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:3.6.3.14 (ATP synthase)
7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of 65 perfume formulations (perfume oils, perfumes, eau de parfum, eau de toilette) on mitochondrial membrane potential (Psim) and mitochondrial respiration have been investigated using a mitochondria-based assay for (Psim, termed Psi-Screen. All the perfume formulations tested are highly active in the Psi-Screen assay, and the major site of inhibition in all cases is NADH-ubiquinone reductase (Complex I). This is confirmed in studies on the inhibition of NADH oxidase and NADH-ubiquinone reductase. Some formulations also inhibit succinate oxidation at either Complex II or Complex III. Evidence for the inhibition of mitochondrial ATPase is presented, as well as for the induction of reactive oxygen species production by perfume inhibition of Complex I. Thus, perfume formulations are multiple inhibitor mixtures which inhibit multiple bioenergetic functions at high dilutions. The implications of these findings are discussed with respect to cell toxicity via necrosis and/or apoptosis. Twenty candidate fragrance chemicals were investigated and all inhibited Complex I (5 at <35 microM). Mass screening strategies and high-throughput screening assays are discussed.
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PMID:Psi-screen, an in vitro toxicity test system: applications in the bioassay of perfumes and fragrance chemicals. 1626 59

We have recently shown that leucine culture upregulates ATP synthase beta-subunit (ATPSbeta) and increases ATP level, cytosolic Ca(2+), and glucose-induced insulin secretion in rat islets. The aim is to test whether glucokinase expression is also affected in rat islets and its role in glucose sensitization during leucine culture. Leucine culture increased glucose-induced NAD(P)H level at 1 and 2 days but not at 1 week. The half-maximal effective concentration of the glucose response curve for NAD(P)H was left-shifted from 5-7 to 2-3 mmol/l. The effect was dose dependent and rapamycin insensitive. Leucine culture did not affect glyceraldehyde effects on NAD(P)H. Leucine pretreatment for 30 min had no effects on NAD(P)H levels. Leucine culture for 2 days also increased glucose-induced cytosolic Ca(2+) elevation, ATP level, and insulin secretion. Leucine increase of glucokinase mRNA levels occurred as early as day 1 and lasted through 1 week. That of ATPSbeta did not occur until day 2 and lasted through 1 week. Leucine effects on both mRNAs were dose dependent. The upregulation of both genes was confirmed by Western blotting. Leucine culture also increased glucose-induced insulin secretion, ATP level, glucokinase, and ATPSbeta levels of type 2 diabetic human islets. In conclusion, leucine culture upregulates glucokinase, which increases NAD(P)H level, and ATPSbeta, which increases oxidation of NADH and production of ATP. The combined upregulation of both genes increases glucose-induced cytosolic Ca(2+) and insulin secretion.
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PMID:Leucine regulation of glucokinase and ATP synthase sensitizes glucose-induced insulin secretion in pancreatic beta-cells. 1638 Apr 93

This study aimed at increasing the pyruvate productivity of a multi-vitamin auxotrophic yeast Torulopsis glabrata by redirecting NADH oxidation from adenosine triphosphate (ATP)-production pathway (oxidative phosphorylation pathway) to non-ATP production pathway (fermentative pathway). Two respiratory-deficient mutants, RD-17 and RD-18, were screened and selected after ethidium bromide (EtBr) mutagenesis of the parent strain T. glabrata CCTCC M202019. Compared with the parent strain, cytochrome aa (3) and b in electron transfer chain (ETC) of RD-18 and cytochrome b in RD-17 were disrupted. As a consequence, the activities of key ETC enzymes of the mutant RD-18, including F(0)F(1)-ATP synthase, complex I, complex I + III, complex II + III, and complex IV, decreased by 22.2, 41.6, 53.1, 23.6, and 84.7%, respectively. With the deficiency of cytochromes in ETC, a large amount of excessive cytosolic NADH was accumulated, which hampered the further increase of the glycolytic flux. An exogenous electron acceptor, acetaldehyde, was added to the strain RD-18 culture to oxidize the excessive NADH. Compared with the parent strain, the concentration of pyruvate and the glucose consumption rate of strain RD-18 were increased by 26.5 and 17.6%, respectively, upon addition of 2.1 mM of acetaldehyde. The strategy for increasing the glycolytic flux in T. glabrata by redirecting the NADH oxidation pathway may provide an alternative approach to enhance the glycolytic flux in yeast.
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PMID:Redirection of the NADH oxidation pathway in Torulopsis glabrata leads to an enhanced pyruvate production. 1640 61

The mitochondrial oxidative phosphorylation system in plants possesses a variety of alternative pathways that decrease respiratory ATP production. These alternative pathways are mediated by three classes of bypass proteins: the type II NAD(P)H dehydrogenases (which circumvent complex I of the electron transport chain), the alternative oxidases (AOXs; which circumvent complexes III and IV) and the uncoupling proteins (which circumvent ATP synthase). We have monitored the expression of all genes encoding respiratory bypass proteins in Arabidopsis thaliana growing with different sources of inorganic nitrogen (N). Resupply of nitrate (NO) to N-limited seedling cultures caused a decrease in the transcript abundance of several type II NAD(P)H dehydrogenase and AOX genes, while resupply of ammonium (NH) led to broad increases in expression in the same gene families. Similar results were observed upon switching between nitrate and ammonium in the absence of N stress. Nitrate signalling was found to be mediated primarily by the nitrate ion itself, whereas ammonium regulation was dependent upon assimilation and affected by changes in apoplastic pH. Corresponding alterations in alternative respiratory pathway capacities were apparent in seedlings supplied with either nitrate or ammonium as an N source and in mitochondria purified from the seedlings. Specifically, AOX capacity and protein abundance, as well as calcium-dependent external NADH oxidation, were substantially elevated after growth on ammonium. The increased capacity of respiratory bypass pathways after switching from nitrate to ammonium was correlated to an overall respiratory increase.
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PMID:Reorganization of the alternative pathways of the Arabidopsis respiratory chain by nitrogen supply: opposing effects of ammonium and nitrate. 1646 May 11

Cycles have a profound role in cellular life at all levels of organization. Well-known cycles in cell metabolism include the tricarboxylic acid and the urea cycle, in which a specific carrier substrate undergoes a sequence of chemical transformations and is regenerated at the end. Other examples include the interconversions of cofactors, such as NADH or ATP, which are present in the cell in limiting amounts and have to be recycled effectively for metabolism to continue. Every living cell performs a rapid turnover of ATP to ADP to fulfil various energetic demands and effectively regenerates the ATP from ADP in an energy-consuming process. The turnover of the ATP cycle is impressive; a human uses about its body weight in ATP per day. Enzymes perform catalytic reaction cycles in which they undergo several chemical and physical transformations before they are converted back to their original states. The ubiquitous F1F(o) ATP synthase is of particular interest not only because of its biological importance, but also owing to its unique rotational mechanism. Here, we give an overview of the membrane-embedded F(o) sector, particularly with respect to the recent crystal structure of the c ring from Ilyobacter tartaricus, and summarize current hypotheses for the mechanism by which rotation of the c ring is generated.
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PMID:Catalytic and mechanical cycles in F-ATP synthases. Fourth in the Cycles Review Series. 1660 97

The effects of purified Helminthosporium maydis T (HmT) toxin on active Ca(2+) transport into isolated mitochondria and microsomal vesicles were compared for a susceptible (T) and a resistant (N) strain of corn (Zea mays). ATP, malate, NADH, or succinate could drive (45)Ca(2+) transport into mitochondria of corn roots. Ca(2+) uptake was dependent on the proton electrochemical gradient generated by the redox substrates or the reversible ATP synthetase, as oligomycin inhibited ATP-driven Ca(2+) uptake while KCN inhibited transport driven by the redox substrates. Purified native HmT toxin completely inhibited Ca(2+) transport into T mitochondria at 5 to 10 nanograms per milliliter while transport into N mitochondria was decreased slightly by 100 nanograms per milliliter toxin. Malate-driven Ca(2+) transport in T mitochondria was frequently more inhibited by 5 nanograms per milliliter toxin than succinate or ATP-driven Ca(2+) uptake. However, ATP-dependent Ca(2+) uptake into microsomal vesicles from either N or T corn was not inhibited by 100 nanograms per milliliter toxin. Similarly, toxin had no effect on proton gradient formation ([(14)C]methylamine accumulation) in microsomal vesicles. These results show that mitochondrial and not microsomal membrane is a primary site of HmT toxin action. HmT toxin may inhibit formation of or dissipate the electrochemical proton gradient generated by substrate-driven electron transport or the mitochondrial ATPase, after interacting with a component(s) of the mitochondrial membrane in susceptible corn.
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PMID:Helminthosporium maydis T Toxin Decreased Calcium Transport into Mitochondria of Susceptible Corn. 1666 14

Submitochondrial particles from soybean (Glycine max L. cv Jupiter) hypocotyls with an ATPase activity of 0.3 to 1.0 micromole per minute per milligram were prepared by sonication with Mg-ATP. The particles catalyzed ATP synthesis with NADH and succinate; the ratios of ATP/O with these substrates were 1.0 and 0.1, respectively. As monitored by oxonol-VI, the particles built up and maintained a membrane potential that was higher with NADH than with succinate or Mg-ATP. The ATPase activity of the particles increased two to threefold by preincubation with 50 millimolar phosphate at a temperature of 38 degrees C. The increase in ATPase activity became higher (five to sixfold) when particles were preincubated with Mg-ATP plus phosphate. Under the latter conditions, collapse of DeltamuH by carbonyl cyanide p-trifluoromethoxyphenylhydrazone prevented the activation. An increase in ATPase activity of the particles was also observed with NADH and succinate, although activation was lower with succinate. With these substrates, phosphate did not increase ATPase activation. When particles were preincubated with Mg-ATP, anions that stimulate ATP hydrolysis (malate, malonate, and bicarbonate) had an activating effect similar to that of phosphate. The data suggest that the soybean mitochondrial ATPase can be activated by DeltamuH but that this activation is increased by the binding of certain anions to a conformation of the enzyme that appears during hydrolytic cycles.
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PMID:Effect of the electrochemical proton gradient and anions on the ATPase activity of soybean submitochondrial particles. 1666 51

The physiological changes in an F1-ATPase-defective mutant of Escherichia coli W1485 growing in a glucose-limited chemostat included a decreased growth yield (60%) and increased specific rates of both glucose consumption (168%) and respiration (171%). Flux analysis revealed that the mutant showed approximately twice as much flow in glycolysis but only an 18% increase in the tricarboxylic acid (TCA) cycle, owing to the excretion of acetate, where most of the increased glycolytic flux was directed. Genetic and biochemical analyses of the mutant revealed the downregulation of many TCA cycle enzymes, including citrate synthase, and the upregulation of the pyruvate dehydrogenase complex in both transcription and enzyme activities. These changes seemed to contribute to acetate excretion in the mutant. No transcriptional changes were observed in the glycolytic enzymes, despite the enhanced glycolysis. The most significant alterations were found in the respiratory-chain components. The total activity of NADH dehydrogenases (NDHs) and terminal oxidases increased about twofold in the mutant, which accounted for its higher respiration rate. These changes arose primarily from the increased (3.7-fold) enzyme activity of NDH-2 and an increased amount of cytochrome bd in the mutant. Transcriptional upregulation appeared to be involved in these phenomena. As NDH-2 cannot generate an electrochemical gradient of protons and as cytochrome bd is inferior to cytochrome bo3 in this ability, the mutant was able to recycle NADH at a higher rate than the parent and avoid generating an excess proton-motive force. We discuss the physiological benefits of the alterations in the mutant.
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PMID:Alterations of cellular physiology in Escherichia coli in response to oxidative phosphorylation impaired by defective F1-ATPase. 1698 Apr 90

A brief period of ischemia followed by timely reperfusion may lead to prolonged, yet reversible, contractile dysfunction (myocardial stunning). Damage to the myocardium occurs not only during ischemia, but also during reperfusion, where a massive release of oxygen-free radicals (OFR) occurs. We have previously utilized 2-DE and MS to define 57 protein spot changes during brief ischemia/reperfusion (15 min ischemia, 60 min reperfusion; 15I/60R) injury in a rabbit model (White, M. Y., Cordwell, S. J., McCarron, H. C. K., Prasan, A. M. et al., Proteomics 2005, 5, 1395-1410) and shown that the majority of these occur because of physical and/or chemical PTMs. In this study, we subjected rabbit myocardium to 15I/60R in the presence of the OFR scavenger N-(2-mercaptopropionyl) glycine (MPG). Thirty-seven of 57 protein spots altered during 15I/60R remained at control levels in the presence of MPG (15I/60R + MPG). Changes to contractile proteins, including myosin light chain 2 (MLC-2) and troponin C (TnC), were prevented by the addition of MPG. To further investigate the individual effects of ischemia and reperfusion, we generated 2-DE gels from rabbit myocardium subjected to brief ischemia alone (15I/0R), and observed alterations of 33 protein spots, including 18/20 seen in both 15I/60R-treated and 15I/60R + MPG-treated tissue. The tissue was also subjected to ischemia in the presence of MPG (15I/0R + MPG), and 21 spot changes, representing 14 protein variants, remained altered despite the presence of the OFR scavenger. These ischemia-specific proteins comprised those involved in energy metabolism (lactate dehydrogenase and ATP synthase alpha), redox regulation (NADH ubiquinone oxidoreductase 51 kDa and GST Mu), and stress response (Hsp27 and 70, and deamidated alpha B-crystallin). We conclude that contractile dysfunction associated with myocardial stunning is predominantly caused by OFR damage at the onset of reperfusion, but that OFR-independent damage also occurs during ischemia. These ischemia-specific protein modifications may be indicative of early myocardial injury.
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PMID:Proteomics of ischemia and reperfusion injuries in rabbit myocardium with and without intervention by an oxygen-free radical scavenger. 1713 70

Gliomas in the form of astrocytomas, anaplastic astrocytomas and glioblastomas are the most common brain tumors in humans. Early detection of these cancers is crucial for successful treatment. Proteomics promises the discovery of biomarkers and tumor markers for early detection and diagnosis. In the current study, a differential gel electrophoresis technology coupled with matrix-assisted laser desorption/ionization-time of flight and liquid chromatography-tandem mass spectroscopy was used to investigate tumor-specific changes in the proteome of human brain cancer. Fifty human brain tissues comprising varying diagnostic groups (non-tumor, grade I, grade II, grade III and grade IV) were run in duplicate together with an internal pool sample on each gel. The proteins of interest were automatically picked, in-gel digested and mass spectrometry fingerprinted. Two hundred and eleven protein spots were identified successfully and were collapsed into 91 unique proteins. Approximately 20 of those 91 unique proteins had, to our knowledge, not been reported previously as differentially expressed in human brain cancer. Alb protein, peroxiredoxin 4 and SH3 domain-binding glutamic acid-rich-like protein 3 were upregulated in glioblastoma multiform versus non-tumor tissues. However, aldolase C fructose-biphosphate, creatine kinase, B chain dihydrolipoyl dehydrogenase, enolase 2, fumarate hydratase, HSP60, lactoylglutathione lyase, lucine aminopeptidase, Mu-crystallin homolog, NADH-UO 24, neurofilament triplet L protein, septin 2, stathmin and vacuolar ATP synthase subunit E were downregulated in glioblastoma multiform compared with non-tumor tissues. These differentially expressed proteins provided novel information on the differences existing between normal brain and gliomas, and thus might prove to be useful molecular indicators of diagnostic or prognostic value.
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PMID:Biomarker discovery: a proteomic approach for brain cancer profiling. 1723 37


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