied. The bimolecular rate constants (turnover number (TN)/Km) of rotenone-insensitive reduction of these compounds are in the range of 1.2 x 10(4)-1.6 x 10(5) M-1s-1. 2-Oxyjuglone acts as inhibitor of NADH:ferricyanide reductase reaction of complex I (KI = 30 microM). All quinone pigments, except javanicin, decrease the TN of reduction of 5,8-dioxy-1,4-naphtoquinone being reduced at its binding site but with significantly lower TN. They do not affect the rotenone-sensitive reduction of ubiquinone-1. The binding of quinone pigments close to the NADH and ferricyanide binding site is suggested. It seems that quinone pigments, especially 2-oxyjuglone, react with complex I faster than it follows from their approximate values of one-electron reduction potential calculated from their reactivities with flavocychrome b2 and adrenodoxin.
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PMID:Fungal quinone pigments as oxidizers and inhibitors of mitochondrial NADH:ubiquinone reductase. 149 45

In the cattle filarial parasite, Setaria digitata, the mitochondria-like particles have been shown to possess site I associated oxidative phosphorylation and rotenone sensitive and insensitive pathways for the dehydrogenation of NADH. Quinone depleted mitochondria-like particles show a loss of activity of these NADH dehydrogenases and also a complete loss of fumarate reductase activity. Reconstitution with quinone restores both NADH linked oxygen uptake and fumarate reductase activity. Thus activities of complex I and fumarate reductase are linked to quinone. Hence an inhibitor at the level of quinone can simultaneously block both aerobic and anaerobic pathways which drive ATP production and may prove useful in the effective control of filariasis.
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PMID:Quinone dependent NADH dehydrogenation in mitochondria-like particles from Setaria digitata, a filarial parasite. 149 58

Citrate is fermented by Klebsiella pneumoniae to 2 acetate, 0.5 formate and 1.2 CO2. The formation of less than 1 formate and greater than 1 CO2 per citrate can be accounted for by the oxidation of formate to CO2 in order to provide reducing equivalents for the assimilation of citrate into cell carbon. A membrane-bound electron transport chain is apparently involved in NADH synthesis by these cells. The electrons from formate oxidation to CO2 are used to reduce ubiquinone to ubiquinol by membrane-bound formate dehydrogenase and ubiquinol further delivers its electrons to NAD+, if this endergonic reaction is powered by delta mu Na+. The endogenous NADH level of K. pneumoniae cells thus increased in the presence of formate in response to a delta pNa+ greater than -100 mV. NADH formation was completely abolished in the presence of oxygen or after addition of hydroxyquinoline-N-oxide, a specific inhibitor of the Na(+)-translocating NADH:ubiquinone oxidoreductase. The increase of endogenous NADH was dependent on the delta pNa+ applied to the cells. Inverted membrane vesicles of K. pneumoniae catalysed the reduction of NAD+ to NADH with formate as electron donor after application of delta mu Na+ of about 120 mV consisting of delta pNa+ of 60 mV and delta psi of the same magnitude. Neither the delta pNa+ nor the delta psi of this size alone was sufficient to drive the endergonic reaction. Strictly anaerobic conditions were required for NADH formation and hydroxyquinoline-N-oxide completely inactivated the reaction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:NADH formation by Na(+)-coupled reversed electron transfer in Klebsiella pneumoniae. 150 43

There is increasing evidence for a defect of mitochondrial respiratory chain function in Parkinson's disease. Specific NADH CoQ1 reductase (complex I) deficiency has been identified in the substantia nigra. Available evidence suggests that this defect is confined to the substantia nigra and is not present elsewhere in the parkinsonian brain. The absence of a detectable mitochondrial abnormality in the substantia nigra of patients with multiple system atrophy also suggests that the complex I deficiency in Parkinson's disease is not simply due to an artifact of neuronal degeneration. Evidence for abnormal mitochondrial function in skeletal muscle is conflicting; two studies showed multiple respiratory chain defects and one study was unable to demonstrate any deficiency. A severe deficiency of complex I activity has been found in platelet mitochondria from parkinsonian patients. This finding has not as yet been confirmed. Platelet homogenates do not show the complex I deficiency, however, suggesting that such a preparation may be too insensitive to detect the defect. The role of complex I deficiency in the events that culminate in dopaminergic cell death in Parkinson's disease remains unresolved. It is likely that if this mitochondrial defect is confirmed, it will be related to a number of other factors, including environmental agents, oxidative stress, and genetic predisposition.
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PMID:Mitochondrial function in Parkinson's disease. The Royal Kings and Queens Parkinson's Disease Research Group. 151 Mar 69

We measured metabolites of tyrosine and tryptophan (TRP) in the frontal cortex, putamen (PT), and pars compacta of the substantia nigra (SN) of control and Parkinson's disease (PD) brain tissues. Dopamine concentrations were significantly decreased in the PT and SN of PD tissue, regardless of L-dopa therapy. However, 3-O-methyldopa (3OMD) concentration showed a significant increase in each region of the PD group treated with L-dopa (PD[+]) as compared with both the control group and the PD group without L-dopa therapy (PD[-]). Therefore, 3OMD concentration appears to be a reliable marker of L-dopa therapy. Serotonin concentration was lower in each region of the PD groups than in the control group. Although the magnitude of decrease was greater in the PD(+) group, there was no statistical significance between the two PD groups. The same patterns of decrease were present in kynurenine (KYN) and kynurenic acid (KYA) concentrations, but the molar ratios of TRP to KYN and KYN to KYA were unchanged among three groups. In contrast, 3-hydroxykynurenine (3OHKY) concentration was increased in the PT PD(-) group and in three regions of the PD(+) group. Since the KYN pathway leads to formation of nicotinamide-adenine dinucleotide (NADH), the present results may be a further indication of a defect in NADH:ubiquinone oxidoreductase (complex I) in mitochondria in PD.
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PMID:Kynurenine pathway abnormalities in Parkinson's disease. 151 57


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