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)

The effects of 4 weeks of endurance training in conditions of normoxia or hypoxia on muscle characteristics and blood lactate responses after a 5-min constant-load exercise (CLE) at 90% of the power corresponding to the maximal oxygen uptake were examined at sea-level in 13 sedentary subjects. Five subjects trained in normobaric hypoxia (HT group, fraction of oxygen in inspired gas = 13.2%), and eight subjects trained in normoxia at the same relative work rates (NT group). The blood lactate recovery curves from the CLE were fitted to a biexponential time function: La(t) = La(0) + A1(1 - e- gamma 1.t) + A2(1 - e- gamma 2.t), where the velocity constants gamma 1 and gamma 2 denote the lactate exchange and removal abilities, respectively, A1 and A2 are concentration parameters that describe the amplitudes of concentration variations in the space represented by the arterial blood, La(t) is the lactate concentration at time t, and La(0) is the lactate concentration at the beginning of recovery from CLE. Before training, the two groups displayed the same muscle characteristics, blood lactate kinetics after CLE, and gamma 1 and gamma 2 values. Training modified their muscle characteristics, blood lactate kinetics and the parameters of the fits in the same direction, and proportions among the HT and the NT subjects. Endurance training increased significantly the capillary density (by 31%), citrate synthase activity (by 48%) and H isozyme proportion of lactate dehydrogenase (by 24%), and gamma 1 (by 68%) and gamma 2 (by 47%) values. It was concluded that (1) endurance training improves the lactate exchange and removal abilities estimated during recovery from exercises performed at the same relative work rate, and (2) training in normobaric hypoxia results in similar effects on lactate exchange and removal abilities to training in normoxia performed at the same relative work rates. These results, which were obtained non-invasively in vivo in humans during recovery from CLE, are comparable to those obtained in vitro or by invasive methods during exercise and subsequent recovery.
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PMID:Blood lactate exchange and removal abilities after relative high-intensity exercise: effects of training in normoxia and hypoxia. 1141 27

We do not know the mode of action of the ketogenic diet in controlling epilepsy. One possibility is that the diet alters brain handling of glutamate, the major excitatory neurotransmitter and a probable factor in evoking and perpetuating a convulsion. We have found that brain metabolism of ketone bodies can furnish as much as 30% of glutamate and glutamine carbon. Ketone body metabolism also provides acetyl-CoA to the citrate synthetase reaction, in the process consuming oxaloacetate and thereby diminishing the transamination of glutamate to aspartate, a pathway in which oxaloacetate is a reactant. Relatively more glutamate then is available to the glutamate decarboxylase reaction, which increases brain [GABA]. Ketosis also increases brain [GABA] by increasing brain metabolism of acetate, which glia convert to glutamine. GABA-ergic neurons readily take up the latter amino acid and use it as a precursor to GABA. Ketosis also may be associated with altered amino acid transport at the blood-brain barrier. Specifically, ketosis may favor the release from brain of glutamine, which transporters at the blood-brain barrier exchange for blood leucine. Since brain glutamine is formed in astrocytes from glutamate, the overall effect will be to favor the release of glutamate from the nervous system.
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PMID:Ketogenic diet, brain glutamate metabolism and seizure control. 1476 86

Mycolic acids are long chain alpha-alkyl branched, beta-hydroxy fatty acids that represent a characteristic component of the Mycobacterium tuberculosis cell wall. Through their covalent attachment to peptidoglycan via an arabinogalactan polysaccharide, they provide the basis for an essential outer envelope membrane. Mycobacteria possess two fatty acid synthases (FAS); FAS-I carries out de novo synthesis of fatty acids while FAS-II is considered to elongate medium chain length fatty acyl primers to provide long chain (C(56)) precursors of mycolic acids. Here we report the crystal structure of Mycobacterium tuberculosis beta-ketoacyl acyl carrier protein synthase (ACP) II mtKasB, a mycobacterial elongation condensing enzyme involved in FAS-II. This enzyme, along with the M. tuberculosis beta-ketoacyl ACP synthase I mtKasA, catalyzes the Claisen-type condensation reaction responsible for fatty acyl elongation in FAS-II and are potential targets for development of novel anti-tubercular drugs. The crystal structure refined to 2.4 A resolution revealed that, like other KAS-II enzymes, mtKasB adopts a thiolase fold but contains unique structural features in the capping region that may be crucial to its preference for longer fatty acyl chains than its counterparts from other bacteria. Modeling of mtKasA using the mtKasB structure as a template predicts the overall structures to be almost identical, but a larger entrance to the active site tunnel is envisaged that might contribute to the greater sensitivity of mtKasA to the inhibitor thiolactomycin (TLM). Modeling of TLM binding in mtKasB shows that the drug fits the active site poorly and results of enzyme inhibition assays using TLM analogues are wholly consistent with our structural observations. Consequently, the structure described here further highlights the potential of TLM as an anti-tubercular lead compound and will aid further exploration of the TLM scaffold towards the design of novel compounds, which inhibit mycobacterial KAS enzymes more effectively.
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PMID:X-ray crystal structure of Mycobacterium tuberculosis beta-ketoacyl acyl carrier protein synthase II (mtKasB). 1717 27

The bacterial chaperonin GroEL and the co-chaperonin GroES assist in the folding of a number of structurally unrelated substrate proteins (SPs). In the absence of chaperonins, SP folds by the kinetic partitioning mechanism (KPM), according to which a fraction of unfolded molecules reaches the native state directly, while the remaining fraction gets trapped in a potentially aggregation-prone misfolded state. During the catalytic reaction cycle, GroEL undergoes a series of allosteric transitions (T<-->R-->R"-->T) triggered by SP capture, ATP binding and hydrolysis, and GroES binding. We developed a general kinetic model that takes into account the coupling between the rates of the allosteric transitions and the folding and aggregation of the SP. Our model, in which the GroEL allosteric rates and SP-dependent folding and aggregation rates are independently varied without prior assumption, quantitatively fits the GroEL concentration-dependent data on the yield of native ribulose bisphosphate carboxylase/oxygenase (Rubisco) as a function of time. The extracted kinetic parameters for the GroEL reaction cycle are consistent with the available values from independent experiments. In addition, we also obtained physically reasonable parameters for the kinetic steps in the reaction cycle that are difficult to measure. If experimental values for GroEL allosteric rates are used, the time-dependent changes in native-state yield at eight GroEL concentrations can be quantitatively fit using only three SP-dependent parameters. The model predicts that the differences in the efficiencies (as measured by yields of the native state) of GroEL, single-ring mutant (SR1), and variants of SR1, in the rescue of mitochondrial malate dehydrogenase, citrate synthase, and Rubisco, are related to the large variations in the allosteric transition rates. We also show that GroEL/S mutants that efficiently fold one SP at the expense of all others are due to a decrease in the rate of a key step in the reaction cycle, which implies that wild-type GroEL has evolved as a compromise between generality and specificity. We predict that, under maximum loading conditions and saturating ATP concentration, the efficiency of GroEL (using parameters for Rubisco) depends predominantly on the rate of R-->R" transition, while the equilibrium constant of the T<-->R has a small effect only. Both under sub- and superstoichiometric GroEL concentrations, enhanced efficiency is achieved by rapid turnover of the reaction cycle, which is in accord with the predictions of the iterative annealing mechanism. The effects are most dramatic at substoichiometric conditions (most relevant for in vivo situations) when SP aggregation can outcompete capture of SP by chaperonins.
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PMID:Kinetic model for the coupling between allosteric transitions in GroEL and substrate protein folding and aggregation. 1831 71

The administration of the convulsant 3-mercaptopropionic acid (150 mg/kg i.p.) increased the respiratory capacity of mitochondria isolated from rat cerebral cortex. This increase was observed when pyruvate-malate were used as substrates, but oxygen uptake was not activated with succinate, glutamate-malate or ?-ketoglutarate. Citrate synthase activity in rat brain homogenates increased (about 40%) after the administration of convulsant doses of 3-mercaptopropionic acid (50 and 150 mg/kg). This effect was found after seizures but not during seizures or after a dose that did not produce convulsions (20 mg/kg). The enhancement of citrate synthase activity was observed at various oxaloacetate concentrations, with an increase in V(max). The enhancement was still evident after incubation and removal of the soluble phase by centrifugation, but not after freeze-thawing.
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PMID:Citrate synthase activity increases in homogenates of the cerebral cortex from rats treated with the convulsant 3-mercaptopropionic acid. 2049 75