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 strain carrying a point mutation affecting the NADH dehydrogenase complex of Escherichia coli has been isolated and its properties examined. The gene carrying the mutation (designated ndh) was located on the E. coli chromosome at about minute 23 and was shown to be cotransducible with the pyrC gene. Strain carrying the ndh- allele were found to be unable to grow on mannitol and to grow very poorly on glucose unless the medium was supplemented with succinate, acetate or casamino acids. The following properties of strains carrying the ndh- allele were established which suggest that the mutation affects the NADH dehydrogenase complex but apparently not the primary dehydrogenase. Membrane preparations possess normal to elevated levels of D-lactate oxidase and succinate oxidase activities but NADH oxidase is absent. NADH is unable to reduce ubiquinone in the aerobic steady state and reduces cytochrome b very slowly when the membranes become anaerobic. NADH dehydrogenase, measured as NADH-dichlorophenolindophenol reductase is reduced but not absent. NADH oxidase is stimulated by menadione although not by Q-3 or MK-1 and in the presence of menadione, cytochrome b is reduced normally by NADH. Further mutants affected in NADH oxidase were isolated using a screening procedure based on the growth characteristics of the original ndh- strain. The mutantions carried by these strains were all cotransducible with the pyrC gene and the biochemical properties of the additional mutants were similar to those of the original mutant. The properties of the group of ndh- mutants established so far suggest that they are affected in the transfer of reducing equivalents from the NADH dehydrogenase complex to ubiquinone.
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PMID:Mutations affecting the reduced nicotinamide adenine dinucleotide dehydrogenase complex of Escherichia coli. 79 16

The fungicide dexon (p-dimethylaminobenzenediazosulfonate, Na-salt) inhibits the NADH oxidase activity of submitochondrial particles (ETP) from beef heart (semi-inhibition concentration 1.4 muM), while the succinate oxidase activity is unaffected. Measurements of the activity of several enzymatic partial reactions of the respiratory chain of ETP suggest that dexon acts directly on the flavine of NADH dehydrogenase. Soluble NADH-cytochrome c-oxidoreductase (MAHLER) and rotenone-insensitive NADH ubiquinone reductase are also inhibited by dexon. At low concentrations of dexon, inhibition of ETP starts slowly only after addition of NADH. Preincubation without NADH increases the amount of inhibition, but does not prevent the time delay. It is assumed that an electron flux through the respiratory chain, or reduction of flavine is prerequisite for the reaction of dexon with the action site. Furthermore, dexon inhibits the NADH dehydrogenase located at the outer surface of the inner membrane of plant mitochondria, accessible to extramitochondrial NADH and insensitive to rotenone, as has been shown on isolated mitochondria from cauliflower (Brassica oleracea L). In addition, dexon inhibits selectively the NADH dehydrogenase of the DT diaphorase (ERNSTER) from rat liver cytosol. In contrast, the dicoumarol-insensitive NADH dehydrogenase (ZINSMEYER et al.) from rat liver cytosol, the NADH-cytochrome b5-reductase (STRITTMATTER) from rat liver microsomes, the rotenone-insensitive NADH-cytochrome c-oxidoreductase of the outer membrane of rat liver mitochondria, soluble NADH-oxidase from Escherichia coli, and NADH-dehydrogenase from human erythrocytes are not inhibited. The results suggest that dexon is a group reagent to certain pyridine nucleotide-dependent flavine enzymes.
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PMID:[Action of the systemic fungicide dexon on several NADH dehydrogenases]. 82 48

The topography of the inner mitochondrial membrane was investigated using inhibitors of electron transport on preparations of beef heart mitochondria and electron transport particles of opposite orientation. Reductions of juglone, ferricyanide, indophenol, coenzyme Q, duroquinone, and cytochrome c by NADH are inhibited to different extents on both sides of the membrane by the impermeant hydrophilic chelators bathophenanthroline sulfonate and orthophenanthroline. The extent of inhibition for each acceptor increased in the order given. At least two chelator-sensitive sites are present on each membrane face between the flavoprotein and coenzyme Q and a chelator-sensitive site is present on the matrix face between the sites of coenzyme Q and duroquinone interaction. Duroquinol oxidation in mitochondria only is stimulated by bathophenanthroline sulfonate. Juglone reduction is stimulated in electron transport particles (only) by p-hydroxymercuribenzenesulfonate, but after mercurial treatment, juglone reduction in both particles and mitochondria is more sensitive to bathophenanthroline sulfonate. Succinate dehydrogenase components are inhibited by hydrophilic orthophenanthroline or bathophenanthroline sulfonate in mitochondria only. Electron flow between the dehydrogenases of succinate and NADH occurs via a chelator-sensitive site located on the matrix face of the membrane. Inter-complex electron flow is prevented by rotenone or thenoyltrifluoroacetone. The lack of succinate-indophenol reductase inhibition by bathophenanthroline sulfonate in the presence of rotenone or thenoyltrifluoroacetone indicates that the rotenone-sensitive site may be located on the matrix face and demonstrates that electrons flow between the NADH and succinate dehydrogenases via a hydrophilic chelator and rotenone-thenoyltrifluoroacetone-sensitive site on the matrix face of the membrane. Inhibiton by hydrophilic chelators only in mitochondria indicates that succinate dehydrogenase as well as NADH dehydrogenase has a transmembranous orientation.
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PMID:Inhibition of mitochondrial electron transport by hydrophilic metal chelators. Determination of dehydrogenase topography. 94 64

A thirty-two year old female had chronic progressive external ophthalmoplegia (CPEO), exertional fatigue, dysarthria, dysphagia, and bilateral hearing impairment. Histochemical stains, obtained from the right vastus lateralis, showed ragged-red fibers and wide-spread abnormalities in the number, size, and the structure of mitochondria under electronomicroscopic examination. A biochemical analysis showed a low activity of NADH-cytochrome C reductase, NADH dehydrogenase and a normal activity of succinate cytochrome C reductase and cytochrome C oxidase. This data suggests a specific defect in the NADH dehydrogenase of complex I (NADH CoQ reductase). We believe that this is the first biochemically defined mitochondrial myopathy reported in Taiwan and provides additional evidence for the existence of biochemical heterogeneity in mitochondrial disorders of CPEO.
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PMID:Chronic progressive external ophthalmoplegia with NADH-CoQ reductase deficiency: report of a case. 132 93

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 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

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

In order to distinguish the pathways involved in the oxidation of matrix NADH in plant mitochondria, the oxidation of NADH and nicotinamide hypoxanthine dinucleotide (reduced form) was investigated in submitochondrial particles prepared from beetroot (Beta vulgaris L. cv. Derwent Globe) and soybeans (Glycine max L. cv. Bragg). Nicotinamide-hypoxanthine-dinucleotide(reduced form)-oxidase activity was more strongly inhibited by rotenone than the NADH-oxidase activity but both of the rotenone-inhibited activities could be stimulated by adding ubiquinone-1. The corresponding ubiquinone-1-reductase activities were inhibited by rotenone (to 69%) and further inhibited by N,N'-dicyclohexylcarbodiimide (to 79%), whilst the K3Fe(CN)6-reductase activities were not sensitive to either rotenone or N,N'-dicyclohexylcarbodiimide. Immunological analysis of mitochondrial proteins using an antiserum raised against purified beetroot complex I indicated very few differences between soybean and fresh and aged beetroot mitochondria, despite their varying sensitivities to rotenone. We confirm that there are two dehydrogenases capable of oxidising internal NADH and that only one of these, namely complex I, is inhibited by rotenone. Further, we conclude that complex I has two potential sites of quinone reduction, both sensitive to N,N'-dicyclohexycarbodiimide inhibition but only one of which is sensitive to rotenone inhibition.
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PMID:Matrix NADH dehydrogenases of plant mitochondria and sites of quinone reduction by complex I. 152 39

To investigate the protein-ubiquinone interaction in the bovine heart mitochondrial succinate-cytochrome c reductase region of the respiratory chain, three fluorine substituted ubiquinone derivatives, 2,3-dimethoxy-6-(9'-fluorodecyl)-1,4-benzoquinone (9FQ), 2-methoxy-5-trifluoromethyl-6-decyl-1,4-benzoquinone (TFQ), and 2-methoxy-5-trifluoromethyl-6-(9'-fluorodecyl)-1,4-benzoquinone (9FTFQ), were synthesized. 9FQ was synthesized by radical coupling of Q0 and bis(10-fluoroundecanoyl)peroxide. The latter was prepared by fluorination of undecylenic acid followed by thionylchloride treatment and peroxidation. TFQ was synthesized from 2,2,2-trifluoro-p-cresol by methylation, nitration, reduction, acetylation, nitration, reduction, oxidation, and radical alkylation. 9FTFQ was prepared by the radical alkylation of 2-methoxy-5-trifluoromethyl-1,4-benzoquinone with bis(10-fluoroundecanoyl)peroxide. All three fluoro-Q derivatives are active (greater than 50% the activity of 2,3-dimethoxy-5-methyl-6-decyl-1,4-benzoquinone) when used as electron acceptors for succinate-ubiquinone reductase. However, only 9FQ is active when used as an electron donor for ubiquinol-cytochrome c reductase or as an electron mediator for succinate-cytochrome c reductase. Both TFQ and 9FTFQ are competitive inhibitors for ubiquinol-cytochrome c reductase. A 19FNMR peak-broadening effect was observed for 9FQ when it was reconstituted with ubiquinone-depleted ubiquinol-cytochrome c reductase. A drastic up-field chemical shift was observed for TFQ when it was reconstituted with ubiquinone-depleted reductase. These results indicate that the binding environments of the benzoquinone ring and the alkyl side chain of the Q molecule are different. The strong up-field chemical shift for TFQ, and lack of significant chemical shift for 9FQ, suggest that the benzoquinone ring is bound near the paramagnetic cytochrome b heme.
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PMID:Protein-ubiquinone interaction in bovine heart mitochondrial succinate-cytochrome c reductase. Synthesis and biological properties of fluorine substituted ubiquinone derivatives. 165 37

Incubation of 10 mM 1-methyl-4-phenylpyridinium (MPP+) with sonicated beef heart mitochondria caused an irreversible time-dependent decrease in NADH-ubiquinone-1 (CoQ1) reductase activity (52% inhibition after 1 h). Inclusion of glutathione, ascorbate, or catalase in the incubation mixture protected the NADH-CoQ1 reductase activity. These results suggest that the interaction of MPP+ with complex I induces free radical generation, which in turn leads to the irreversible inhibition of complex I activity. The generation of free radicals by neurotoxin-induced inhibition of complex I has important implications for our interpretation of the increased oxidative stress observed in Parkinson's disease substantia nigra and for our understanding of the cause(s) of dopaminergic cell death in this disorder.
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PMID:Irreversible inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium: evidence for free radical involvement. 172 21


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