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)

Prolonged heart ischaemia causes an inhibition of oxidative phosphorylation and an increase of Ca2+ in mitochondria. We investigated whether elevated Ca2+ induces changes in the oxidative phosphorylation system relevant to ischaemic damage, and whether Ca2+ and other inducers of mitochondrial permeability transition cause the release of cytochrome c from isolated heart mitochondria. We found that 5 microM free Ca2+ induced changes in oxidative phosphorylation system similar to ischaemic damage: increase in the proton leak and inhibition of the substrate oxidation system related to the release of cytochrome c from mitochondria. The phosphorylating system was not directly affected by high Ca2+ and ischaemia. The release of cytochrome c from mitochondria was caused by Ca2+ and 0.175-0.9 mM peroxynitrite but not by NO, and was prevented by cyclosporin A. Adenylate kinase and creatine kinase were also released after incubation of mitochondria with Ca2+, however, the activity of citrate synthase in the incubation medium with high and low Ca2+ did not change. The data suggest that release of cytochrome c and other proteins of intermembrane space may be due to the opening of the mitochondrial permeability transition pore, and may be partially responsible for inhibition of mitochondrial respiration induced by ischaemia, high calcium, and oxidants.
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PMID:Release of cytochrome c from heart mitochondria is induced by high Ca2+ and peroxynitrite and is responsible for Ca(2+)-induced inhibition of substrate oxidation. 998 44

To investigate the hypothesis that training-induced increases in muscle mitochondrial potential are not obligatory to metabolic adaptations observed during submaximal exercise, regardless of peak aerobic power (VO(2 peak)) of the subjects, a short-term training study was utilized. Two groups of untrained male subjects (n = 7/group), one with a high (HI) and the other with a low (LO) VO(2 peak) (means +/- SE; 51.4 +/- 0.90 vs. 41.0 +/- 1.3 ml. kg(-1). min(-1);P < 0.05), cycled for 2 h/day at 66-69% of VO(2 peak) for 6 days. Muscle tissue was extracted from vastus lateralis at 0, 3, and 30 min of standardized cycle exercise before training (0 days) and after 3 and 6 days of training and analyzed for metabolic and enzymatic changes. During exercise after 3 days of training in the combined HI + LO group, higher (P < 0.05) concentrations (mmol/kg dry wt) of phosphocreatine (40.5 +/- 3.4 vs. 52.2 +/- 4.2) and lower (P < 0.05) concentrations of P(i) (61.5 +/- 4.4 vs. 53.3 +/- 4.4), inosine monophosphate (0.520 +/- 0.19 vs. 0.151 +/- 0.05), and lactate (37.9 +/- 5.5 vs. 22.8 +/- 4.8) were observed. These changes were also accompanied by reduced levels of calculated free ADP, AMP, and P(i). All adaptations were fully expressed by 3 min of exercise and by 3 days of training and were independent of initial VO(2 peak) levels. Moreover, maximal activity of citrate synthase, a measure of mitochondrial capacity, was only increased with 6 days of training (5.71 +/- 0.29 vs. 7.18 +/- 0.37 mol. kg protein(-1). h(-1); P < 0. 05). These results demonstrate that metabolic adaptations to prolonged exercise occur within the first 3 days of training and during the non-steady-state period. Moreover, neither time course nor magnitude of metabolic adaptations appears to depend on increases in mitochondrial potential or on initial aerobic power.
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PMID:Initial aerobic power does not alter muscle metabolic adaptations to short-term training. 1040 26

Bacteroids formed by Mesorhizobium ciceri CC 1192 in symbiosis with chickpea plants (Cicer arietinum L.) contained a single form of citrate synthase [citrate oxaloacetate-lyase (CoA-acetylating) enzyme; EC 4.1.3.7], which had the same electrophoretic mobility as the enzyme from the free-living cells. The citrate synthase from CC 1192 bacteroids had a native molecular mass of 228 +/- 32 kDa and was activated by KCl, which also enhanced stability. Double reciprocal plots of initial velocity against acetyl-CoA concentration were linear, whereas the corresponding plots with oxaloacetate were nonlinear. The Km value for acetyl-CoA was 174 microM in the absence of added KCl, and 88 microM when the concentration of KCl in reaction mixtures was 100 mM. The concentrations of oxaloacetate for 50% of maximal activity were 27 microM without added KCl and 14 microM in the presence of 100 mM KCl. Activity of citrate synthase was inhibited 50% by 80 microM NADH and more than 90% by 200 microM NADH. Inhibition by NADH was linear competitive with respect to acetyl-CoA (Kis = 23.1 +/- 3 microM) and linear noncompetitive with respect to oxaloacetate (Kis = 56 +/- 3.8 microM and Kii = 115 +/- 15.4 microM). NADH inhibition was relieved by NAD+ and by micromolar concentrations of 5'-AMP. In the presence of 50 or 100 mM KCl, inhibition by NADH was apparent only when the proportion of NADH in the nicotinamide adenine dinucleotide pool was greater than 0.6. In the microaerobic environment of bacteroids, NADH may be at concentrations that are inhibitory for citrate synthase. However, this inhibition is likely to be relieved by NAD+ and 5'-AMP, allowing carbon to enter the tricarboxylic acid cycle.
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PMID:Biochemical controls of citrate synthase in chickpea bacteroids. 1064 3

Chronic exposure to high altitude is known to result in changes in the mechanisms regulating O(2) delivery to the contracting muscle. However, the effects of acclimatization on metabolism in the contracting muscle cell remain unclear. In this study, we have investigated the hypothesis that acclimatization would result in a closer coupling between ATP utilization and ATP production and that the improved energy state would be accompanied by a reorganization of the metabolic pathways consisting of an increased oxidative and decreased glycolytic potential. Five men, mean age of 28 +/- 2 (SE) yr, performed a standardized, two-stage submaximal cycling task in normoxia for 20 min at each of 59 and 74% peak O(2) consumption before and 3-4 days after returning from a 21-day expedition to Mount Denali (6,194 m). Acclimatization was without effect in altering the resting values of the adenine nucleotides (ATP, ADP, AMP), inosine monophosphate (IMP), or phosphocreatine (PCr) in the vastus lateralis. During exercise (40 min) after acclimatization compared with preacclimatization, PCr was not as depressed (33.2 +/- 7.1 vs. 40.6 +/- 5.4 mmol/kg dry wt) and IMP (0.289 +/- 0.11 vs. 0. 131 +/- 0.03 mmol/kg dry wt) and lactate (26.1 +/- 6.2 vs. 18.6 +/- 8.8 mmol/kg dry wt) in contracting muscle were not as elevated (P < 0.05). Although no effect of acclimatization was observed for the maximal activity (mol. kg protein(-1). h(-1)) of citrate synthase (4. 76 +/- 0.44 vs. 4.94 +/- 0.45), lactate dehydrogenase was increased by 13% (36.5 +/- 2.6 vs. 41.2 +/- 3.1, P < 0.05). It is concluded that acclimatization results in an improved energy state in the contracting muscle when tested under normoxic conditions; however, these effects are not associated with a higher oxidative potential or a lower glycolytic potential as hypothesized.
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PMID:Human skeletal muscle exercise metabolism following an expedition to mount denali. 1104 73

The metabolic characteristics of five muscle groups in the spiny lobster Jasus edwardsii were examined in order to compare their anaerobic and oxidative capacities. Enzyme activities of phosphorylase, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase were highest in abdominal muscles supporting anaerobic burst activity. Hexokinase, citrate synthase, and HOAD activities in the leg and antennal muscles indicated higher aerobic potential. Arginine kinase activities were high in all muscle groups indicating that muscle phosphagens are an important energy reserve. Arginine phosphate concentrations in 4th periopod and abdominal flexor muscle from lobsters sampled in the field were higher than any values from captive animals, and approximately five times those for ATP. Muscle lactates were high in captive animals. Responses to emersion during simulated live transport appear to exploit the capacity for functional anaerobiosis and further differentiated the muscle groups. Abdominal muscles were especially sensitive and after 24 h showed significant increases in lactate, glucose, ADP, and AMP. ATP levels appeared to be maintained by muscle phosphagens and raised doubts about the efficacy of the adenylate energy charge in evaluating the emersion response. Haemolymph glucose, lactic acid, and ammonia peaked after 24 h emersion and were largely restored following re-immersion. We propose that arginine phosphate concentrations in the 4th periopod are an appropriate index of metabolic stress, and could lead to improved commercial handling protocols.
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PMID:Metabolic characteristics of muscles in the spiny lobster, Jasus edwardsii, and responses to emersion during simulated live transport. 1125 May 38

Yeast NAD(+)-specific isocitrate dehydrogenase (IDH) is an allosterically regulated tricarboxylic acid cycle enzyme that has been shown to bind specifically and with high affinity to 5'-untranslated regions of yeast mitochondrial mRNAs. The absence of IDH has been shown to result in reduced expression of mitochondrial translation products, leading to the suggestion that this macromolecular interaction may contribute to regulating rates of translation. The interaction with mitochondrial mRNAs also produces a dramatic inhibition of IDH catalytic activity that is specifically alleviated by AMP, the primary allosteric activator of IDH. Using mutant forms of IDH with defined catalytic or regulatory kinetic defects, we found that residue changes altering ligand binding in the catalytic site reduce the inhibitory effect of a transcript from the mitochondrial COX2 mRNA. In contrast, residue changes altering binding of allosteric regulators do not prevent inhibition by the COX2 RNA transcript but do prevent alleviation of inhibition by AMP. Results obtained using surface plasmon resonance methods suggest that the mRNA transcript may bind at the active site of IDH. Also, the presence of AMP has little effect on overall affinity but renders the binding of mRNA ineffective in catalytic inhibition of IDH. Finally, by expressing mutant forms of IDH in vivo, we determined that detrimental effects on levels of mitochondrial translation products correlate with a substantial reduction in catalytic activity. However, concomitant loss of IDH and of citrate synthase eliminates these effects, suggesting that any role of IDH in mitochondrial translation is indirect.
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PMID:Analysis of interactions with mitochondrial mRNA using mutant forms of yeast NAD(+)-specific isocitrate dehydrogenase. 1634 68

The hyperthermophilic archaeon Pyrobaculum islandicum uses the citric acid cycle in the oxidative and reductive directions for heterotrophic and autotrophic growth, respectively, but the control of carbon flow is poorly understood. P. islandicum was grown at 95 degrees C autotrophically, heterotrophically, and mixotrophically with acetate, H2, and small amounts of yeast extract and with thiosulfate as the terminal electron acceptor. The autotrophic growth rates and maximum concentrations of cells were significantly lower than those in other media. The growth rates on H2 and 0.001% yeast extract with and without 0.05% acetate were the same, but the maximum concentration of cells was fourfold higher with acetate. There was no growth with acetate if 0.001% yeast extract was not present, and addition of H2 to acetate-containing medium greatly increased the growth rates and maximum concentrations of cells. P. islandicum cultures assimilated 14C-labeled acetate in the presence of H2 and yeast extract with an efficiency of 55%. The activities of 11 of 19 enzymes involved in the central metabolism of P. islandicum were regulated under the three different growth conditions. Pyruvate synthase and acetate:coenzyme A (CoA) ligase (ADP-forming) activities were detected only in heterotrophically grown cultures. Citrate synthase activity decreased in autotrophic and acetate-containing cultures compared to the activity in heterotrophic cultures. Acetylated citrate lyase, acetate:CoA ligase (AMP forming), and phosphoenolpyruvate carboxylase activities increased in autotrophic and acetate-containing cultures. Citrate lyase activity was higher than ATP citrate synthase activity in autotrophic cultures. These data suggest that citrate lyase and AMP-forming acetate:CoA ligase, but not ATP citrate synthase, work opposite citrate synthase to control the direction of carbon flow in the citric acid cycle.
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PMID:Citric acid cycle in the hyperthermophilic archaeon Pyrobaculum islandicum grown autotrophically, heterotrophically, and mixotrophically with acetate. 1674 Sep 41

Essential dynamics sampling simulations of the domain conformations of unliganded Escherichia coli adenylate kinase have been performed to determine whether the ligand-induced closed-domain conformation is accessible to the open unliganded enzyme. Adenylate kinase is a three- domain protein with a central CORE domain and twoflanking domains, the LID and the NMPbind domains. The sampling simulations were applied to the CORE and NMPbind domain pair and the CORE and LID domain pair separately. One aim is to compare the results to those of a similar study on the enzyme citrate synthase to determine whether a similar domain-locking mechanism operates in adenylate kinase. Although for adenylate kinase the simulations suggest that the closed-domain conformation of the unliganded enzyme is at a slightly higher free energy than the open for both domain pairs, the results are radically different to those found for citrate synthase. In adenylate kinase the targeted domain conformations could always be achieved, whereas this was not the case in citrate synthase due to an apparent free-energy barrier between the open and closed conformations. Adenylate kinase has been classified as a protein that undergoes closure through a hinge mechanism, whereas citrate synthase has been assigned to the shear mechanism. This was quantified here in terms of the change in the number of interdomain contacting atoms upon closure which showed a considerable increase in adenylate kinase. For citrate synthase this number remained largely the same, suggesting that the domain faces slide over each other during closure. This suggests that shear and hinge mechanisms of domain closure may relate to the existence or absence of an appreciable barrier to closure for the unliganded protein, as the latter can hinge comparatively freely, whereas the former must follow a more constrained path. In general though it appears a bias toward keeping the unliganded enzyme in the open-domain conformation may be a common feature of domain enzymes.
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PMID:Essential dynamics sampling study of adenylate kinase: comparison to citrate synthase and implication for the hinge and shear mechanisms of domain motions. 1729 45

Disturbances in energy homeostasis can result in obesity and other metabolic diseases. Here we report a metabolic pathway present in normal human skeletal muscle myoblasts that is activated by the small polyphenolic molecule kaempferol (KPF). Treatment with KPF leads to an approximately 30% increase in skeletal myocyte oxygen consumption. The mechanism involves a several-fold increase in cyclic AMP (cAMP) generation and protein kinase A activation, and the effect of KPF can be mimicked via treatment with dibutyryl cAMP. Microarray and real-time PCR studies identified a set of metabolically relevant genes influenced by KPF including peroxisome proliferator-activated receptor gamma coactivator-1alpha, carnitine palmitoyl transferase-1, mitochondrial transcription factor 1, citrate synthase, and uncoupling protein-3, although KPF itself is not a direct mitochondrial uncoupler. The cAMP-responsive gene for type 2 iodothyronine deiodinase (D2), an intracellular enzyme that activates thyroid hormone (T3) for the nucleus, is approximately threefold upregulated by KPF; furthermore, the activity half-life for D2 is dramatically and selectively increased as well. The net effect is an approximately 10-fold stimulation of D2 activity as measured in cell sonicates, with a concurrent increase of approximately 2.6-fold in the rate of T3 production, which persists even 24 h after KPF has been removed from the system. The effects of KPF on D2 are independent of sirtuin activation and only weakly reproduced by other small polyphenolic molecules such as quercetin and fisetin. These data document a novel mechanism by which a xenobiotic-activated pathway can regulate metabolically important genes as well as thyroid hormone activation and thus may influence metabolic control in humans.
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PMID:The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation. 1732 47

One characteristic of ageing skeletal muscle is a decline in mitochondrial function. Activation of AMP-activated protein kinase (AMPK) occurs in response to an increased AMP/ATP ratio, which is one potential result of mitochondrial dysfunction. We have previously observed higher AMPK activity in old (O; 30 months) vs young adult (YA; 8 months) fast-twitch muscle in response to chronic overload. Here we tested the hypothesis that AMPK would also be hyperactivated in O vs YA fast-twitch extensor digitorum longus muscles from Fischer(344) x Brown Norway (FBN) rats (n = 8 per group) in response to high-frequency electrical stimulation of the sciatic nerve (HFES) or injection of AICAR, an activator of AMPK. Muscles were harvested immediately after HFES (10 sets of six 3-s contractions, 10 s rest between contractions, 1 min rest between sets) or 1 h after AICAR injection (1 mg (g body weight)(-1) subcutaneously). The phosphorylations of AMPKalpha and acetyl-CoA carboxylase (ACC2; a downstream AMPK target) were both greatly increased (P <or= 0.05) in response to HFES in O muscles, but were either unresponsive (AMPK alpha) or much less responsive (ACC) in YA muscles. AMPK alpha2 activity was also greatly elevated in response to HFES in O muscles (but not YA muscles) despite a lower total AMPK alpha2 protein content in O vs YA muscles. In contrast, AMPK alpha2 activity was equally responsive to AICAR treatment in both age groups. Since mitochondrial content and/or efficiency could potentially underlie AMPK hyperactivation, we measured levels of mitochondrial proteins as well as citrate synthase (CS) activity. While CS activity was increased by 25% in O vs YA muscles, uncoupling protein-3 (UCP-3) protein level was upregulated with age by 353%. Thus, AMPK hyperactivation in response to contractile activity in aged fast-twitch muscle may be the result of compromised cellular energetics and not necessarily due to an inherent defect in responsiveness of the AMPK molecule per se.
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PMID:AMP-activated protein kinase response to contractions and treatment with the AMPK activator AICAR in young adult and old skeletal muscle. 1927 78


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