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)

A lambda gt10 bovine brain and a lambda gt11 bovine heart cDNA library were screened with oligonucleotide probes corresponding to partial protein sequences directly determined from the isolated 51-kDa subunit of the bovine respiratory-chain NADH dehydrogenase. Clones were isolated that encode a protein of 464 amino acids containing all the 11 partial tryptic peptide sequences determined from the 51-kDa subunit. The size and amino acid composition of this protein agree with those determined for the purified 51-kDa subunit. Furthermore, this protein contains a putative NADH-binding domain, a possible FMN-binding site, and a putative binding site for an iron-sulfur cluster. The above evidence indicates that the cloned protein is the 51-kDa subunit or its precursor. A search for sequence similarity with proteins in the Protein Identification Resource data base has revealed that the 51-kDa subunit has 32% amino acid sequence identity with a major portion of the alpha subunit of the soluble NAD(+)-reducing hydrogenase from Alcaligenes eutrophus. In particular, there are three segments of high sequence similarity (70-88%) between the two proteins which correspond to the three ligand-binding sites.
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PMID:cDNA-derived amino acid sequence of the NADH-binding 51-kDa subunit of the bovine respiratory NADH dehydrogenase reveals striking similarities to a bacterial NAD(+)-reducing hydrogenase. 203 66

A systematic study of the effects of the synthetic glucocorticoid, methylprednisolone (MP), on respiration and energy coupling in tightly-coupled mitochondria isolated from rat tissues has been initiated. In intact rat skeletal muscle, liver and heart mitochondria, incubation, in vitro, with greater than or equal to 0.1 mM MP caused inhibition of the state 3 respiratory rates with succinate and NAD-linked substrates. In skeletal muscle and heart mitochondria, the oxidation of succinate was significantly more sensitive to MP than was that of the NAD-linked substrates. No effects were seen at low concentrations (less than 0.02 mM) of MP. In all three tissues, these data together with analysis of the partial reactions of the electron transport chain and steady-state kinetic analysis of cytochrome reduction indicated that in isolated mitochondria high concentrations of MP: (a) inhibit the oxidation of NAD-linked substrates at the level of the respiratory chain between the primary NADH dehydrogenase flavoprotein and coenzyme Q, most likely at the iron-sulfur centers or coenzyme Q-binding proteins of complex I; and (b) inhibit succinate oxidation in intact (but not disrupted) mitochondria, not by inhibiting electron transfer along the respiratory chain, but possibly at the level of succinate transport into the mitochondria. The results of these studies suggest that the therapeutic effects of MP in mitochondrial disease result from indirect effects rather than direct effects on the mitochondrial membrane. More importantly, the absence of an effect at low MP concentrations provides the baseline information needed for further studies to be carried out in vivo.
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PMID:In vitro effects of glucocorticoid on mitochondrial energy metabolism. 204 73

Some inflammatory mediators have been studied for their influence on the energy reactions of the liver mitochondria. Mediators were injected intraperitoneally to rats 15 min before decapitation in the following doses (per 100 g of the body) weight: histamine--0.5 mg, serotonin--0.5 mg, bradykinin--0.2 mg, andekalin--0.5 units. Histamine action in the body is connected with modification of the respiratory mitochondria chain and, like the oligomycin action, is directed to attended oxidation and phosphorylation points. Serotonin increases the mitochondria sensitivity to separating agents in succinate oxidation. It is supposed that serotonin-induced inhibition of oxidation of NAD-dependent substances is connected with NADH2 dehydrogenase inhibition or transhydrogenase reaction activation. Bradykinin has activated NAD-dependent substance oxidation and increased respiratory chain sensitivity on the SoQ link to 2,4-dinitrophenol action. Andekalin exerts an analogous effect intensifying ADP-, DNP- and Ca-stimulated respiration of mitochondria during succinate oxidation. Mechanism of the inflammatory mediators influence on the energy metabolism is discussed.
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PMID:[Effect of inflammatory mediators on respiration in rat liver mitochondria]. 208 96

Complex I catalyzed the NADH-oxidase and NADH-Q reductase reactions with a pH-dependent lag-phase. The enzyme activated during a short-term aerobic incubation remained active for a relatively long period of time (tens of minutes at 25 degrees C). Similar NADH-induced slow changes in the activity of the reverse electron transfer were found earlier in our laboratory. The synchronous change of the enzyme activity in the forward and reverse directions points to the existence of the slowly interconverting states of complex I, namely, an active state catalyzing the NADH oxidation and delta mu H(+)-dependent NAD+ reduction and an inactive state.
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PMID:[Activation of complex I in the reaction of NADH oxidation and delta mu H+-dependent NAD+ reduction by succinate]. 211 Nov 81

The NADH dehydrogenase complex isolated from Paracoccus denitrificans is composed of approximately 10 unlike polypeptides and contains noncovalently bound FMN, non-heme iron, and acid-labile sulfide [Yagi, T. (1986) Arch. Biochem. Biophys. 250, 302-311]. When the Paracoccus NADH dehydrogenase complex was irradiated by UV light in the presence of [adenylate-32P]NAD, radioactivity was incorporated exclusively into one of three polypeptides of Mr approximately 50,000. Similar results were obtained when [adenylate-32P]NADH was used. The labeling of the Mr 50,000 polypeptide was diminished when UV irradiation of the enzyme with [adenylate-32P]NAD was performed in the presence of NADH, but not in the presence of NADP(H). The labeled polypeptide was isolated by preparative sodium dodecyl sulfate gel electrophoresis and was shown to cross-react with antiserum to the NADH-binding subunit (Mr = 51,000) of bovine NADH-ubiquinone oxidoreductase. Its amino acid composition was also very similar to that of the bovine NADH-binding subunit. These chemical and immunological results indicate that the Mr 50,000 polypeptide is an NADH-binding subunit of the Paracoccus NADH dehydrogenase complex.
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PMID:Identification of the NADH-binding subunit of NADH-ubiquinone oxidoreductase of Paracoccus denitrificans. 211 69

The fuel preference of human muscle mitochondria has been given. Substrates which are oxidized with low velocity cannot be used to detect defects in oxidative phosphorylation. After general anaesthesia, the oxygen uptake with the different substrates is much lower than after local analgesia. The latter was therefore used in the subsequent study. In 15 out of 18 patients with ocular myopathy, defects in oxidative phosphorylation could be detected in isolated muscle mitochondria prepared from freshly biopsied tissue. Measurement of the activity of segments of the respiratory chain in homogenate from frozen muscle showed no, or minor defects. In two of these patients showing exercise intolerance, decreased oxidation of NAD(+)-linked substrates and apparently normal mitochondrial DNA, further study revealed deficiency of pyruvate dehydrogenase in a girl with ptosis and a high Km of complex I for NADH in a man. Both patients responded to vitamin therapy.
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PMID:Oxidative phosphorylation in human muscle in patients with ocular myopathy and after general anaesthesia. 211 84

NADH-ubiquinone reductase of bovine heart submitochondrial particles as prepared is unable to catalyze either the direct or reverse electron transfer from NADH to ubiquinone. The deactivated state of the enzyme in coupled particles was revealed as: (i) the absence of the rotenone-sensitive, delta mu H(+)-dependent succinate-ferricyanide reductase activity; (ii) a prominent lag in the aerobic succinate-supported, delta mu H(+)-dependent NAD+ reduction; and (iii) a lag in the rotenone-sensitive NADH-ubiquinone reductase or NADH oxidase activities. Being inactive as NADH-ubiquinone reductase (direct or reverse), the enzyme is fully active as rotenone-insensitive NADH-ferricyanide reductase. The enzyme can be activated by preincubation with substrates (NADH or NADPH) only under the conditions where the turnover of the NADH-ubiquinone reductase reaction (but not in the NADH-ferricyanide reductase) occurs. Partial activation of the enzyme was observed when the particles were preincubated with rotenone. Neither NADH under the conditions when the ubiquinone pool was reduced nor succinate plus delta mu H+ or dithionite were able to activate the enzyme. Once activated, the enzyme remains in the active state for quite a long time (more than 5 h at 0 degree C). The deactivation rate is extremely temperature-dependent, being insensitive to NAD+, ferricyanide or succinate. A comparison of the enzyme activation/deactivation kinetics showed that the same mechanism is involved in the slow activation of the direct and reverse electron transfer from NADH to ubiquinone. Activated particles catalyze the aerobic delta mu H(+)-dependent succinate-supported reverse electron transfer in the absence of ATP at a rate comparable with that of NADH-ubiquinone reductase.
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PMID:Slow active/inactive transition of the mitochondrial NADH-ubiquinone reductase. 211 5

Defects of complex I of the mitochondrial respiratory chain are important causes of neurological disease. We report studies that demonstrate a severe deficiency of complex I activity with less severe abnormalities of complexes III and IV (less than 5, 63, and 30% of control values, respectively) in a skeletal muscle mitochondrial fraction from a 22-yr-old female with weakness, lactic acidemia, and the deposition of intramuscular neutral lipid. The observation that lipid accumulates in this and other patients with complex I deficiency suggests impaired mitochondrial fatty acid oxidation. To investigate this mechanism we have shown impaired flux through beta-oxidation [( U-14C]hexadecanoate oxidation was 66% of control rate) and accumulation of specific acyl-CoA ester intermediates. The changes in fatty acid metabolism in complex I deficiency are secondary to the reduced state within the mitochondrial matrix with low NAD+/NADH ratios.
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PMID:Impaired mitochondrial beta-oxidation in a patient with an abnormality of the respiratory chain. Studies in skeletal muscle mitochondria. 215 51

Several NAD(P)H-dependent ferri-reductase activities were detected in sub-cellular extracts of the yeast Saccharomyces cerevisiae. Some were induced in cells grown under iron-deficient conditions. At least two cytosolic iron-reducing enzymes having different substrate specificities could contribute to iron assimilation in vivo. One enzyme was purified to homogeneity: it is a flavoprotein (FAD) of 40 kDa that uses NADPH as electron donor and Fe(III)-EDTA as artificial electron acceptor. Isolated mitochondria reduced a variety of ferric chelates, probably via an 'external' NADH dehydrogenase, but not the siderophore ferrioxamine B. A plasma membrane-bound ferri-reductase system functioning with NADPH as electron donor and FMN as prosthetic group was purified 100-fold from isolated plasma membranes. This system may be involved in the reductive uptake of iron in vivo.
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PMID:Iron-reductases in the yeast Saccharomyces cerevisiae. 218 97

N-Arylazido-beta-alanyl-NAD+ [N3'-O-(3-[N-(4-azido-2-nitrophenyl)amino]propionyl)NAD+] has been prepared by alkaline phosphatase treatment of arylazido-beta-alanyl-NADP+ [N3'-O-(3-[N-(4-azido-2-nitrophenyl)amino]propionyl)NADP+]. This NAD+ analogue was found to be a potent competitive inhibitor (Ki = 1.45 microM) with respect to NADH for the purified bovine heart mitochondrial NADH dehydrogenase (EC 1.6.99.3). The enzyme was irreversibly inhibited as well as covalently labeled by this analogue upon photoirradiation. A stoichiometry of 1.15 mol of N-arylazido-beta-alanyl-NAD+ bound/mol of enzyme, at 100% inactivation, was determined from incorporation studies using tritium-labeled analogue. Among the three subunits, 0.85 mol of the analogue was bound to the Mr = 51,000 subunit, and each of the two smaller subunits contained 0.15 mol of the analogue when the dehydrogenase was completely inhibited upon photolysis. Both the irreversible inactivation and the covalent incorporation could be prevented by the presence of NADH during photolysis. These results indicate that N-arylazido-beta-alanyl-NAD+ is an active-site-directed photoaffinity label for the mitochondrial NADH dehydrogenase, and are further evidence that the Mr = 51,000 subunit contains the NADH binding site. Previous studies using A-arylazido-beta-alanyl-NAD+ [A3'-O-(3-[N-(4-azido-2-nitrophenyl)amino]propionyl)NAD+] demonstrated that the NADH binding site is on the Mr = 51,000 subunit [Chen, S., & Guillory, R. J. (1981) J. Biol. Chem. 256, 8318-8323]. Results are also presented to show that N-arylazido-beta-alanyl-NAD+ binds the dehydrogenase in a more effective manner than A-arylazido-beta-alanyl-NAD+.
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PMID:N-arylazido-beta-alanyl-NAD+, a new NAD+ photoaffinity analogue. Synthesis and labeling of mitochondrial NADH dehydrogenase. 234 Feb 77


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