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:2.3.3.1 (citrate synthase)
4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown previously that the combination of a long-acting, non-sulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor (trandolapril) and the Ca2+ channel blocker verapamil improve insulin-stimulated glucose transport in skeletal muscle of the obese Zucker rat, a model of insulin resistance, hyperinsulinemia, and dyslipidemia. In the present study, we investigated the interactions of chronic treatment (28 days) with verapamil (20 mg/kg) and a short-acting, sulfhydryl-containing ACE inhibitor (captopril, 50 mg/kg) in combination on insulinemia, lipidemia, glucose tolerance, and insulin action on skeletal muscle glucose transport (2-deoxyglucose uptake in epitrochlearis) in lean and obese Zucker rats. In lean animals, verapamil alone and in combination with captopril actually increased (P < .05) plasma insulin, whereas in obese animals, verapamil alone worsened the hyperinsulinemia already present, and this effect was abolished by cotreatment with captopril. Captopril alone or in combination with verapamil reduced plasma free fatty acid (FFA) levels in obese rats, but not in lean rats. Captopril alone reduced the glucose-insulin index in obese animals given an oral glucose load, and this was associated with a significant increase in insulin-mediated muscle glucose transport. The greatest improvement in these responses was elicited in obese animals receiving combined captopril and verapamil treatment, and was associated with increases in muscle GLUT-4 glucose transporter protein and hexokinase and citrate synthase activities. In conclusion, these findings indicate that the short-acting, sulfhydryl-containing ACE inhibitor captopril can elicit beneficial metabolic effects on the hyperinsulinemia, dyslipidemia, glucose intolerance, and insulin resistance of muscle glucose transport of the obese Zucker rat. Moreover, there is a positive interactive effect on these pathophysiological parameters between captopril and verapamil in this animal model of insulin resistance.
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PMID:Interactions of captopril and verapamil on glucose tolerance and insulin action in an animal model of insulin resistance. 971 96

Diabetic states are characterized by a raised serum/islet level of triglycerides and a lowered EC50 (concentration at half-maximal stimulation) for glucose-induced insulin secretion. Culturing islets with long-chain fatty acids (FAs) replicates the basal insulin hypersecretion. In a previous study, we showed that the mechanism involved deinhibition of hexokinase by a 60% decrease in glucose-6-phosphate (G-6-P). The key event was proposed to be an increased phosphofructokinase (PFK) Vmax secondary to an upregulatory effect of the FA metabolite, long-chain acyl-coenzyme A (LC-CoA). We now show another contributory factor, a lowered content of the PFK inhibitor citrate. Citrate synthase Vmax and citrate levels were lowered 45% in rat islets cultured with 250 micromol/l oleate for 24 h. Both effects were reversed by triacsin C, an inhibitor of fatty acyl-CoA synthetase, the enzyme that generates LC-CoA. Culturing islets with high doses of glucose (16.7 mmol/l) for 48 h should also raise cytosolic LC-CoA. As predicted, citrate synthase Vmax was lowered and PFK Vmax was increased, both in a triacsin C-reversible fashion. These results show shared selected functional and biochemical properties in beta-cells of so-called glucotoxicity and lipotoxicity.
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PMID:Shared biochemical properties of glucotoxicity and lipotoxicity in islets decrease citrate synthase activity and increase phosphofructokinase activity. 983 20

Complete spinal cord lesion leads to profound metabolic abnormalities and striking changes in muscle morphology. Here we assess the effects of electrically stimulated leg cycling (ESLC) on whole body insulin sensitivity, skeletal muscle glucose metabolism, and muscle fiber morphology in five tetraplegic subjects with complete C5-C7 lesions. Physical training (seven ESLC sessions/wk for 8 wk) increased whole body insulin-stimulated glucose uptake by 33+/-13%, concomitant with a 2.1-fold increase in insulin-stimulated (100 microU/ml) 3-O-methylglucose transport in isolated vastus lateralis muscle. Physical training led to a marked increase in protein expression of GLUT4 (378+/-85%), glycogen synthase (526+/-146%), and hexokinase II (204+/-47%) in vastus lateralis muscle, whereas phosphofructokinase expression (282+/-97%) was not significantly changed. Hexokinase II activity was significantly increased, whereas activity of phosphofructokinase, glycogen synthase, and citrate synthase was not changed after training. Muscle fiber type distribution and fiber area were markedly altered compared to able-bodied subjects before ESLC training, with no change noted in either parameter after ECSL training. In conclusion, muscle contraction improves insulin action on whole body and cellular glucose uptake in cervical cord-injured persons through a major increase in protein expression of key genes involved in the regulation of glucose metabolism. Furthermore, improvements in insulin action on glucose metabolism are independent of changes in muscle fiber type distribution.
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PMID:Exercise-induced overexpression of key regulatory proteins involved in glucose uptake and metabolism in tetraplegic persons: molecular mechanism for improved glucose homeostasis. 983 60

The archaeon Pyrodictium occultum is one of the most thermophilic organisms presently known. Previous experiments provided support for the significant contribution of a high-molecular-mass protein complex to the extreme thermotolerance of P. occultum. This protein complex, the 'thermosome', is composed of two subunits, alpha and beta, which form a hexadecameric double ring complex. In order to obtain the thermosome in amounts sufficient for structural and functional investigations, we produced the two subunits jointly and separately in Escherichia coli BL21(DE3). In all three cases, we isolated soluble, high-molecular-mass double-ring complexes from E. coli BL21(DE3). On electron micrographs, the recombinant complexes were indistinguishable from each other and from the natural thermosome. To characterize the quaternary structure of the recombinant particles, we used native gel electrophoresis, analytical gel filtration, and analytical ultracentrifugation. Spectral analysis, using absorption, fluorescence emission and far-UV circular dichroism spectroscopy were applied to compare the three recombinant protein complexes with the natural thermosome from P. occultum. All three recombinant complex species exhibit ATPase activity. Furthermore, we could demonstrate that the recombinant complexes slow down the aggregation of citrate synthase, alcohol dehydrogenase, and insulin. Thus, we conclude that the recombinant protein complexes exhibit a chaperone-like activity, interacting with non-native proteins; they do so at temperatures far below the lower physiological limit of growth.
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PMID:Recombinant homo- and hetero-oligomers of an ultrastable chaperonin from the archaeon Pyrodictium occultum show chaperone activity in vitro. 987 54

The archaeon Methanopyrus kandleri is the most thermophilic methanogen presently known. It contains a chaperonin (thermosome) which represents a 951 kDa homo-hexadecameric protein complex with NH4+-dependent ATPase activity. Since its synthesis is not increased upon heat shock, we set out to test its chaperone function. In order to obtain the chaperonin in amounts sufficient for functional investigations, the gene encoding the 60 kDa subunit was expressed in E. coili BL21 (DE3) cells. Purification yielded soluble, high-molecular-mass double-ring complexes, indistinguishable from the natural thermosome. In order to study the functional properties of the recombinant protein complex, pig citrate synthase, yeast alcohol dehydrogenase, yeast alpha-glucosidase, bovine insulin, and Thermotoga phosphoglycerate kinase were used as model substrates. The results demonstrate that the recombinant M. kandleri thermosome possesses a chaperone-like activity in vitro, inhibiting aggregation as the major off-pathway-reaction during thermal unfolding and refolding of proteins after chemical denaturation. However, the chaperonin only forms dead-end complexes with its non-native substrates, no release is detectable at temperatures between 25 and 60 degrees C.
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PMID:The recombinant thermosome from the hyperthermophilic archaeon Methanopyrus kandleri: in vitro analysis of its chaperone activity. 1006 37

Spontaneously hypertensive rats (SHR) demonstrate elevated blood pressure, cardiac hypertrophy, glucose intolerance, and insulin resistance compared with age-matched Wistar-Kyoto rats (WKY). We investigated concurrent effects of captopril on blood pressure, cardiac mass, myocardial enzyme activities, glucose tolerance, and insulin action in young male SHR. At 10 weeks of age, SHR were randomized into two groups, one receiving distilled water, the other a captopril solution (50 mg/kg body weight/day). We also examined age-matched WKY receiving distilled water. Blood pressure was measured by tail-cuff during the 4-week treatment period and oral glucose tolerance was tested at the end of treatment. Hearts were weighed and ventricular tissue was assayed for activities of 3-hydroxyacyl-CoA dehydrogenase, citrate synthase, and hexokinase. Growth rates were similar between captopril-treated and control SHR, but less than those of WKY. Captopril reduced blood pressure (134 +/- 8 v 177 +/- 8 mm Hg, P < .05) and left ventricular mass (-18%, P < .05) in SHR. Cardiac enzyme activities also changed with captopril treatment, reflecting an increased capacity for beta-oxidation of fatty acids and reduced potential for glucose phosphorylation in the left ventricle of SHR. Serum concentrations of glucose, insulin, and free fatty acids after a brief fast and in response to oral glucose were not different after captopril treatment, suggesting no improvement in insulin action or glucose tolerance. In summary, treatment of young male SHR with captopril reduces blood pressure and cardiac mass, and promotes a small but significant increase in cardiac capacity for oxidation of fatty acids and reduction of glucose phosphorylation. In contrast, metabolic effects of captopril on oral glucose tolerance and insulin action were not evident.
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PMID:Metabolic, hemodynamic, and cardiac effects of captopril in young, spontaneously hypertensive rats. 1037 67

The glucose-fatty acid cycle of Randle entails two elements: decreased pyruvate dehydrogenase (PDH) activity, which inhibits glucose oxidation, and inhibition of phosphofructokinase (PFK) by a rise in citrate so that glucose-6-phosphate (G-6-P) levels increase, thereby inhibiting hexokinase activity and hence glucose utilization. Chronic exposure of islets to long-chain fatty acids (FA) is reported to lower PDH activity, but the effect on glucose oxidation and glucose-induced insulin secretion is uncertain. We investigated rat islets that were cultured for 4 days with 0.25 mmol/l oleate/5.5 mmol/l glucose. Glucose oxidation was doubled at 2.8 mmol/l glucose and unchanged at 27.7 mmol/l glucose in the FA-cultured islets despite a 35% decrease in assayed PDH activity. Pyruvate content was increased 60%, which may well compensate for the decreased PDH activity and maintain flux through the citric acid cycle. However, a greater diversion of pyruvate metabolism through the pyruvate-malate shuttle is suggested by unchanged pyruvate carboxylase Vmax and a fourfold higher release of malate from isolated mitochondria. The FA-cultured islets also showed increased basal glucose usage and insulin secretion together with a lowered level of G-6-P and 50% reductions in citrate synthase Vmax and the citrate content. Thus, the effects of chronic FA exposure on islet glucose metabolism differ from the glucose-fatty acid interactions reported in some other tissues.
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PMID:Glucose-fatty acid cycle to inhibit glucose utilization and oxidation is not operative in fatty acid-cultured islets. 1048 Jun 4

The effects of acute exercise on myocardial content of glut-1 and glut-4 transporters, insulin and IGF-1 receptors were assessed in control and chronically exercised 24-month-old C57B1/6 mice. Myocardial glut-1, glut-4, insulin receptor (Ins R) and insulin like growth factor-1 receptor (IGF-1 R) protein levels were unaffected by 36 weeks of chronic exercise. However, myocardial protein content of glut-1, but not glut-4, was increased 12 h following an acute exercise bout in control (46%) and chronically exercised (83%) aged animals. This increased glut-1 response following acute exercise occurred despite the finding that the chronic exercise failed to increase cardiac or skeletal muscle oxidative capacity as indicated by no change in citrate synthase activity. Myocardial IGF-1 R content was unaffected by acute exercise whereas Ins R protein content was decreased 12 h following the acute exercise bout in the chronically exercised (-52%) and control (-28%) animals. The effect of acute exercise on the protein content of glut-1 and Ins R was 80 and 84% greater respectively, in the chronically exercised animals. This suggests that the amplitude of the expression of these two proteins may be increased by chronic exercise, thus constituting a form of adaptation.
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PMID:Resistance of the aged myocardium to exercise-induced chronic changes in glucose transport related protein content. 1058 Jun 96

The study purpose was to determine the effect of functional electrical stimulation (FES)-leg cycle ergometer training (30 minutes on 3 d/wk for 8 weeks) on the GLUT-1 and GLUT-4 content of paralyzed skeletal muscle. Biopsy samples of vastus lateralis muscle were obtained pre- and post-training from five individuals with motor-complete spinal cord injury ([SCI] four men and one woman aged 31 to 50 years, 3 to 25 years postinjury involving C5-T8). Western blot analysis indicated that GLUT-1 increased by 52% and GLUT-4 increased by 72% with training (P < .05). This coincided with an increase in the muscle oxidative capacity as indicated by a 56% increase in citrate synthase (CS) activity (P < .05) and an improvement in the insulin sensitivity index as determined from oral glucose tolerance tests (P < .05). It is concluded that FES endurance training is effective to increase glucose transporter protein levels in paralyzed skeletal muscle of individuals with SCI.
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PMID:Functional electrical stimulation exercise increases GLUT-1 and GLUT-4 in paralyzed skeletal muscle. 1058 49

HtrA, which has a high molecular mass of about 500 kDa, is a periplasmic heat shock protein whose proteolytic activity is essential for the survival of Escherichia coli at high temperatures. To determine the structural organization of HtrA, we have used electron microscopy and chemical cross-linking analysis. The averaged image of HtrA with end-on orientation revealed a six-membered, ring-shaped structure with a central cavity, and its side-on view showed a two-layered structure. Thus, HtrA behaves as a dodecamer consisting of two stacks of hexameric ring. HtrA can degrade thermally unfolded citrate synthase and malate dehydrogenase but cannot when in their native form. HtrA degraded partially unfolded casein more rapidly upon increasing the incubation temperature. However, it hydrolyzed oxidized insulin B-chain, which is fully unfolded, at nearly the same rate at all of the temperatures tested. HtrA also rapidly degraded reduced insulin B-chain generated by treatment of insulin with dithiothreitol but not A-chain or intact insulin. Moreover, HtrA degraded fully unfolded alpha-lactalbumin, of which all four disulfide bonds were reduced, but not the native alpha-lactalbumin and its unfolded intermediates containing two or three disulfide bonds. These results indicate that unfolding of the protein substrates, such as by exposure to high temperatures or reduction of disulfide bonds, is essential for their access into the inner chamber of the double ring-shaped HtrA, where cleavage of peptide bonds may occur. Thus, HtrA with a self-compartmentalizing structure may play an important role in elimination of unfolded proteins in the periplasm of Escherichia coli.
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PMID:Selective degradation of unfolded proteins by the self-compartmentalizing HtrA protease, a periplasmic heat shock protein in Escherichia coli. 1060 Mar 91


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