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)

Dopamine, due to metabolism by monoamine oxidase or autoxidation, can generate toxic products such as hydrogen peroxide, oxygen-derived radicals, semiquinones, and quinones and thus exert its neurotoxic effects. Intracerebroventricular injection of dopamine into rats pretreated with the monoamine oxidase nonselective inhibitor pargyline caused mortality in a dose-dependent manner with LD50 = 90 micrograms. Norepinephrine was less effective with LD50 = 141 micrograms. The iron chelator desferrioxamine completely protected against dopamine-induced mortality. In the absence of pargyline more rats survived, indicating that the products of dopamine enzymatic metabolism are not the main contributors to dopamine-induced toxicity. Biochemical analysis of frontal cortex and striatum from rats that received a lethal dose of dopamine did not show any difference from control rats in lipid and protein peroxidation and glutathione reductase and peroxidase activities. Moreover, dopamine significantly reduced the formation of iron-induced malondialdehyde in vitro, thus suggesting that earlier events in cell damage are involved in dopamine toxicity. Indeed, dopamine inhibited mitochondrial NADH dehydrogenase activity with IC50 = 8 microM, and that of norepinephrine was twice as much (IC50 = 15 microM). Dopamine-induced inhibition of NADH dehydrogenase activity was only partially reversed by desferrioxamine, which had no effect on norepinephrine-induced inhibition. These results suggest that catecholamines can cause toxicity not only by inducing an oxidative stress state but also possibly through direct interaction with the mitochondrial electron transport system. The latter was further supported by the ability of ADP to reverse dopamine-induced inhibition of NADH dehydrogenase activity in a dose-dependent manner.
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PMID:Dopamine neurotoxicity: inhibition of mitochondrial respiration. 783 65

The distribution of acetylcholinesterase (AChE), NADH dehydrogenase (NADHd), and cytochrome oxidase (CO) was determined in the nucleus of the solitary tract (NST) in the golden hamster. Histochemical staining was compared to cytoarchitectonic subdivisions of the NST (Whitehead: J. Comp. Neurol. 276:547-572, 1988) and to terminal fields of primary afferents of the nerves that innervate the tongue. These three histochemical methods resulted in differential staining patterns within the NST that were related to certain subdivisions. Transganglionic transport of horseradish peroxidase (HRP) was used to determine the central projections of the chorda tympani (CT), the lingual branch of the trigeminal (L-V), and the lingual-tonsilar branch of the glossopharyngeal nerves (L-IX). Alternate or the same brain sections were processed to reveal transported HRP, and NADHd or AChE levels. Increased staining of the neuropil with NADHd and AChE was coincident with the dense part of the afferent terminal fields of all three nerves in the NST and the laterally adjacent dorsomedial part of the spinal trigeminal nucleus. CO showed this pattern only for the most rostral part of the CT field. The densest AChE staining coincided with gustatory afferent terminal fields. The histochemical staining facilitated the interpretation of the organization of the NST. For example, at caudal levels of the gustatory NST, it is suggested that taste processing is localized predominantly in the medial part of the rostral central, and somatosensory processing in the rostral lateral subdivision. AChE or NADHd staining should facilitate studies of connections, topography, and neuroplastic changes of the gustatory NST.
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PMID:Organization of the nucleus of the solitary tract in the hamster: acetylcholinesterase, NADH dehydrogenase, and cytochrome oxidase histochemistry. 824 61

The objective of this study was to explore the possible cause(s) underlying the previously observed, age-related increase in the rate of mitochondrial H2O2 release in the housefly. The hypothesis that an imbalance between different respiratory complexes may be a causal factor was tested. Cytochrome c oxidase activity was found to sharply decline in the latter part of the life span of the flies. Effects of different substrates and respiratory inhibitors were determined in order to ascertain if a decrease in cytochrome c oxidase activity could be responsible for the increased H2O2 release. H2O2 was measured spectrofluorometrically using horseradish peroxidase and p-hydroxphenylacetate as an indicator. Neither NADH-linked substrates nor succinate caused a stimulation of H2O2 production. H2O2 release by mitochondria, inhibited with rotenone and antimycin A, was greatly increased upon supplementation with alpha-glycerophosphate; however, the further addition of KCN or myxothiazol, to such preparations, caused a depression of H2O2 generation. In contrast, relatively low concentrations of KCN or myxothiazol were found to stimulate H2O2 release in insect mitochondria supplemented with alpha-glycerophosphate and exposed to rotenone, but not antimycin A. Results are interpreted to suggest that partial inhibition of cytochrome c oxidase activity can lead to the stimulation of mitochondrial H2O2 production in the housefly at site(s) other than NADH dehydrogenase and ubisemiquinone/cytochrome b region; a possible source may be glycerophosphate dehydrogenase.
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PMID:Aging, cytochrome oxidase activity, and hydrogen peroxide release by mitochondria. 839 19

The rate constants of H2O2 decomposition, interaction of catalase complex I with H2O2, and the effective rate constants of catalase inactivation during enzymatic catalysis (k(in)) were determined by transformation of complete kinetic curves of H2O2 decomposition by catalase in reversed micelles of Aerosol OT (AOT) in octane and aqueous solution. Effects of hydration of micelles and AOT, H2O2, and catalase concentrations in the micellar systems on each of three kinetic constants were investigated. Optimal conditions were found which provide for high operational stability and catalytic activity of catalase in micellar systems versus aqueous solutions. Stability of catalase enhances (decreased k(in)) in the presence of reduced glutathione and ethanol in AOT micelles. In reversed AOT micelles, catalase partially dissociates to subunits because their peroxidase activity was demonstrable in cumene hydroperoxide-dependent oxidation of tetramethylbenzidine. Catalase dissociation to monomers is significantly decreased in mixed micelles composed of AOT, Triton X-45, Triton X-100, or Tween-85 and octanol.
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PMID:[Catalytic properties of catalase in microemulsions of surface-active agents in octane]. 899 90

The cDNA encoding the smallest membrane-anchoring subunit (QPs3) of bovine heart mitochondrial succinate-ubiquinone reductase was cloned and sequenced. This cDNA is 1330 base pairs long with an open reading frame of 474 base pairs that encodes the 103 amino acid residues of mature QPs3 and a 55-amino acid residue presequence. The cDNA insert has an 820-base pair long 3'-untranslated region, including a poly(A) tail. The molecular mass of QPs3, deduced from the nucleotide sequence, is 10,989 Da. QPs3 is a very hydrophobic protein; the hydropathy plot of the amino acid sequence reveals three transmembrane helices. Previous photoaffinity labeling studies of succinate-ubiquinone reductase, using 3-azido-2-methyl-5-methoxy[3H]-6-decyl-1,4-benzoquinone ([3H]azido-Q), identified QPs3 as one of the putative Q-binding proteins in this reductase. An azido-Q-linked peptide with a retention time of 66 min is obtained by high performance liquid chromatography of the chymotrypsin digest of carboxymethylated and succinylated [3H]azido-Q-labeled QPs3 purified from labeled succinate-ubiquinone reductase by a procedure involving phenyl-Sepharose 4B column chromatography, preparative SDS-polyacrylamide gel electrophoresis, and acetone precipitation. The amino acid sequence of this peptide is NH2-L-N-P-C-S-A-M-D-Y-COOH, corresponding to residues 29-37. The structure of QPs3 in the inner mitochondrial membrane is proposed based on the hydropathy profile of the amino acid sequence, on the predicted tendencies to form alpha-helices and beta-sheets, and on immunobinding of Fab' fragmenthorseradish peroxidase conjugates prepared from antibodies against two synthetic peptides, corresponding to the NH2 terminus region and the loop connecting helices 2 and 3 of QPs3, in mitoplasts and submitochondrial particles. The ubiquinone-binding domain in the proposed model of QPs3 is probably located at the end of transmembrane helix 1 toward the C-side of the mitochondrial inner membrane.
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PMID:The smallest membrane anchoring subunit (QPs3) of bovine heart mitochondrial succinate-ubiquinone reductase. Cloning, sequencing, topology, and Q-binding domain. 921 43

Diphenyleneiodonium (DPI) has frequently been used to inhibit reactive oxygen species (ROS) production mediated by flavoenzymes, particularly NAD(P)H oxidase. This study was undertaken to examine if DPI could also inhibit production of superoxide and H2O2 by mitochondria, the major source of cellular ROS. Detection of mitochondrial superoxide by lucigenin-derived chemiluminescence (CL) with unstimulated monocytes/macrophages showed that DPI at concentrations that inhibit NAD(P)H oxidase markedly diminished the production of superoxide by mitochondrial respiration. Similarly, the extracellular H2O2 derived from mitochondrial respiration as detected by luminol-derived CL in the presence of horseradish peroxidase was also greatly reduced by DPI. DPI was as potent as rotenone in inhibiting the production of superoxide and H2O2 by mitochondrial respiration. With substrate-supported isolated mitochondria, DPI was shown to reduce mitochondrial superoxide production probably through inhibiting NADH-ubiquinone oxidoreductase (complex I).
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PMID:Diphenyleneiodonium, an NAD(P)H oxidase inhibitor, also potently inhibits mitochondrial reactive oxygen species production. 987 31

Isoniazid is the most widely used antituberculosis drug. Genetic studies in Mycobacterium smegmatis identified the inhA-encoded, NADH-dependent enoyl acyl carrier protein reductase as the primary target for this drug. A reactive form of isoniazid inhibits InhA by reacting with the NAD(H) cofactor bound to the enzyme active site forming a covalent adduct (isonicotinic acyl NADH) that is apt to bind with high affinity. Resistance can occur by increased expression of InhA or by mutations that lower the enzyme's affinity to NADH. Both of these resistance mechanisms are observed in 30% of clinical tuberculosis isolates. Mutation in katG, which encodes catalase peroxidase, is the most common source for resistance. Another mechanism for isoniazid resistance, in M. smegmatis, occurs by defects in NADH dehydrogenase (Ndh) of the respiratory chain. Genetic data indicated that ndh mutations confer resistance by lowering the rate of NADH oxidation and increasing the intracellular NADH/NAD+ ratio. An increased amount of NADH may prevent formation of isonicotinic acyl NADH or may promote displacement of the isonicotinic acyl NADH from InhA. While our studies have identified this mechanism in M. smegmatis, results reported in early literature lead us to believe that it can occur in Mycobacterium tuberculosis.
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PMID:Mechanisms for isoniazid action and resistance. 994 10

In the last few years the presence in thylakoid membranes of chloroplasts of a NAD(P)H-plastoquinone oxidoreductase complex (Ndh complex) homologous to mitochondrial complex I has been well established. Herein, we report the identification of the Ndh complex in barley etioplast membranes. Two plastid DNA-encoded polypeptides of the Ndh complex (NDH-A and NDH-F) were relatively more abundant in etioplast membranes than in thylakoids from greening chloroplasts. Conversion of etioplast into chloroplast, after light exposure of barley seedlings grown in the dark, was accompanied by a decrease in the NADH dehydrogenase activity associated to plastid membranes. Using native-PAGE and immunolabelling techniques we have determined that a NADH specific dehydrogenase activity associated with plastid membranes, which was more active in etioplasts than in greening chloroplasts, contained the NDH-A and NDH-F polypeptides. These results complemented by those obtained through blue-native-PAGE indicated that NDH-A and NDH-F polypeptides are part of a 580 kDa NADH dependent dehydrogenase complex present in etioplast membranes. This finding proves that accumulation of the Ndh complex is independent of light. The decrease in the relative levels and specific activity of this complex during the transition from etioplast to chloroplasts was accompanied by a parallel decrease in the specific activity of peroxidase associated to plastid membranes. Based on the mentioned observations it is proposed that an electron transport chain from NADH to H2O2 could be active in barley etioplasts.
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PMID:Identification of the Ndh (NAD(P)H-plastoquinone-oxidoreductase) complex in etioplast membranes of barley: changes during photomorphogenesis of chloroplasts. 1075 Jul 8

Oxidative damage of creatine kinase (CK) induced by Adriamycin((R)) (ADM) with peroxidase was investigated using horseradish peroxidase (HRP). ADM oxidatively inactivated CK during its interaction with HRP in the presence of H(2)O(2) (HRP-H(2)O(2)). The red color of ADM was lost during oxidation by HRP-H(2)O(2). Adding catalase stopped the color change of ADM induced by HRP-H(2)O(2), indicating that ADM was oxidized by HRP complex I or II. CK was inactivated readily, even when it was added to the reaction mixture containing colorless ADM. Some sulfhydryl groups of CK, which have an important role in its enzyme activity, were very sensitive to ADM activated by HRP-H(2)O(2), suggesting that inactivation of CK is due to oxidation of SH groups at the active center. Presumably, oxidative ADM quinone is involved dominantly in the inactivation of CK. Among the anthracycline drugs tested in this study, only ADM and epirubicin caused inactivation of CK and alcohol dehydrogenase and loss of the red color during oxidation by HRP-H(2)O(2).
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PMID:Inactivation of creatine kinase by Adriamycin during interaction with horseradish peroxidase. 1080 50

Mitochondria are widely believed to be the source of reactive oxygen species (ROS) in a number of neurodegenerative disease states. However, conditions associated with neuronal injury are accompanied by other alterations in mitochondrial physiology, including profound changes in the mitochondrial membrane potential DeltaPsi(m). In this study we have investigated the effects of DeltaPsi(m) on ROS production by rat brain mitochondria using the fluorescent peroxidase substrates scopoletin and Amplex red. The highest rates of mitochondrial ROS generation were observed while mitochondria were respiring on the complex II substrate succinate. Under this condition, the majority of the ROS signal was derived from reverse electron transport to complex I, because it was inhibited by rotenone. This mode of ROS generation is very sensitive to depolarization of DeltaPsi(m), and even the depolarization associated with ATP generation was sufficient to inhibit ROS production. Mitochondria respiring on the complex I substrates, glutamate and malate, produce very little ROS until complex I is inhibited with rotenone, which is also consistent with complex I being the major site of ROS generation. This mode of oxidant production is insensitive to changes in DeltaPsi(m). With both substrates, ubiquinone-derived ROS can be detected, but they represent a more minor component of the overall oxidant signal. These studies demonstrate that rat brain mitochondria can be effective producers of ROS. However, the optimal conditions for ROS generation require either a hyperpolarized membrane potential or a substantial level of complex I inhibition.
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PMID:DeltaPsi(m)-Dependent and -independent production of reactive oxygen species by rat brain mitochondria. 1167 54


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