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: KEGG:D02011 (FAD)
5,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of butylated hydroxyanisole (BHA), a commonly used food antioxidant, on oxygen consumption, ATPase activity, and the redox state of some electron carriers of rat liver mitochondria have been studied. It was observed that BHA slightly stimulated state 4 respiration but strongly inhibited ADP- and uncoupler-stimulated respiration on NAD(+)- and FAD-linked substrates. ATPase activity and vectorial H+ ejection were affected only slightly by BHA, suggesting that BHA predominantly inhibits mitochondrial electron flow. Experiments to determine its site of action showed that BHA did not noticeably affect electron flow through cytochrome oxidase; in contrast, NADH:duroquinone reductase activity and electron flow through ubiquinone-cytochrome b-cytochrome c complex were inhibited strongly because the oxidation of duroquinol was affected markedly. The BHA block of electron transport was bypassed by both N,N,N',N'-tetramethyl-p-phenylenediamine and 2,6-dichlorophenolindophenol. Also, the presence of BHA changed the redox state of cytochrome b and c1 to a more oxidized level. These observations suggest that electron transport is inhibited by BHA at the NADH-ubiquinone and at the ubiquinone-cytochrome b levels. From Hill plots, it is clear that more than one binding site is involved in complete inhibition; in addition, available evidence suggests that there may be two sites at the substrate side of ubiquinone and another two sites at the oxygen side of ubiquinone. Consequently, mitochondrial ATP synthesis would be interrupted. This event could be related to the toxicity of BHA.
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PMID:Effect of butylated hydroxyanisole on electron transport in rat liver mitochondria. 214 54

The effect of halothane, a potent and popular volatile anesthetic, on isolated rat liver mitochondria was examined. Halothane inhibited state 3 and dinitrophenol-induced uncoupled respiration with NAD(+)-linked substrates, but not with FAD-linked substrates, and did not affect the oxidation-reduction state of mitochondrial cytochromes. Moreover, halothane increased state 4 respiration and ATPase activity and decreased the extra-mitochrondrial pH change coupled to ATP synthesis. These results indicate that halothane impairs mitochondrial ATP production by interfering with both the electron transport from NAD+ to FAD and the coupling of oxidative phosphorylation. Halothane only slightly affected the membrane potential, which is commonly dissipated by typical classical uncouplers. Moreover, halothane inhibited both ATP-driven and respiration-driven Ca2+ accumulation in mitochondria and stimulated Ca2+ release from mitochondrial stores at concentrations higher than those at which it inhibited ATP production. These findings indicate that the uncoupling action of halothane is not classical. During halothane anesthesia, these mitochondrial abnormalities may contribute to hepatocyte dysfunctions.
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PMID:Halothane impairs the bioenergetic functions of isolated rat liver mitochondria. 216 74

Bacterial plasmids have genes that confer highly specific resistances to As, Bi, Cd, Cu, Cr, Hg, Pb, Te, Zn, and other toxic heavy metals. For each toxic cation or anion, generally a different resistance system exists, and these systems may be "linked" together on multiple resistance plasmids. For Cd2+, AsO2-, AsO4(3)-, Hg2+, and organomercurials, DNA sequence analysis has supplemented direct physiological and biochemical experiments to produce sophisticated understanding. The cadA ATPase of S. aureus plasmids is a 727 amino acid membrane ATPase that pumps Cd2+ from the cells as rapidly as it is accumulated. This polypeptide is related by sequence to other cation translocating ATPases, including the membrane K+ ATPases of Escherichia coli and Streptococcus faecalis, the H+ ATPases of yeast and Neurospora, the Na+/K+ ATPases of vertebrate animals, and the Ca2+ ATPases of rabbit muscle. The conserved residues include the aspartyl residue that is phosphorylated, the lysine involved in ATP binding, and the proline within a membrane translocating region. The arsenate and arsenite translocating ATPase consists of 3 polypeptides (from DNA sequence analysis), including a recognizable ATP binding protein (arsA), an integral membrane protein (arsB gene), and a substrate specificity subunit (arsC gene). Inorganic mercury and organomercurial degradation is carried out by a series of about 6 polypeptides, including 2 soluble intracellular enzymes (organomercurial lyase and mercuric reductase). The latter is related by sequence and function to glutathione reductase and lipoamide dehydrogenase of prokaryotes and eukaryotes. These enzymes are dimeric, FAD-containing, NAD(P)H-dependent oxidoreductases. Other recognizable polypeptides in the mer system include a DNA-binding regulatory protein from the merR gene and a Hg2+ transport system consisting of a periplasmic Hg2(+)-binding protein (merP gene) and a membrane protein (merT gene) in gram negative systems.
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PMID:DNA sequence analysis of bacterial toxic heavy metal resistances. 248 81

The effect of hyperthermia (1 hr, 41 degrees C) on the functional properties of Ehrlich ascites tumor mitochondria was investigated. Mitochondria isolated from Ehrlich ascites tumor after exposure of whole cells to 41 degrees C for 1 hr still phosphorylate and maintain a normal acceptor control ratio (ACR). The temperature decreases state 4 and ADP-and FCCP-stimulated respiration on various substrates entering at three energy-conserving sites of the respiratory chain. The inhibition of oxygen consumption by NAD- and FAD-linked substrates was 40% for state 4 and 70% for ADP- or FCCP-stimulated respiration. State 4 and FCCP-stimulated respiration of mitochondria on TMPD + ascorbate was affected 38% and 45%, respectively. ATPase activity was unaffected by hyperthermia, indicating that under these experimental conditions, the inhibition of ADP-stimulated respiration does not depend on an effect on either Fo F1-ATPase or adenine translocase, the activity of which is required for ATP entry prior to ATPase activity. Because of the inability to detect a specific site of action of temperature, it is conceivable that hyperthermia might inhibit substrate oxidation by altering some components of the inner mitochondrial membrane, which regulates the kinetic properties of the membrane-associated enzymes.
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PMID:Effect of hyperthermia on electron transport in Ehrlich ascites tumor mitochondria. 295 47

The effect of lonidamine, an antispermatogenic and antitumor drug, on the oxygen consumption, ATPase activity, and redox state of the electron carriers of Ehrlich ascites tumor mitochondria has been studied. Lonidamine inhibits ADP- and uncoupler-stimulated respiration on various NAD- and FAD-linked substrates, but does not affect state 4 respiration. Experiments to determine its site of action showed that lonidamine does not significantly inhibit electron flow through cytochrome oxidase. Electron flow through site 2, the ubiquinone-cytochrome b-cytochrome c1 complex, also was unaffected by lonidamine, which failed to inhibit the oxidation of duroquinol. Moreover, inhibition of electron flow through site 2 was also excluded because of the inability of the N,N,N',N'-tetramethyl-p-phenylenediamine bypass to relieve the lonidamine inhibition of the oxidation of pyruvate + malate. The F0F1ATPase activity and vectorial H+ ejection are also unaffected by lonidamine. The inhibition of succinate oxidation by lonidamine was found to take place at a point between succinate and iron-sulfur center S3. Spectroscopic experiments demonstrated that lonidamine inhibits the reduction of mitochondrial NAD+ by pyruvate + malate and other NAD-linked substrates in the transition from state 1 to state 4. However, lonidamine does not inhibit reduction of added NAD+ by submitochondrial vesicles or by soluble purified NAD-linked dehydrogenases. These observations, together with other evidence, suggest that electron transport in tumor mitochondria is inhibited by lonidamine at the dehydrogenase-coenzyme level, particularly when the electron carriers are in a relatively oxidized state and/or when the inner membrane-matrix compartment is in the condensed state. The action of lonidamine in several respects resembles the selective inhibition of electron transport in tumor cells produced by cytotoxic macrophages (D. L. Granger and A. L. Lehninger (1982) J. Cell Biol. 95, 527).
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PMID:Action of the antitumor and antispermatogenic agent lonidamine on electron transport in Ehrlich ascites tumor mitochondria. 622 86

The intraperitoneal injection of glucagon or the intravenous infusion of oleic acid provoked a rapid change in the properties of rat liver mitochondrial ATPase. When mitochondria of treated animals were isolated an increase in ATPase activity was observed as well as a modification on the response to activators and inhibitors and to the sulfhydryl reagent N-ethylmaleimide. Sensitivity to the activators dinitrophenol or bicarbonate decreased, whereas the sensitivity to inhibitors KOCN and KSCN increased, and an inhibitory effect of N-ethylmaleimide appeared. These effects gradually disappeared when mitochondrial suspensions were kept at 10 degrees C, and after approximately 5 h ATPase from mitochondria of treated and control animals behaved almost identically. If the oxidizing agent dichlorophenolindophenol was added to the isolated mitochondria the effects induced by glucagon or fatty acids immediately disappeared. The activation caused by the reducing agent dithionite on ATPase activity in mitochondria from control animals did not take place in fresh mitochondria from treated animals; however, dithionite was effective in these latter mitochondria when tested 5 h later after keeping them at 10 degrees C. The intravenous infusion of oleic acid produced a rise in the [NADH]/[NAD+] and [Total flavin]/[FAD] ratios in mitochondria, and values double as those in the controls were observed; these values gradually approached those of the control mitochondria when kept at 10 degrees C; after 24 h these ratios were the same in mitochondrial suspensions from treated and nontreated animals. These results suggest that the modification of the properties of mitochondrial ATPase induced by glucagon or fatty acids might be mediated by a change in the mitochondrial redox state.
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PMID:Effect of injected glucagon or fatty acids on mitochondrial ATPase. 632 87

The effect of the association of gossypol and Lonidamine on the electron transport in Ehrlich ascites tumor mitochondria has been investigated by addition of drugs to isolated mitochondria. The results may be summarized as follows. (1) Low concentrations of gossypol increase the rate of oxygen consumption at the level of three energy-conserving sites of the respiratory chain. Higher concentrations result in an inhibition of oxygen consumption at (or near) both energy-conserving sites 1 and 2, while energy-conserving site 3 is unaffected. (2) Gossypol, at concentrations at which it exerts its uncoupling effect, stimulates ATPase activity. Higher concentrations inhibit the enzyme activity. (3) The addition of gossypol to mitochondria respiring on pyruvate plus malate or succinate induces a more oxidized state of NAD+ and cytochrome b, respectively. (4) Gossypol enhances the effect of Lonidamine on oxygen consumption. Lonidamine does not affect state 4 respiration, but in the presence of gossypol, it determines a marked decrease in the rate of oxygen consumption. The inhibition of oxidation of NAD-linked substrates is greater than that of FAD-linked substrates. (5) It may be concluded that gossypol is very effective in potentiating the effect of Lonidamine. Moreover, it may be suggested that the antitumor activity of Lonidamine is enhanced if it is used in combination with other drugs and/or treatments, such as hyperthermia, which modify the energy status of mitochondria.
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PMID:The effect of gossypol and Lonidamine on electron transport in Ehrlich ascites tumor mitochondria. 670 94

In 63 children with severe meningococcal infection (MI) and meningitides of another origin red cell metabolism was studied: levels of ATP, ADP, AMP, ATP/ADP, ATP/AMP, energetic charge, 2,3-DPG, FAD, piruvate, lactate, activity of lactate dehydrogenase, piruvate kinase, glucose-6-phosphate dehydrogenase, glutatione reductase, Mg2+, Na+, K(+)-dependent ATPase. All the disease periods were characterized by combined pathobiochemical shifts of different degree typical for varying metabolic systems and correlating with the infection severity. The discussion covers pathogenetic and clinical significance of red cell metabolism shifts in patients with MI and purulent meningitides.
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PMID:[The dynamics of erythrocyte metabolism in severe forms of meningococcal infection and suppurative meningitis in children]. 904 77

Respiratory activity in hepatic mitochondria have been examined following administration of the carcinogen aflatoxin, (AFB1) to rats. Measurement in isolated mitochondria of respiration rates in presence of ADP (state 3) and after its depletion (state 4) revealed that these rates were not significantly altered in livers of rats obtained 4-8 hours after single injection of AFB1 (7 mg/kg of body weight). After 12-24 hours, however, a generalized inhibition in state 3 respiration rate and ADP phosphorylation rate had been evident with several FAD- and NAD-linked oxidizing substrates. But the ADP:0 ratio did not show any alteration. State 4 respiration rates, on the other hand, were increased remarkably (38-94% depending on substrate used), thereby recording in each case a decrease in respiratory control ratio (state 3:state 4 ratio), indicating probable damage to mitochondrial membrane as a result of AFB1 ingestion. This was also evident from greater basal ATPase and Mg(2+)-ATPase activities and low total ATPase activity. After 48-72 hours of AFB1 treatment, the respiratory rates as well as the ATPase activities returned to normal levels, suggesting probable recovery of mitochondrial functions from the toxic effects of AFB1.
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PMID:Alteration of energy-linked functions in rat hepatic mitochondria following aflatoxin B1 administration. 911 Feb 45

The thiourea insecticide/acaricide diafenthiuron represents a biologically inactive propesticide that requires transformation into the active carbodiimide derivative. The carbodiimide inhibits mitochondrial respiration by selective and covalent binding to the proteolipid (8 kDa) of Fo-ATPase in the inner membrane and to porin (30 kDa) in the outer membrane. The thiourea can be activated by light as well as by cytochrome P450 in the insect. To get insight into the enzymatic mechanisms of activation, model in vitro studies were performed using [14C]diafenthiuron and microsomes from various vertebrate livers and from locust Malpighian tubules. Though there was a common set of metabolites, their quantities varies significantly with the species and assay conditions. As a typical product, p-hydroxydiafenthiuron was identified in assay with rat and mouse microsomes. The sulfomonoxide predominated in hen and fish assays, whereas pig and bovine microsomes almost exclusively produced the carbodiimide. The sulfoxide was shown to be a precursor of the carbodiimide. Formation of all metabolites was dependent on the presence of NADPH and active microsomes. The effects of inhibitors and the requirement for NAPDH suggested a role of cytochrome P450-dependent monooxygenase(s) in the formation of both the hydroxylated product and the carbodiimide. FAD-dependent monooxygenases (FMOs) may also be involved in a step following sulfoxidation. These in vitro studies revealed potential mechanisms contributing to biological selectivity of the effects of a pesticide that acts in a non-selective mode at a conserved mitochondrial site.
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PMID:Metabolism of diafenthiuron by microsomal oxidation: procide activation and inactivation as mechanisms contributing to selectivity. 1169 92


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