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)

(1) The mitochondrial ATPase (EC 3.6.1.3) Ehrlich ascites cell mitochondria, was inhibited by D-glucose under physiological concentrations of ATP. The generation of ADP by the mitochondrial bound hexokinase, seems to be the reason for the D-glucose inhibitory effect. Reversal of the inhibitory effect of ADP on Ehrlich ascites cell mitochondria ATPase by an ATP-regenerating system was achieved. (2) Dissociation of mitochondrial bound hexokinase from the mitochondria eliminated the inhibitory effect of D-glucose. Rebinding of the hexokinase to the mitochondria regenerated the D-glucose inhibitory effect on Ehrlich ascites cell mitochondria ATPase. (3) Bioflavonoids such as quercetin inhibit the mitochondrial hexokinase activity, but do not change the mitochondrial ATPase activity of isolated Ehrlich ascites tumor cell mitochondria. (4) The inhibitory effect of bioflavonoids on mitochondrial bound hexokinase activity is shown to be dissociable from the ascites tumor cell mitochondria and seems to be associated with regulatory rather than catalitic sites of the enzyme.
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PMID:Bioflavonoid regulation of ATPase and hexokinase activity in Ehrlich ascites cell mitochondria. 1 95

Cells from a rapidly growing rat Zajdela hepatoma were shown to contain (on a protein basis) five-times less mitochondria than hepatocytes from resting or regenerating rat liver. Transcripts of four nuclear genes for representative mitochondrial membrane proteins (beta-F1 subunit and N,N'-dicyclohexyl-carbodiimide-binding protein of ATP synthase, subunit IV of cytochrome oxidase and ADP/ATP translocase) were present in 2-4 times higher amounts in the poly(A)-rich RNA of the hepatoma than in the corresponding RNA fraction from resting or regenerating rat liver. The liver and hepatoma transcripts for the beta-F1 subunit were translated in an in-vitro system with equal efficiency. Pulse-chase labeling of isolated Zajdela hepatoma cells and hepatocytes from resting and regenerating liver revealed a relative excess of the newly synthesized beta-F1 subunit in the tumor cells. The half-life of the beta-F1 subunit was significantly shorter in the hepatoma cells than in hepatocytes from resting and regenerating liver. The contents of transcripts of three mitochondrial genes examined (cytochrome oxidase subunits I and II and NADH-ubiquinone reductase subunit 2) in Zajdela hepatoma mitochondria were about five-times higher than in the mitochondria of the resting cells and 3-4 times higher than in the organelles of the regenerating organ. The results indicate that events other than transcription (most likely post-translational) may be responsible for the reduced content of mitochondria in tumor cells.
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PMID:Increased steady-state levels of several mitochondrial and nuclear gene transcripts in rat hepatoma with a low content of mitochondria. 137 34

A full length cDNA clone of the alpha subunit of mitochondrial ATP synthase (EC 3.6.1.34) has been isolated from a cDNA library prepared from LX-1 human tumor cells in the lambda-Zap vector. The clone is 1883 base pairs (bp) in length and contains a 1659 bp open reading frame encoding a polypeptide of 553 residues. The deduced amino acid sequence is highly homologous to ATP synthase from several other species.
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PMID:Nucleotide sequence of a cDNA for the alpha subunit of human mitochondrial ATP synthase. 183 Apr 91

N-(4-Methylphenylsulfonyl)-N'-(4-chlorophenyl)urea (MPCU) is a new agent that exhibits high therapeutic activity against human and rodent tumor models. Initial studies indicated that in vitro [3H]MPCU was concentrated 4- to 6-fold in GC3/c1 human colon adenocarcinoma cells in an azide-sensitive manner. In this study the dependence of uptake and concentrative accumulation of MPCU upon temperature, plasma membrane potential, and the electrochemical potential of mitochondria has been examined. Accumulation and efflux of MPCU were temperature dependent. At 3.6 microM MPCU, initial rates of uptake (15 s) were 1.4, 38.0, and 84.2 pmol/min/10(6) cells at 2 degrees C, 23 degrees C, and 37 degrees C, respectively. The rate of uptake and concentrative accumulation within GC3/c1 cells was not altered in high K+ buffer or by 1 mM ouabain, indicating that plasma membrane potential was not significant in these processes. Concentrative accumulation, but not initial uptake, was inhibited by carbonyl cyanide p-trifluoromethoxyphenylhydrazone, 2,4-dinitrophenol, and sodium azide. Glucose partially antagonized the inhibition of these agents which uncouple oxidative phosphorylation. Oligomycin, an inhibitor of mitochondrial ATP synthase, did not inhibit uptake or concentrative accumulation of MPCU. However, oligomycin in the presence of 2-deoxyglucose significantly inhibited concentrative accumulation of MPCU. These results suggested that concentrative accumulation of MPCU was dependent upon the mitochondrial transmembrane gradient rather than ATP, although direct implication of ATP could not be excluded. To examine which component of this gradient was predominant in causing MPCU sequestration, the ionophores valinomycin and nigericin were used. Valinomycin, which collapses the charge gradient across the mitochondrial matrix membrane, caused only slight inhibition of MPCU accumulation, and the effect was similar at 2 or 10 mumol. In contrast, nigericin (which collapses the pH gradient and increases mitochondrial membrane potential) inhibited by approximately 90% concentrative accumulation of MPCU. These data suggested that MPCU was being concentrated in mitochondria and that this was dependent upon the pH gradient across mitochondrial membrane. In cells exposed to MPCU or the analogue N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)urea, enlargement of mitochondria was observed within 24 h and appeared to be the initial morphological change associated with drug treatment. These results implicate mitochondria as a site of sequestration of diarylsulfonylureas and as a potential site of action.
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PMID:Evidence for mitochondrial localization of N-(4-methylphenylsulfonyl)-N'-(4-chlorophenyl)urea in human colon adenocarcinoma cells. 229 7

The effect of rhein, 4,5-dihydroxyanthraquinone-2-carboxylic acid, on oxygen consumption and the rate of aerobic and anaerobic lactate production by Ehrlich ascites tumor cells has been investigated. The rate of oxygen uptake decreases with the increase of rhein concentration. Rhein also inhibits aerobic and anaerobic glycolysis. The rate of aerobic lactate production decreases with the drug concentration and the maximal effect was observed at 0.100 mM. Anaerobic lactate production is also inhibited and the maximum effect is reached at 0.220 mM. The possibility that the lactate production decrease was secondary to an effect on mitochondrial ATPase was excluded on the basis of the data with DNP and oligomycin. Rhein reduces the intracellular level of lactate, pyruvate and glucose-6-phosphate. Glucose utilization and 2-deoxy-D-glucose uptake are decreased to the same extent as the inhibition of aerobic lactate production, whereas glucose phosphorylation is unaffected. It is, therefore, concluded that the inhibition of glycolysis of Ehrlich ascites tumor cells by rhein is caused by an impairment of glucose uptake.
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PMID:Effect of rhein on the glucose metabolism of Ehrlich ascites tumor cells. 237 63

Bone remodeling is a constant phenomenon balancing between osteoblastic bone formation and osteoclastic bone resorption in the neighbourhood of a cellular micro-environment including stromal and hemopoietic cells. Numerous local factors and hormones modulate such a mechanism and act synergistically, usually through the indirect production of osteoblastic coupling factors. The majority of the cytokines acting on bone remodeling possess both actions upon activation of mature osteoclasts and differentiation of hemopoietic osteoclast progenitors. Components from bone matrix which include non-collagenous bone proteins and other local factors are major products acting on bone remodeling. The presence of a cancer may determine changes in bone remodeling, directly through tumor-mediated resorption or indirectly through the action of local or systemic factors with or without tumor involvement of bone. Bone remodeling associated with cancer is usually an uncoupled phenomenon with decreased bone formation and increased bone resorption. In B-cell malignancies, abnormal bone remodeling is an early event linked to specific bone involvement. Abnormal osteoclast differentiation (micro- or macro-resorption) represents a major difference between myeloma and other B-cell malignancies. Several synergistic factors produced by tumor cells and micro-environment are usually implicated in the pathogenesis of bone lytic lesions, hypercalcemia or histomorphometric bone changes associated with cancers.
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PMID:[Bone tissue and cancer]. 240 92

A study of kinetic properties of mitochondrial ATPase in Morris hepatoma 3924A is reported. The results show that submitochondrial particles isolated from the tumor tissue exhibited a three-fold increase in both the Km for ATP hydrolysis and Ki for the competitive inhibitor [beta, gamma-imido]ATP with regard to normal rat liver. Eadie-Hofstee analysis of the kinetics of ATP hydrolysis show that both the high and the low affinity constants for ATP were enhanced in the hepatoma with respect to the rat liver enzyme. Kinetic analysis of passive proton conduction through the F0 sector of ATPase does not reveal any difference between Morris hepatoma and rat liver. In Morris hepatoma particles, 50% inhibition of the hydrolase activity required 10 times more oligomycin than in control particles. On the contrary, 50% inhibition of proton conduction occurred in both hepatoma and rat liver particles at the same concentration of oligomycin. It is concluded that in Morris hepatoma the catalytic process in F1 and the functional connection between F1 and F0 of the ATP synthase are altered with regard to control rat liver.
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PMID:Kinetic properties of mitochondrial H+-adenosine triphosphatase in Morris hepatoma 3924A. 253 Oct 32

Transport of precursor of F1-ATPase beta-subunit into isolated mitochondria of Zajdela hepatoma and rat liver was examined. The hepatoma mitochondria were more active in the process than the liver organelles indicating that the relative F1-ATPase deficiency in the tumor mitochondria does not result from an impaired transport of F1-ATPase subunits into the tumor organelles. Similar results were obtained using digitonin-treated rat hepatocytes and Zajdela hepatoma cells instead of isolated mitochondria. The suitability of the digitonin-treated cells in the study of protein transport into mitochondria in vitro is demonstrated and the advantages of this system over isolated mitochondria are discussed.
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PMID:In vitro transport of F1-ATPase beta-subunit into mitochondria of Zajdela hepatoma and rat liver. 286 22

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

Glycolysis of 3T3 and Ehrlich ascites tumor cells was greatly enhanced by Nonidet P-40 or Triton X-100 at about 100 micrograms/mg cell protein. This enhanced glycolysis was partly sensitive to rutamycin and partly sensitive to ouabain, suggesting that the detergent released the control of the ATPase of the mitochondria and of the plasma membrane Na+K+-ATPase. Nonidet P-40 had no effect on glycolysis in cell-free extracts from Ehrlich ascites tumor cells to which soluble mitochondrial ATPase was added. Measuring ouabain-sensitive 22Na efflux and using ouabain-sensitive lactate production as a measure of ATP hydrolysis by the Na+K+ pump, it was shown that Nonidet P-40 greatly decreased the efficiency of the Na+K+ pump. Quercetin increased the efficiency of pumping in EAT cells both in the absence and presence of the detergent.
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PMID:On the mechanism of glycolysis stimulation by neutral detergents in 3T3 and Ehrlich ascites tumor cells. 299 84


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