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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phospholamban ablation is associated with significant increases in the sarcoplasmic reticulum Ca(2+)-ATPase activity and the basal cardiac contractile parameters. To determine whether the observed phenotype is due to loss of phospholamban alone or to accompanying compensatory mechanisms, hearts from phospholamban-deficient and age-matched wild-type mice were characterized in parallel. There were no morphological alterations detected at the light microscope level. Assessment of the protein levels of the cardiac sarcoplasmic reticulum Ca(2+)-ATPase, calsequestrin, myosin, actin, troponin I, and troponin T revealed no significant differences between phospholamban-deficient and wild-type hearts. However, the ryanodine receptor protein levels were significantly decreased (25%) upon ablation of phospholamban, probably in an attempt to regulate the release of Ca2+ from the sarcoplasmic reticulum, which had a significantly higher diastolic Ca2+ content in phospholamban-deficient compared with wild-type hearts (16.0 +/- 2.2 versus 8.6 +/- 1.0 mmol Ca2+/kg dry wt, respectively). The increases in Ca2+ content were specific to junctional sarcoplasmic reticulum stores, as there were no alterations in the Ca2+ content of the mitochondria or A band. Assessment of ATP levels revealed no alterations, although oxygen consumption increased (1.6-fold) to meet the increased ATP utilization in the hyperdynamic phospholamban-deficient hearts. The increases in oxygen consumption were associated with increases (2.2-fold) in the active fraction of the mitochondrial pyruvate dehydrogenase, suggesting increased tricarboxylic acid cycle turnover and ATP synthesis. 31P nuclear magnetic resonance studies demonstrated decreases in phosphocreatine levels and increases in ADP and AMP levels in phospholamban-deficient compared with wild-type hearts. However, the creatine kinase activity and the creatine kinase reaction velocity were not different between phospholamban-deficient and wild-type hearts. These findings indicate that ablation of phospholamban is associated with downregulation of the ryanodine receptor to compensate for the increased Ca2+ content in the sarcoplasmic reticulum store and metabolic adaptations to establish a new energetic steady state to meet the increased ATP demand in the hyperdynamic phospholamban-deficient hearts.
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PMID:Compensatory mechanisms associated with the hyperdynamic function of phospholamban-deficient mouse hearts. 894 45

Mitochondria of rapidly developing mungbean seedlings were fractionated into four populations: two density classes, each from a 1500S and a 150S pellet. Each of the four populations exhibited cytochrome c oxidase (COX) activity and contained mitochondrial DNA and cardiolipin; plastid and glyoxysome content were found to be relatively low. Five mitochondrial membrane proteins, COXII/III, ATPase alpha/beta and porin, and a matrix enzyme, manganese superoxide dismutase (MnSOD), were detected by immunoblots in all four populations. Another matrix enzyme, pyruvate dehydrogenase was detected only in the two respiratory-competent 1500S populations. The two 150S populations contained a previously unidentified organelle that lacked demonstrable respiratory capability. This organelle, which we have tentatively referred to as "slow-sedimenting (ss-) mitochondrion", was small in size (below light-optics resolution, 70-300nm, majority < or =200nm) and possessed a peculiar looking boundary membrane, ribosomes, and an occasional prominent electron-dense spot. Characteristically, ss-mitochondria were almost always in contact with a filament-aligned membrane-like structure of varying length. Cristae structure, while undetected in small ss-mitochondria, appeared in larger individuals. Typical mitochondria were found in the denser 1500S population, while the lighter 1500S population consisted of 300-800 nm mitochondria exhibiting a varying degree of size-dependent inner membrane folding. Using electron microscopy (EM) immunolocalization and serial sectioning, we have identified in situ organelles resembling in size and in fine structure the ss-mitochondria, which also exhibit a size-dependent folding of the inner membrane. These results suggest that small ss-mitochondria may undergo a progressive development in situ. Taken together, our findings demonstrate the existence of a pattern of structure-function-coordinated gross heterogeneity among mitochondria. This pattern of mitochondrial heterogeneity, characterized both in isolated mitochondria and in situ, implies that small ss-mitochondria may represent a type of "nascent mitochondria" derived from a yet unidentified mitochondria-propagation mode operating during rapid seedling growth. Mitochondrial division by binary fission, characterized by the appearance of dumbbell-shaped intermediates, was also detected.
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PMID:Population heterogeneity of higher-plant mitochondria in structure and function. 954 77

This paper reviews the model of the control of mitochondrial substrate oxidation by Ca2+ ions. The mechanism is the activation by Ca2+ of four mitochondrial dehydrogenases, viz. glycerol 3-phosphate dehydrogenase, the pyruvate dehydrogenase multienzyme complex (PDH), NAD-linked isocitrate dehydrogenase (NAD-IDH) and 2-oxoglutarate dehydrogenase (OGDH). This results in the increase, or near-maintenance, of mitochondrial NADH/NAD ratios in the activated state, depending upon the tissue and the degree of 'downstream' activation by Ca2+, likely at the level of the F1Fo ATPase. Higher values of the redox span of the respiratory chain allow for greatly increased fluxes through oxidative phosphorylation with a minimal drop in protonmotive force and phosphorylation potential. As PDH, NAD-IDH and OGDH are all located within the inner mitochondrial membrane, it is changes in matrix free Ca2+ [Ca2+]m which act as a signal to these activities. In this article, we review recent work in which [Ca2+]m is measured in cells and tissues, using different techniques, with special emphasis on the question of the degree of damping of [Ca2+]m relative to changes in cytosol free Ca2+ in cells with rapid transients in cytosol Ca2+, e.g. cardiac myocytes. Further, we put forward the point of view that the failure of mitochondrial energy transduction to keep pace with cellular energy needs in some forms of heart failure may involve a failure of [Ca2+]m to be raised adequately to allow the activation of the dehydrogenases. We present new data to show that this is so in cardiac myocytes isolated from animals suffering from chronic, streptozocin-induced diabetes. This raises the possibility of therapy based upon partial inhibition of mitochondrial Ca2+ efflux pathways, thereby raising [Ca2+]m at a given, time-average value of cytosol free Ca+2.
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PMID:Role of mitochondrial calcium transport in the control of substrate oxidation. 974 30

Normalization of intracellular sodium (Na) after postischemic reperfusion depends on reactivation of the sarcolemmal Na(+)-K(+)-ATPase. To evaluate the requirement of glycolytic ATP for Na(+)-K(+)-ATPase function during postischemic reperfusion, 5-s time-resolution 23Na NMR was performed in isolated perfused rat hearts. During 20 min of ischemia, Na increased approximately twofold. In glucose-reperfused hearts with or without prior preischemic glycogen depletion, Na decreased immediately upon postischemic reperfusion. In glycogen-depleted pyruvate-reperfused hearts, however, the decrease of Na was delayed by approximately 25 s, and application of the pyruvate dehydrogenase (PDH) activator dichloroacetate (DA) did not shorten this delay. After 30 min of reperfusion, Na had almost normalized in all groups and contractile recovery was highest in the DA-treated hearts. In conclusion, some degree of functional coupling of glycolytic ATP and Na(+)-K(+)-ATPase activity exists, but glycolysis is not essential for recovery of Na homeostasis and contractility after prolonged reperfusion. Furthermore, the delayed Na(+)-K(+)-ATPase reactivation observed in pyruvate-reperfused hearts is not due to inhibition of PDH.
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PMID:Postischemic Na(+)-K(+)-ATPase reactivation is delayed in the absence of glycolytic ATP in isolated rat hearts. 1129 21

In this study, we modify and extend the bilevel optimization framework OptKnock for identifying gene knockout strategies in the Escherichia coli metabolic network, leading to the overproduction of representative amino acids and key precursors for all five families. These strategies span not only the central metabolic network genes but also the amino acid biosynthetic and degradation pathways. In addition to gene deletions, the transport rates of carbon dioxide, ammonia, and oxygen, as well as the secretion pathways for key metabolites, are introduced as optimization variables in the framework. Computational results demonstrate the importance of manipulating energy-producing/consuming pathways, controlling the uptake of nitrogen and oxygen, and blocking the secretion pathways of key competing metabolites. The identified pathway modifications include not only straightforward elimination of competing reactions but also a number of nonintuitive knockouts quite distant from the amino acid-producing pathways. Specifically, OptKnock suggests three reactions (i.e., pyruvate kinase, phosphotransacetylase, and ATPase) for deletion, in addition to the straightforward elimination of 2-ketoglutarate dehydrogenase, to generate a glutamate-overproducing mutant. Similarly, phosphofructokinase and ATPase are identified as promising knockout targets to complement the removal of pyruvate formate lyase and pyruvate dehydrogenase for enhancing the yield of alanine. Although OptKnock in its present form does not consider regulatory constraints, it does provide useful suggestions largely in agreement with existing practices and, more importantly, introduces a framework for incorporating additional modeling refinements as they become available.
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PMID:Exploring the overproduction of amino acids using the bilevel optimization framework OptKnock. 1470 28

Wilson's disease results from mutations in the P-type Cu(2+)-ATPase causing Cu(2+) toxicity. We previously demonstrated that exposure of mixed neuronal/glial cultures to 20 microM Cu(2+) induced ATP loss and death that were attenuated by mitochondrial substrates, activators, and cofactors. Here, we show differential cellular sensitivity to Cu(2+) that was equalized to 5 microM in the presence of the copper exchanger/ionophore, disulfiram. Because Cu(2+) facilitates formation of oxygen radicals (ROS) which inhibit pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH), we hypothesized that their inhibition contributed to Cu(2+)-induced death. Toxic CU(2+) exposure was accompanied by early inhibition of neuronal and hepatocellular PDH and KGDH activities, followed by reduced mitochondrial transmembrane potential, DeltaPsi(M). Thiamine (1-6 mM), and dihydrolipoic acid (LA, 50 microM), required cofactors for PDH and KGDH, attenuated this enzymatic inhibition and subsequent death in all cell types. Furthermore, liver PDH and KGDH activities were reduced in the Atp7b mouse model of Wilson's disease prior to liver damage, and were partially restored by oral thiamine supplementation. These data support our hypothesis that Cu(2+)-induced ROS may inhibit PDH and KGDH resulting in neuronal and hepatocellular death. Therefore, thiamine or lipoic acid may constitute potential therapeutic agents for Wilson's disease.
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PMID:Cu2+ toxicity inhibition of mitochondrial dehydrogenases in vitro and in vivo. 1512 4

A family presented with three affected children with Leigh syndrome, a progressive neurodegenerative disorder. Analysis of the OXPHOS complexes in muscle of two affected patients showed an increase in activity of pyruvate dehydrogenase and a decrease of complex V activity. Mutation analysis revealed the T9176C mutation in the mtATPase 6 gene (OMIM 516060) and the mutation load was above 90% in the patients. Unaffected maternal relatives were tested for carrier-ship and one of them, with a mutation load of 55% in blood, was pregnant with her first child. The possibility of prenatal diagnosis was evaluated. The main problem was the lack of data on genotype-phenotype associations for the T9176C mutation and on variation of the mutation percentage in tissues and in time. Therefore, multiple tissues of affected and unaffected carriers were analysed. Eventually, prenatal diagnosis was offered with understanding by the couple that there could be considerable uncertainty in the interpretation of the results. Prenatal diagnosis was carried out twice on cultured and uncultured chorion villi and amniotic fluid cells. The result was a mutation percentage just below the assumed threshold of expression (90%). The couple decided to continue the pregnancy and an apparently healthy child was born with an as yet unclear prognosis. This is the first prenatal diagnosis for a carrier of the T9176C mutation. Prenatal diagnosis for this mutation is technically reliable, but the prognostic predictions are not straightforward.
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PMID:Transmission and prenatal diagnosis of the T9176C mitochondrial DNA mutation. 1570 56

We examined the metabolic and ionoregulatory responses of the Amazonian cichlid, Astronotus ocellatus, to 20 h exposure to severe hypoxia (0.37 +/- 0.19 mg O(2)/l; 4.6% air saturation) or 8 h severe hypoxia followed by 12 h recovery in normoxic water. During 20 h exposure to hypoxia, white muscle [ATP] was maintained at normoxic levels primarily through a 20% decrease in [creatine phosphate] (CrP) and an activation of glycolysis yielding lactate accumulation. Muscle lactate accumulation maintained cytoplasmic redox state ([NAD(+)]/[NADH]) and was associated with an inactivation of the mitochondrial enzyme pyruvate dehydrogenase (PDH). The inactivation of PDH was not associated with significant changes in cytoplasmic allosteric modulators ([ADP(free)], redox state, or [pyruvate]). Hypoxia exposure caused an approximately 65% decrease in gill Na(+)/K(+) ATPase activity, which was not matched by changes in Na(+)/K(+) ATPase alpha-subunit protein abundance indicating post-translational modification of Na(+)/K(+) ATPase was responsible for the decrease in activity. Despite decreases in gill Na(+)/K(+) ATPase activity, plasma [Na(+)] increased, but this increase was possibly due to a significant hemoconcentration and fluid shift out of the extracellular space. Hypoxia caused an increase in Na(+)/K(+) ATPase alpha-subunit mRNA abundance pointing to either reduced mRNA degradation during exposure to hypoxia or enhanced expression of Na(+)/K(+) ATPase alpha-subunit relative to other genes.
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PMID:Metabolic and ionoregulatory responses of the Amazonian cichlid, Astronotus ocellatus, to severe hypoxia. 1721 39

Cancer immunotherapy relies on the identification and characterization of tumour antigens that can be recognized by effector T cells. Here, we used a proteomics-based approach to identify tumour antigens recognized by serum antibodies from patients with breast cancer. Specific reactivity against a set of spots was identified and their identity was revealed by MALDI-TOF peptide mass fingerprinting. They include disintegrin and metalloprotease 10, aldolase A, beta-ATPase F1, heat shock protein 27, deaminase, pyruvate dehydrogenase protein X component, and Vimentin. Western blot analysis using recombinant proteins expressed in E. coli confirmed the specific reactivity with patient sera. Several tumour antigens were expressed on the surface of the T7 phage and shown to trigger specific immune responses in BALB/c mice following oral immunisation. Furthermore, these immune responses inhibited tumour growth and metastasis of the 4T1 mammary adenocarcinoma cell line. Collectively, the present data indicate that proteomics-based strategy can identify tumour antigens whose surface display on phages or bacteria can provide an effective strategy for mucosal cancer vaccines. In addition, arrayed phage-displayed tumour antigens could be useful as a serum-based screening test for the detection of several tumour antigens.
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PMID:Mucosal vaccination with phage-displayed tumour antigens identified through proteomics-based strategy inhibits the growth and metastasis of 4T1 breast adenocarcinoma. 1809 64

The heart adapts the rate of mitochondrial ATP production to energy demand without noticeable changes in the concentration of ATP, ADP and Pi, even for large transitions between different workloads. We suggest that the changes in demand modulate the cytosolic Ca2+ concentration that changes mitochondrial Ca2+ to regulate ATP production. Thus, the rate of ATP production by the mitochondria is coupled to the rate of ATP consumption by the sarcomere cross-bridges (XBs). An integrated model was developed to couple cardiac metabolism and mitochondrial ATP production with the regulation of Ca2+ transient and ATP consumption by the sarcomere. The model includes two interrelated systems that run simultaneously utilizing two different integration steps: (1) The faster system describes the control of excitation contraction coupling with fast cytosolic Ca2+ transients, twitch mechanical contractions, and associated fluctuations in the mitochondrial Ca2+. (2) A slower system simulates the metabolic system, which consists of three different compartments: blood, cytosol, and mitochondria. The basic elements of the model are dynamic mass balances in the different compartments. Cytosolic Ca2+ handling is determined by four organelles: sarcolemmal Ca2+ influx and efflux; sarcoplasmic reticulum (SR) Ca2+ release and sequestration (SR); binding and dissociation from sarcomeric regulatory troponin complexes; and mitochondrial Ca2+ flows. Mitochondrial Ca2+ flows are determined by the Ca2+ uniporter and the mitochondrial Na+Ca2+ exchanger. The cytosolic Ca2+ determines the rate of ATP consumption by the sarcomere. Ca2+ binding to troponin regulates the rate of XBs recruitment and force development. The mitochondrial Ca2+ concentration determines the pyruvate dehydrogenase activity and the rate of ATP production by the F(1)-F(0) ATPase. The workload modulates the cytosolic Ca2+ concentration through feedback loops. The preload and afterload affect the number of strong XBs. The number of strong XBs determines the affinity of troponin for Ca2+, which alters the cytosolic Ca2+ transient. Model simulations quantify the role of Ca2+ in simultaneously controlling the power of contraction and the rate of ATP production. It explains the established empirical observation that significant changes in the metabolic fluxes can occur without significant changes in the key nucleotide (ATP and ADP) concentrations. Quantitative investigations of the mechanisms underlying the cardiac control of biochemical to mechanical energy conversion may lead to novel therapeutic modalities for the ischemic and failing myocardium.
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PMID:The role of Ca2+ in coupling cardiac metabolism with regulation of contraction: in silico modeling. 1837 79


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