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)

NADH:ubiquinone reductase (complex I) of the mitochondrial inner membrane respiratory chain binds a number of mitochondrial matrix NAD-linked dehydrogenases. These include pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase complex, mitochondrial malate dehydrogenase, and beta-hydroxyacyl-CoA dehydrogenase. No binding was detected between complex I and cytosolic malate dehydrogenase, glutamate dehydrogenase, NAD-isocitrate dehydrogenase, lipoamide dehydrogenase, citrate synthase, or fumarase. The dehydrogenases that bound to complex I did not bind to a preparation of complex II and III, nor did they bind to liposomes. The binding of pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase complex, and mitochondrial malate dehydrogenase to complex I is a saturable process. Based upon the amount of binding observed in these in vitro studies, there is enough inner membrane present in the mitochondria to bind the dehydrogenases in the matrix space. The possible metabolic significance of these interactions is discussed.
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PMID:Complex I binds several mitochondrial NAD-coupled dehydrogenases. 643 16

Considerable variations were found in the in vitro effect of alloxan on mouse liver enzymes associated with the citric acid cycle. The following approximative alloxan concentrations induced 50% inhibition of enzyme activity: 10(-6)M for aconitase, 10(-4)M for NAD-linked isocitrate dehydrogenase, glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinyl-CoA synthetase and fumarase, and 10(-3)M for citrate synthase and NADP-linked isocitrate dehydrogenase. Pyruvate dehydrogenase, succinate dehydrogenase and malate dehydrogenase were not inhibited by 10(-3)M alloxan. The inhibition of aconitase was competitive both when using mouse liver and purified porcine heart enzyme. The Ki values for the purified enzyme in the presence of 5 microM alloxan were 0.22 microM with citrate, 4.0 microM with cis-aconitate and 0.62 microM with isocitrate as substrate. The high sensitivity of aconitase for inhibition by alloxan probably plays a prominent role for the toxic effects of alloxan.
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PMID:Inhibition by alloxan of mitochondrial aconitase and other enzymes associated with the citric acid cycle. 651 May 22

In Bacillus subtilis, conditions causing partial deprivation of guanine nucleotides initiated sporulation and caused the synthesis of citrate synthase, aconitase, and alpha-ketoglutarate dehydrogenase. Alpha-ketoglutarate dehydrogenase could also be induced by acetate, and the specific activity of this enzyme was elevated in mutants that had high intracellular acetyl coenzyme A concentrations because they lacked citrate synthase activity. After deprivation of guanine nucleotides, the intracellular concentration of acetyl coenzyme A also increased, which explained the induction of alpha-ketoglutarate dehydrogenase. Furthermore, the decreases in alpha-ketoglutarate and L-malate concentrations observed during this deprivation accounted for the observed increases in citrate synthase activity (which was repressed by alpha-ketoglutarate and malate) and aconitase activity (which was repressed by alpha-ketoglutarate).
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PMID:Induction of citric acid cycle enzymes during initiation of sporulation by guanine nucleotide deprivation. 678 18

Defects in complex I and alpha-ketoglutarate dehydrogenase (alpha-KGDH) occur in the substantia nigra in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) are implicated in the cause of PD as endogenous toxins and are inhibitors of complex I. However, their effects on alpha-KGDH and other mitochondrial non-respiratory chain enzymes are unknown. We have examined the effects of six isoquinoline derivatives (isoquinoline, N-methylisoquinolinium, N-n-propylisoquinolinium, 1,2,3,4-tetrahydroisoquinoline, N-methyl-1,2,3,4-tetrahydroisoquinoline and salsolinol) and MPP+ on the activities of alpha-KGDH, citrate synthase (CS) and glutamate dehydrogenase (GDH) in mitochondrial fragments from rat forebrain. None of the compounds examined had any effect on CS or GDH activity. In contrast, all isoquinoline derivatives investigated and MPP+ inhibited alpha-KGDH activity in a concentration-dependent manner with IC50s ranging from 2.0 to 18.9 mM. MPP+ was previously shown to inhibit alpha-KGDH, but this is the first report of inhibition of alpha-KGDH by isoquinoline derivatives. These findings may represent an additional mechanism contributing to mitochondrial dysfunction and cell death in Parkinson's disease.
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PMID:Inhibition of alpha-ketoglutarate dehydrogenase by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 766 87

We conducted an extensive mass isotopomer analysis of citric acid cycle and gluconeogenic metabolites isolated from livers of overnight fasted rats perfused with 4 mM glucose, 0.2 mM octanoate, 1 mM [U-13C3]lactate, and 0.2 mM [U-13C3]pyruvate, in the anterograde or retrograde mode. In both perfusion modes, two distinct isotopomer patterns were observed: (i) those of phosphoenolpyruvate, glucose, malate, and aspartate and (ii) those of citrate, alpha-ketoglutarate, glutamate, and glutamine. Key citric acid cycle parameters and, hence, rates of gluconeogenesis, calculated (Lee, W.-N.P. (1989) J. Biol. Chem. 264, 13002-13004 and Lee, W.-N.P. (1993) J. Biol. Chem. 268, 25522-25526) from our mass isotopomer data did not only vary, but lead to conclusions inconsistent with Lee's citric acid cycle model. Compared to lactate and pyruvate uptake, which sets an upper limit to glucose production, rates of gluconeogenesis calculated (i) with the phosphoenolpyruvate and citrate data were similar, but those calculated (ii) with the glutamate data amounted to only 60%, which is unlikely. All these conclusions are independent of the perfusion modes. We provide evidence that the following processes contribute to the observed labeling discrepancy: (i) the reversibility of the isocitrate dehydrogenase reaction and (ii) an active citrate cleavage pathway for the transfer of the oxaloacetate carbon skeleton from mitochondria to the cytosol. Also, a good fit of our labeling data was obtained with a model of citric acid cycle and gluconeogenesis which we developed to incorporate the above reactions (Fernandez, C.A., and Des Rosiers, C. (1995) J. Biol. Chem. 270, 10037-10042). The following conclusions can be drawn from the calculated reaction rates: (i) about half of the lactate conversion to glucose occurs via the citrate cleavage pathway, (ii) the flux through the reversal of the isocitrate dehydrogenase reaction is almost as fast as that through the citrate synthase reaction, and (iii) the flux through citrate synthase and alpha-ketoglutarate dehydrogenase is 1.6- and 3.2-fold that through pyruvate carboxylase, respectively.
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PMID:Isotopomer analysis of citric acid cycle and gluconeogenesis in rat liver. Reversibility of isocitrate dehydrogenase and involvement of ATP-citrate lyase in gluconeogenesis. 773 Mar 4

We have developed and implemented a model that can predict the positional isotopomer distribution of various hepatic metabolites labeled with [U-13C3]lactate and/or [U-13C3]pyruvate for given relative flux rates through the citric acid cycle and gluconeogenesis reactions. Our model includes (i) isotopic exchange between alpha-ketoglutarate and glutamate, (ii) a reversible isocitrate dehydrogenase reaction, (iii) an active ATP-citrate lyase, and (iv) aspartate and malate shuttles with separate cytosolic and mitochondrial pools for oxaloacetate, malate, and fumarate. A parameter estimation routine fit the mass isotopomer distribution of selected metabolites measured by gas chromatography-mass spectrometry to the model predicted distributions. We fit measured mass isotopomer distributions of phosphoenolpyruvate, citrate, alpha-ketoglutarate, glutamate, and pyruvate isolated from fasted rat livers perfused with [U-13C3]lactate + [U-13C3]pyruvate. This fitting yielded rates which we express relative to that of pyruvate carboxylase: citric acid cycle represented by the irreversible alpha-ketoglutarate dehydrogenase = 0.32; citrate synthase = 0.64; reversal of isocitrate dehydrogenase = 0.52; citrate lyase = 0.33, aspartate shuttle = 0.24, and malate shuttle = 0.44. Rates calculated for the cytosolic and mitochondrial fumarate and malate dehydrogenase reactions are subject to uncertainties as indicated by identifiability analyses. Previous forms of our model that did not include pyruvate kinase, exchange of alpha-ketoglutarate with glutamate, reversibility of isocitrate dehydrogenase, and/or ATP-citrate lyase activity were not as successful at predicting our measured values. This model offers a general tool for studying the regulation of the citric acid cycle and gluconeogenesis and can be readily modified for any 13C-labeled lactate or pyruvate substrate.
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PMID:Modeling of liver citric acid cycle and gluconeogenesis based on 13C mass isotopomer distribution analysis of intermediates. 773 Mar 5

A comparative study was carried out on the glucose metabolism in Babesia microti (BM) and Babesia rodhaini (BR) by analyzing the enzyme activities. The lactate dehydrogenase (LDH) activity in BM showed significantly lower values than that in BR, whereas citrate synthase (CS) and malate dehydrogenase (MDH) activities were remarkably higher in BM. In addition, pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (ICDH), alpha-ketoglutarate dehydrogenase (KGDH), and succinate dehydrogenase (SDH) activities also tended to be higher in BM. Then, the change of enzyme activities related to the proliferation of parasites was examined. In BM infected mice, the parasitemia increased from day 15 to day 19 after inoculation (a.i.). While BM showed decrease of G6PD and LDH activities at day 19 a.i., it showed remarkably increased activities in CS and MDH (368 and 8,842 nmol/min.mg protein, respectively). In addition, PDH, ICDH, KGDH, and SDH activities also tended to increase from day 15 to 19 a.i. In BR infected mice, parasitemia increased from day 9 to day 12 a.i. LDH activity showed a considerable increase at day 12 a.i. (12,920 IU/mg.protein). Although CS and MDH activities also showed a slight increase at day 12 a.i., the activities of PDH, ICDH, KGDH and SDH didn't change from day 9 to 12 a.i. Since these changes observed in the enzyme activities of BM and BR seemed to be correlated with their proliferation, it was suggested that BM and BR depended on aerobic and anaerobic pathways, respectively, for their glucose metabolism.
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PMID:Enzyme activities related to glucose metabolism in Babesia microti and Babesia rodhaini. 775 34

The results from the experiments performed with a mutant deficient in citrate synthase activity can be summarized as follows. (1) Totally blocking entry into the TCA cycle did not appreciably alter the cellular ATP yield. The unchanged yield suggests that for growth on abundant glucose, the sensitivity of ATP yield to TCA cycle flux is low. ATP production in the mutant is altered, in part, by modulating the relative amounts of formate and acetate produced. (2) The in vivo operation of pyruvate-formate lyase and malic enzyme corresponds to proposals developed from in vitro studies. Namely, pyruvate activates the former, and acetyl CoA inhibits the latter. Overall, the diversion of pyruvate to formate under aerobic conditions constitutes an adaptation of the mutant to the enzymatic lesion. The low alpha-ketoglutarate dehydrogenase flux estimated for the mutant indicates that the enzyme is highly repressed in cells growing rapidly on glucose, which is in accord with prior induction-repression studies. Moreover, the lack of a change in uptake flux during the bulk of batch growth is consistent with prior induction-repression studies. (3) The mutant exhibits a heightened sensitivity to CO2 as compared to wild-type counterparts. Growth rate is increased, and the production of formate, malate, glycerate, and pyruvate is reduced. This sensitivity illustrates that citrate synthase is more than an expendable component in an amphibolic pathway. Its presence in wild-type cells "immunizes" against the effect of CO2 fluctuations. (4) The effects of CO2 can be tentatively explained by assuming that the PEP carboxylase-catalyzed reaction is stimulated.
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PMID:Flux adaptations of citrate synthase-deficient Escherichia coli. 783 22

Weiss et al. (Circ. Res. 70: 392-408, 1992) proposed a model of the citric acid cycle (CAC) in myocytes and a system of 17 differential equations that can be used to describe the changes over time in enrichment of carbons C-2 and C-4 of glutamate under conditions of metabolic steady state. They also proposed an empirical measure (KT) of flux through the CAC, which has been shown to be correlated to O2 consumption in rat hearts perfused with acetate or a mixture of glucose and acetate. We report a new method for estimation of the absolute rate of the flux through the CAC in heart (vTCA), without the numerical solution of differential equations. Unlike KT, our estimate is equal to the rate of flux catalyzed by the alpha-ketoglutarate dehydrogenase complex (vTCA), not merely correlated with it. We also estimate the rate of flux catalyzed by aspartate aminotransferase (vTA) and by NADP(+)-dependent malic enzyme (an anaplerotic reaction). The formula for vTCA during administration of [2-13C]acetate is as follows: vTCA = M[(C-2ssLC-4)/[C-4ss(LC-4-LC-2)]], where C-2ss and C-4ss represent steady-state fractional enrichment, LC-2 and LC-4 represent dominant rate constants of C-2 and C-4 of glutamate, respectively, and M is the sum of concentrations of aspartate, glutamate, and intermediates of the CAC. The assumptions underlying our formula are as follows: 1) metabolic steady state is maintained, 2) exchange of molecules between cytosolic and mitochondrial compartments is rapid, 3) 13C enters pools of the CAC only from acetyl CoA via citrate synthase, 4) [citrate]/[glutamate] < 1 + (vTCA/vTA), and 5) (m-[glutamate])/M < C-2ss/C-4ss.
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PMID:Estimation of TCA cycle flux, aminotransferase flux, and anaplerosis in heart: validation with syntactic model. 790 Jul 86

In substantia nigra from patients with Parkinson's disease, there are decreased levels of reduced glutathione (GSH) and diminished activities of mitochondrial complex I and alpha-ketoglutarate dehydrogenase (alpha-KGDH), along with increased activity of superoxide dismutase (SOD). However, the interrelationship among these events is uncertain. We now report the effect of decreased brain GSH levels on SOD and mitochondrial respiratory enzyme activity in rat brain. In addition, we have investigated the ability of thioctic acid, an endogenous antioxidant, to alter these parameters. Unilateral or bilateral intracerebroventricular (ICV) administration of buthionine sulphoximine (BSO; 1 x 3.2 mg or 2 x 1.6 mg) over a 48-hr period reduced cortical GSH by 55-70%. There was no change in the activity of complex I, II/III, or IV or of citrate synthase in cortex. Similarly, there was no alteration of mitochondrial or cytosolic SOD activity. Thioctic acid (50 or 100 mg/kg IP) alone had no effect on cortical GSH levels in control animals and did not reverse the decrease in GSH levels produced by unilateral or bilateral ICV BSO administration. Thioctic acid (50 or 100 mg/kg IP) had no overall effect on complex I, II/III, or IV or on citrate synthase activity in control animals. Thioctic acid also did not alter cortical mitochondrial respiratory enzyme activity in BSO-treated rats. At the lower dose, thioctic acid tended to increase mitochondrial and cytosolic SOD activity in control animals and in BSO-treated rats. However, at the higher dose, thioctic acid tended to decrease mitochondrial SOD activity. Overall, there was no consistent effect of thioctic acid (50 or 100 mg/kg IP) on SOD activity in control or BSO-treated animals. This study shows that BSO-induced glutathione deficiency does not lead to alterations in mitochondrial respiratory enzyme activity or to changes in SOD activity. GSH depletion in Parkinson's disease therefore may not account for the alterations occurring in complex I and mitochondrial SOD in substantia nigra. Thioctic acid did not alter brain GSH levels or mitochondrial function. Interestingly, however, it did produce some alterations in SOD activity, which may reflect either its antioxidant activity or its ability to act as a thiol-disulphide redox couple.
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PMID:Mitochondrial respiratory enzyme function and superoxide dismutase activity following brain glutathione depletion in the rat. 898 27


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