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)

Midazolam, a water soluble benzodiazepine used as a preanaesthetic and hypnotic drug, showed a concentration-related (0.1-0.75 mM) depressant effect on both Adenosine 5'-diphosphate (ADP)-induced oxygen consumption and oxidative phosphorylation of rat liver mitochondria if the substrate was oxidized at different steps in the oxidation chain, but not when the substrate was ascorbate plus tetramethyl-p-phenylenediamine (complex IV). Furthermore, midazolam did not affect citrate synthase activity, but inhibited the 2,4 dinitrophenol (DNP)-uncoupled mitochondrial respiration. This result shows that midazolam primarily acts as a mitochondrial electron transport inhibitor. This inhibition is mainly due to the fact that midazolam decreases NADH ubiquinone reductase (complex I) and ubiquinol cytochrome c reductase (complex III) activities, but it also inhibits complex II activity. Spectrophotometric measurements of redox states of rat skeletal muscle mitochondria cytochromes show a decrease in the reduction of aa3 and c+c1 cytochromes in the presence of the benzodiazepine. Midazolam significantly decreased the reduced ubiquinone/total ubiquinone ratio (evaluated by means of HPLC and electrochemical detection) in rat liver mitochondria in both beta-hydroxybutyrate and succinate. Ubisemiquinone may be the redox component affected by midazolam, whether or not bound to the iron-sulfur proteins present in all three mitochondrial complexes. These effects of midazolam, not necessarily related to the preanaesthetic and hypnotic action are probably mediated via mitochondrial benzodiazepine receptors.
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PMID:Biochemical characterization of the effects of the benzodiazepine, midazolam, on mitochondrial electron transfer. 882 37

Decyl aurachins C and D are two synthetic compounds related to the natural products aurachins C and D extracted from Stigmatella aurantiaca. Titrations of a range of partial respiratory activities in membranes from facultative phototrophs indicate that decyl aurachin C is more effective than aurachin D in inhibiting the quinol oxidase. Decyl aurachin C also affects the NADH-ubiquinone oxidoreductase of Rhodobacter capsulatus and the cytochrome bc1 complexes of Rb.capsulatus and Rhodospirillum centenum. Titration of the light-induced respiration in Rsp.centenum allowed us to estimate an upper limit for the ubiquinol oxidase concentration of 1.5 +/- 0.2 nmol/mg protein, or a ubiquinol oxidase/cytochrome c oxidase ratio of 3:1.
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PMID:The effects of decyl aurachins C and D on the respiratory electron flow of facultative phototrophic bacteria. 884 34

We found that NADPH-dependent ubiquinone reductase (NADPH-UQ reductase) in rat liver cytosol reduces ubiquinone (UQ) to ubiquinol (UQH2) in lipid membranes and consequently inhibits lipid peroxidation [Takahashi T., et al., Biochem. J., 309, 883-890 (1995)]. Here we examined whether or not this UQH2-regenerating system functions as a cellular antioxidant defense in animals. Rats were given UQ-10 for 2 weeks, and were then exposed to carbon tetrachloride (CCl4). The UQ-10 supplement increased only in the NADPH-UQ reductase and the UQH2-10 pool of rat liver without any appreciable change in the levels of other antioxidant factors. On the other hand, CCl4 markedly increased plasma aspartate aminotransferase and alanine aminotransferase, liver weight and thiobarbituric acid reacting substances formation, which are indicators of CCl4-hepatitis, and it decreased the liver levels of L-ascorbic acid, reduced form of glutathione (GSH), alpha-tocopherol, NADPH-UQ reductase and glutathione S-transferase. However, all the above indicators of CCl4-induced hepatitis were significantly improved in rats given UQ-10. Furthermore, alpha-tocopherol, but neither L-ascorbic acid nor GSH, was significantly saved. UQ-10 supplement also was recovered glutathione S-transferase and NADPH-UQ reductase activities slightly. These results indicated that UQ-10 given to rats increased the cellular UQH2-10 pool and cytosolic NADPH-UQ reductase activity in their livers, resulting in the inhibition of lipid peroxidation in the biomembranes, and consequently protected the rats from the CCl4-hepatotoxicity.
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PMID:Cellular antioxidant defense by a ubiquinol-regenerating system coupled with cytosolic NADPH-dependent ubiquinone reductase: protective effect against carbon tetrachloride-induced hepatotoxicity in the rat. 887 5

The behavior of ubisemiquinone radicals and the iron-sulfur clusters 2 of NADH:ubiquinone oxidoreductase (Complex I) in coupled and uncoupled submitochondrial particles (SMP), oxidizing either NADH or succinate under steady-state conditions, was studied. Multifrequency EPR spectra revealed that the two new g2 lines of the clusters 2, only observed during coupled electron transfer under conditions where energy dissipation is rate-limiting [De Jong, A. M. Ph., Kotlyar, A. B., & Albracht, S. P. J. (1994) Biochim. Biophys. Acta 1186, 163-171], are the result of a spin-spin interaction of 2.8 mT. Investigation of the radical signals present in coupled SMP indicated that more than 90% of the radicals can be ascribed to two types of semiquinones which are bound to Complex I (QI-radicals) or ubiquinol:cytochrome c oxidoreductase (Complex III; QIII-radicals). The presence of QIII-radicals, but not that of QI-radicals, was completely abolished by uncoupler. Part of the QI-radicals weakly interact with the clusters 2 of Complex I. This uncoupler-sensitive interaction can amount to a splitting of the radical EPR signal of at most 1 mT, considerably weaker than the 2.8 mT splitting of the g2 lines of the clusters 2. We propose that the 2.8 mT splitting of these g2 lines results from an energy-induced spin-spin interaction between the two clusters 2 within the TYKY subunit of Complex I. The two clusters 2 show no interaction during electron transfer is uncoupled SMP or in fully-reduced anaerobic-coupled SMP. The results point to a direct role of the Fe-S clusters 2 and the QI-radicals in the mechanism of coupled electron transfer catalyzed by Complex I.
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PMID:The iron-sulfur clusters 2 and ubisemiquinone radicals of NADH:ubiquinone oxidoreductase are involved in energy coupling in submitochondrial particles. 902 Jul 88

This paper is a study of factors influencing the rate of lipid peroxidation in beef heart submitochondrial particles induced by NAD(P)H via the NADH-ubiquinone oxidoreductase (Complex I) of the respiratory chain. In accordance with earlier observations, both NADH and NADPH initiated lipid peroxidation in the presence of ADP-Fe3+. The rate of the reaction, measured as oxygen consumption and formation of thiobarbituric acid reactive substances, was biphasic as a function of NADH concentration, reaching a maximum at low NADH concentrations and then declining. In contrast, the NADPH-initiated lipid peroxidation showed a monophasic concentration profile of hyperbolic character. Rotenone did not eliminate the biphasicity of the NADH-induced reaction, indicating that this was not due to an antioxidant effect of reduced ubiquinone at high NADH concentrations. This conclusion was further supported by the demonstration that extraction of ubiquinone from the particles did not relieve the inhibition of lipid peroxidation by high NADH concentrations. However rhein, another inhibitor of Complex I, eliminated the biphasicity, and even caused a substantial stimulation of the NADH-induced lipid peroxidation in the particles upon extraction of ubiquinone by pentane. No similar effect occurred in the case of NADPH-induced lipid peroxidation. Furthermore, rhein facilitated both NADH- and NADPH-induced lipid peroxidation even in the absence of added ADP-Fe3+, in a fashion similar to that earlier reported with succinate in the presence of theonyltrifluoroacetone. Based on these findings and measurements of the redox states of ubiquinone and cytochromes in the presence of KCN and NADH or NADPH, it is concluded that Complex I may distinguish between electron input from NADH and NADPH by differences in the site(s) of substrate binding and in the pathways and rates of NADH and NADPH oxidation.
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PMID:Pro- and anti-oxidant activities of the mitochondrial respiratory chain: factors influencing NAD(P)H-induced lipid peroxidation. 903 Feb 67

Renal cell carcinoma (RCC), a human kidney cancer from the proximal tubular epithelium, accounts for about 3% of adult malignancies. Molecular and cytogenetic analysis have highlighted deletions, translocations, or loss of heterozygosity in the 3p21-p26, a putative RCC locus, as well as in 6q, 8p, 9pq, and 14pq. Studies on phenotypic expression of human kidney tissue and on post-translational modifications in RCC have not yet provided a marker for early renal cell carcinoma diagnosis. Current diagnostic methods do not help to detect the tumor before advanced stages. We therefore used two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) to study normal and tumor kidney tissues in ten patients suffering from RCC. A human kidney protein map in the SWISS-2DPAGE database accessible through the ExPASy WWW Molecular Biology Server was established. Of 2789 separated polypeptides, 43 were identified by gel comparison, amino acid analysis, N-terminal sequencing, and/or immunodetection. The comparison between normal and tumor kidney tissues showed four polypeptides to be absent in RCC. One of them was identified as ubiquinol cytochrome c reductase (UQCR), whose locus has elsewhere been tentatively assigned to chromosome 19p12 or chromosome 22. A second polypeptide was identified as mitochondrial NADH-ubiquinone oxido-reductase complex I whose locus is located on chromosome 18p11.2 and chromosome 19q13.3. These result suggest that the lack of UQCR and of mitochondrial NADH-ubiquinone oxidoreductase complex I expression in RCC may be caused by unknown deletions, or by changes in gene transcription or translation. It might indicate that mitochondrial disfunction plays a major role in RCC genesis or evolution.
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PMID:Renal cell carcinoma and normal kidney protein expression. 915 Sep 47

To investigate the energy-conserving function of the NADH:ubiquinone reductase (complex I), we have selected oxonol VI [bis(3-propyl-5-oxoisoxazol-4-yl)pentamethine oxonol] as the most sensitive probe for measuring the reactions of membrane potential generation in submitochondrial particles. Calibration of the oxonol signals with potassium diffusion potentials shows a non-linear response after a threshold around -50 mV. Thermodynamic evaluations indicate that the upper limit of the oxonol response to the potential generated by complex I is around -220 mV, which is close to the maximal protonmotive force in coupled submitochondrial particles. NADH addition to particles in which ubiquinol oxidation is blocked by inhibitors of other respiratory complexes generates oxonol signals corresponding to membrane potentials of -130 to -180 mV. These signals are produced by about four turnovers of the complex reducing endogenous ubiquinone (i.e. non-steady-state conditions) and are equivalent to a charge separation similar to that of the antimycin-sensitive reactions of ubiquinol:cytochrome c reductase (complex III). The transient oxonol signals under non-steady-state conditions are thus informative of crucial steps in the electrogenic reactions catalyzed by complex I. The possible nature of these electrogenic reactions is discussed in relation to proposed mechanisms for complex I.
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PMID:Measurement of the membrane potential generated by complex I in submitochondrial particles. 916 27

The complex I function in sub-mitochondrial particles was studied in platelets from patients and healthy carriers with 11778/ND4 or 3460/ND1 mtDNA point mutations associated with LHON. Both 11778/ND4 and 3460/ND1 mutations induced rotenone resistance and 11778/ND4 showed an increased K(m) for ubiquinol-2 with respect to the control group. It was concluded that even with different pathogenic mechanisms both mutations affect the quinone binding site of complex I.
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PMID:Changes in mitochondrial complex I activity and coenzyme Q binding site in Leber's hereditary optic neuropathy (LHON). 926 34

This article provides an updated overview of the plethora of complex I inhibitors. The inhibitors are presented within the broad categories of natural and commercial compounds and their potency is related to that of rotenone, the classical inhibitor of complex I. Among commercial products, particular attention is dedicated to inhibitors of pharmacological or toxicological relevance. The compounds that inhibit the NADH-ubiquinone reductase activity of complex I are classified according to three fundamental types of action on the basis of available evidence and recent insights: type A are antagonists of the ubiquinone substrate, type B displace the ubisemiquinone intermediate, and type C are antagonists of the ubiquinol product.
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PMID:Inhibitors of NADH-ubiquinone reductase: an overview. 959 4

The hydrophobic isoprene tail of ubiquinone-2 (Q2) exihibits binding specificity in redox reactions with bovine heart mitochondrial complex I (Ohshima, M., Miyoshi, H., Sakamoto, K., Takegami, K., Iwata, J., Kuwabara, K., Iwamura, H., and Yagi, T. (1998) Biochemistry 37, 6436-6445) and the Escherichia coli bo-type ubiquinol oxidase (Sakamoto, K., Miyoshi, H., Takegami, K., Mogi, T., Anraku, Y., and Iwamura, H. (1996) J. Biol. Chem. 271, 29897-29902). To identify the structural factor(s) of the diprenyl tail of Q2 governing the specific interaction with these enzymes, we synthesized a series of novel Q2 analogues in which only one of the structural factors of the diprenyl tail was systematically modified. In bovine complex I, the presence of the methyl branch and the pi-electron system in the first isoprene unit are responsible for high-affinity binding of Q2 to the ubiquinone reduction site, which results in a low Km and kcat values of Q2 reduction. The position of the methyl group in the tail is strictly recognized by the enzyme. In contrast to complex I, in bo-type ubiquinol oxidase, either of the two pi-electron systems in the tail is required for high-affinity binding of Q2H2 to the enzyme, while the presence of the methyl branch and the location of the pi-electron systems are not strictly recognized by the enzyme. We concluded that the role of the ubiquinone tail is not simply the enhancement of the hydrophobicity of the molecule and that molecular recognition of the tail by the quinone redox site differs among the respiratory enzymes.
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PMID:Role of the isoprenyl tail of ubiquinone in reaction with respiratory enzymes: studies with bovine heart mitochondrial complex I and Escherichia coli bo-type ubiquinol oxidase. 979 Jun 73


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