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:1.1.1.41 (isocitrate dehydrogenase)
3,101 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isolated working rat hearts perfused with Krebs-Hensleit buffer were arrested and made ischemic. After 22 min, the hearts were reperfused with buffer, yielding restoration of function. Nucleotide levels rose and fell in the cardiac tissue as ischemia was imposed; the changes were consistent with the energy needs of the tissue. ATP concentrations in the tissues fell by 75% during ischemia, AMP levels were low initially and subsequently rose 5-fold, and ADP levels were essentially unchanged. Upon reperfusion ATP levels rebounded, although not to initial values, and AMP returned to initial values. During ischemia, there was a 10-fold or greater rise in inosine, hypoxanthine, and xanthine levels which fell to normally low levels upon reperfusion. Lactate dehydrogenase (LDH) activity rose during ischemia and returned to baseline upon reperfusion. Changes in LDH isozyme distribution suggest that, during ischemia, there is an increased proportion of liver-associated forms which returns to normally low levels upon reperfusion. Glutamate oxalacetate transaminase activity rose slightly at 5 min of ischemia, but, by 22 min of ischemia, it had fallen to 60% of initial values. Upon reperfusion, activity rose and, by 15 min, had reached 127% of initial values. On the other hand, there is no significant change in levels of extractable creatine kinase or isocitrate dehydrogenase activities as a result of the various conditions imposed on the hearts. As an index of protein oxidation, carbonyl levels in extractable protein rose during ischemia and were over four times the initial values at 5 min of reperfusion but, with continued reperfusion, declined to approximately 150% of initial values at 15 min.
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PMID:Biochemical effects of ischemia on isolated, perfused rat heart tissues. 157 15

During operation, biopsies from the gastrocnemius muscle and, in some cases, from the sartorius muscle were taken from 32 patients with peripheral arterial occlusive disease and from 5 subjects with normal peripheral circulation. In patients with inadequate circulation only during exercise, when compared with the control group, increased activities of enzymes involved in oxidative metabolism (malate dehydrogenase, nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase, cytochrome C oxidase, creatine kinase), in amino acid metabolism (asparate aminotransferase, alanine aminotransferase), and in anaerobic glycoysis (lactate dehydrogenase) were found. In patients with circulatory disturbances that manifested themselves already at rest, enzyme activities were, with the exception of LDH, lower than those of patients with exclusively exercise-related insufficiency. By means of intraindividual comparisons with the corresponding enzyme activities in the sartorius muscle, the author was able to show that the changes found were not simply the result of differences in training conditions. The diminished concentrations of energy-rich phosphate are an expression of the anaerobic metabolic state in patients with inadequate circulation at rest. It is concluded that chronic ischemia of muscle leads to changes in the energy metabolism of the cell. In the presence of more nearly adequate circulation at rest, the portion of oxidative potential of the total energy metabolism increases. In contrast, if there is an inadequate circulation at rest, the mainly anaerobic glycolysis becomes quantitatively predominant.
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PMID:Investigations on the biochemical characteristics of chronically underperfused muscle. 201 45

The intensity of free radical processes and the regulation of NADP-isocitrate dehydrogenase (EC 1.1.1.42; NADP-IDH) activity have been studied in the cytoplasmic fraction of normal and ischemized rat myocardium. Chemiluminescence parameters, such as the light sum (S) of slow flash and the tangent of the kinetic curve slope angle (tanalpha1), which characterize the intensity of free radical processes, were increased in ischemia 2.1- and 20.0-fold, respectively. The slow flash intensity (Imax) was increased 22-fold. The contents of lipid peroxidation products--diene conjugates and malonic dialdehyde--were increased 11.9- and 4.7-fold, respectively, suggesting pronounced oxidative stress. Using homogenous enzyme preparations of NADP-IDH isolated from the normal and experimentally ischemized rat myocardium, a number of catalytic properties of the enzyme were characterized for normal and pathologic conditions. NADP-IDH from the normal and ischemized myocardium had the same electrophoretic mobility and was regulated similarly by Fe2+, Cu2+, Zn2+, and also with succinate and fumarate. However, under normal and pathologic conditions NADP-IDH was different in the affinity for substrates and in the sensitivity to inhibitory effects of hydrogen peroxide, reduced glutathione, and of Ca2+. The degree of synergy in the enzyme inhibition with Fe2+ and H2O2 was less pronounced in ischemia. The inhibitory effect of the reaction product 2-oxoglutarate was higher under normal conditions than in ischemia (the Ki values were 0.22 and 0.75 mM, respectively). The specific features of the NADP-IDH regulation in ischemia are suggested to promote the stimulation of the enzyme functioning during increased level of free radical processes, and this seems to be important for NADPH supplying for the glutathione reductase/glutathione peroxidase antioxidant system of cardiomyocytes.
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PMID:Intensity of free radical processes and regulation of cytoplasmic NADP-isocitrate dehydrogenase in rat cardiomyocytes under normal and ischemic conditions. 1212 79

Little is known about the role of mitochondrial NADP(+)-isocitrate dehydrogenase (NADP(+)-ICDH) in the heart, where this enzyme shows its highest expression and activity. We tested the hypothesis that in the heart, NADP(+)-ICDH operates in the reverse direction of the citric acid cycle (CAC) and thereby may contribute to the fine regulation of CAC activity (Sazanov and Jackson, FEBS Lett 344: 109-116, 1994). We documented a reverse flux through this enzyme in rat hearts perfused with the medium-chain fatty acid octanoate using [U-(13)C(5)]glutamate and mass isotopomer analysis of tissue citrate (Comte et al., J Biol Chem 272: 26117-26124, 1997). In this study, we assessed the significance of our previous finding by perfusing hearts with long-chain fatty acids and tested the effects of changes in O(2) supply. We showed that under all of these conditions citrate was enriched in an isotopomer containing five (13)C atoms. This isotopomer can only be explained by substrate flux through reversal of the NADP(+)-ICDH reaction, which is evaluated at 3-7% of flux through citrate synthase. Small variations in reversal fluxes induced by low-flow ischemia that mimicked hibernation occurred despite major changes in contractile function and O(2) consumption of the heart as well as citrate and succinate release rates and tissue levels. Our data show a reverse flux through NADP(+)-ICDH and support its hypothesized role in the fine regulation of CAC activity in the normoxic and O(2)-deprived heart.
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PMID:Reverse flux through cardiac NADP(+)-isocitrate dehydrogenase under normoxia and ischemia. 1223 3

Oxidative status of rat cardiomyocytes during ischemia induced by occlusion of the descending branch of the coronary artery was studied by the methods of Fe-induced chemiluminescence and spectrophotometry of primary and secondary lipid peroxidation product. The concentrations of low-molecular-weight antioxidants a-tocopherol and citrate and activities of NADP-dependent isocitrate dehydrogenase (EC 1.1.1.41) and aconitate hydratase (EC 4.2.1.3) were also measured. Ischemia was associated with intensification of free radical processes, increased antioxidant activity in subcellular fractions of the myocardium, activation of NADP-isocitrate dehydrogenase, accumulation of citrate, and inhibition of aconitate hydratase. Differential centrifugation, ion exchange chromatography on various ion exchangers, and electrophoresis in polyacrylamide gel revealed no redistribution of enzyme activity between the cytoplasmic and mitochondrial cardiomyocyte fractions during ischemia.
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PMID:Oxidative status and distribution of NADP-dependent isocitrate dehydrogenase and aconitate hydratase in rat cardiomyocytes under normal conditions and during ischemia. 1245 32

Angiotensin II (AngII) type 1 receptor (AT1R) blockers (ARBs) limit left ventricular (LV) dysfunction and necrosis after reperfused myocardial infarction (RMI) and proteomics can detect changes in protein levels after injury. We applied proteomics to detect changes in levels of specific protein in the ischemic zone (IZ) and non-ischemic zone (NIZ) of dog hearts after in vivo RMI (90 min of anterior ischemia; 120 min of reperfusion) and treatment with intravenous vehicle (control) and the ARBs valsartan or irbesartan (10 mg/kg) over 30 min before RMI. We also assessed LV function, infarction and apoptosis. Both ARBs limited the RMI-induced LV dysfunction, infarct size and apoptosis. Proteomics detected differential expression of 5 randomly selected proteins in the IZ compared to the NIZ after RMI: decrease in a subunit of ATP synthase isoform precursor (consistent with increased conversion to a subunit under metabolic stress), M chain creatine kinase (consistent with cellular damage) and ventricular myosin light chain-1 (consistent with structural damage and decreased contractility); and increase in NAD+ -isocitrate dehydrogenase (ICDH) and alpha subunit and ATP synthase D chain (mitochondrial, consistent with metabolic dysfunction). Importantly, changes in NAD+ -ICDH and ATP synthase D chain were reversed by ARB therapy. Thus, proteomics can detect regional changes in metabolic, contractile, and structural proteins after RMI and several of these proteins are favorably modified by ARBs, suggesting that they may be novel therapeutic targets.
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PMID:AT1 receptor blockade alters metabolic, functional and structural proteins after reperfused myocardial infarction: detection using proteomics. 1552 79

The changes in the regulation of at mitochondrial NADP-isocitrate dehydrogenase (NADP-ICDH) in a rat heart during have been analysed. Increase of enzyme activity in the cytosol and mitochondria of the heart ischemia was detected. Catalytic properties of the mitochondrial NADP-ICDH at norm and pathology have been compared on homogeneous enzyme preparations. Enzyme from the normoxic and ischemic heart showed the same electrophoretical mobility and molecular mass. Enzyme isolated from the ischemic heart mitochondria demonstrated higher activation energy and lower thermal stability. NADP-isocitrate dehydrogenase at the normoxic and ischemic conditions exhibited different Km for substrates and regulatory behaviour in relation to ATP, ADP, 2-oxoglutarate, citrate, malate, reduced and oxidised glutathione. The inhibitory effect of the Fe2+ and H2O2 mixture associated with the generation of hydroxyl radicals was lower in the ischemic enzyme. We hypothesise that the specific features of regulation behaviour of NADP-ICDH from the ischemic tissues permits the enzyme to supply NADPH to the glutathione reductase/glutathione peroxidase system.
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PMID:Regulation of mitochondrial NADP-isocitrate dehydrogenase in rat heart during ischemia. 1682 14

Age-related decline in the capacity to withstand stress, such as ischemia and reperfusion, results in congestive heart failure. Though the mechanisms underlying cardiac decay are not clear, age dependent somatic damages to mitochondrial DNA (mtDNA), loss of mitochondrial function, and a resultant increase in oxidative stress in heart muscle cells may be responsible for the increased risk for cardiovascular diseases. The effect of a safe nutritional supplement, POLY-MVA, containing the active ingredient palladium alpha-lipoic acid complex, was evaluated on the activities of the Krebs cycle enzymes such as isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase as well as mitochondrial complexes I, II, III, and IV in heart mitochondria of aged male albino rats of Wistar strain. Administration of 0.05 ml/kg of POLY-MVA (which is equivalent to 0.38 mg complexed alpha-lipoic acid/kg, p.o), once daily for 30 days, was significantly (p<0.05) effective to enhance the Krebs cycle dehydrogenases, and mitochondrial electron transport chain complexes. The unique electronic and redox properties of palladium alpha-lipoic acid complex appear to be a key to this physiological effectiveness. The results strongly suggest that this formulation might be effective to protect the aging associated risk of cardiovascular and neurodegenerative diseases.
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PMID:Palladium alpha-lipoic acid complex formulation enhances activities of Krebs cycle dehydrogenases and respiratory complexes I-IV in the heart of aged rats. 1950 Jun 41

Asperosaponin VI is a saponin of the medicinal herb Dipsacus asper (Xuduan), and no pharmacological activity has been reported yet. In this study, we investigated the anti-myocardial ischemia effects of Asperosaponin VI (ASA VI) both in vivo and in vitro. An animal model of myocardial ischemia(MI) injury was induced by coronary occlusion, pretreatment with ASA VI (10 and 20mg/kg, i.v.) could protect the heart from ischemia injury by decreasing the levels of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), glutamic oxalacetic transaminase (GOT) and cardiac troponin T (cTnT) in serum, increasing the levels of catalase, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) levels in heart, and decreasing that of malondialdehyde (MDA) level in acute MI rats. ASA VI also raised the activities of mitochondrial enzymes (succinate dehydrogenase (SDH), isocitrate dehydrogenase (ICDH), malate dehydrogenase (MDH) and alpha-ketoglutarate dehydrogenase (alpha-KGDH)) and those of adenosine triphosphate (ATP) content, but lowered Ca(2+) level. Electrocardiograph parameters and histopathological observations demonstrated the same protective effects. In vitro experiment, neonatal rat cardiomyocytes were incubated to test the direct cytoprotective effect of ASA VI against H(2)O(2) exposure. Pretreatment with ASA VI (30 and 60 microg/ml) prior to H(2)O(2) exposure increased cell viability and inhibited H(2)O(2)-induced reactive oxygen species increase. ASA VI (15, 30 and 60 microg/ml) also increased the activities of LDH in the cultured supernatant and SOD in cardiomyocytes, but decreased the cardiomyocytes MDA level. Our results suggested that ASA VI could provide significant cardioprotective effects against acute MI in rats. The mechanisms might be attributed to scavenging lipid peroxidation products and reactive oxygen species, increasing antioxidant defense enzymes and preventing mitochondrial damage.
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PMID:Protective roles of Asperosaponin VI, a triterpene saponin isolated from Dipsacus asper Wall on acute myocardial infarction in rats. 1990 36

Brain function depends on complex metabolic interactions among only a few different cell types, with astrocytes providing critical support for neurons. Astrocyte functions include buffering the extracellular space, providing substrates to neurons, interchanging glutamate and glutamine for synaptic transmission with neurons, and facilitating access to blood vessels. Whereas neurons possess highly oxidative metabolism and easily succumb to ischemia, astrocytes rely more on glycolytic metabolism and hence are less susceptible tolack of oxygen. Astrocytoma cells seem to retain basic metabolic mechanisms of astrocytes; for example, they show a high glycolytic rate, lactate extrusion, ability to flourish under hypoxia, and opportunistic use of mechanisms to enhance cell division and maintain growth. Differences in metabolism between neurons and astrocytes may also extend to astrocytoma cells, providing therapeutic opportunities against astrocytomas, including sensitivity to acetate, a high rate of glycolysis and lactate extrusion, glutamate uptake transporters, differential sensitivities of monocarboxylate transporters, presence of glycogen, high interlinking with gap junctions, use of nicotinamide adenine dinucleotide phosphate for lipid synthesis, using different isoforms of synthetic enzymes (e.g. isocitrate dehydrogenase, pyruvate carboxylase, pyruvate kinase, lactate dehydrogenase), and different glucose uptake mechanisms. These unique metabolic susceptibilities may augment conventional therapeutic attacks based on cell division differences and surface receptors alone.
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PMID:Neuronal-astrocyte metabolic interactions: understanding the transition into abnormal astrocytoma metabolism. 2129 95


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