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At least 109 records · Page 6Linked to original sources
PubMed1995

Estimation of TCA cycle flux, aminotransferase flux, and anaplerosis in heart: validation with syntactic model.

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.

Aspartate Aminotransferases↗
PubMed1999

PDH activation by dichloroacetate reduces TCA cycle intermediates at rest but not during exercise in humans.

We hypothesized that dichloroacetate (DCA), which stimulates the pyruvate dehydrogenase complex (PDH), would attenuate the increase in muscle tricarboxylic acid cycle intermediates (TCAI) during exercise by increasing the oxidative disposal of pyruvate and attenuating the flux through anaplerotic pathways. Six subjects were infused with either saline (Con) or DCA (100 mg/kg body mass) and then performed a moderate leg kicking exercise for 15 min, followed immediately by intense exercise until exhaustion (Exh; approximately 4 min). Resting active fraction of PDH (PDH(a)) was markedly increased (P </= 0.05) after DCA vs. Con (2.65 +/- 0.27 vs. 0.64 +/- 0.07 mmol. min(-1). kg wet wt(-1)); however, there were no differences between trials after 1 or 15 min of exercise or at Exh. The sum of five measured TCAI (SigmaTCAI; approximately 90% of total TCAI pool) was lower (P </= 0.05) after DCA vs. Con at rest (0. 78 +/- 0.11 vs. 1.52 +/- 0.23 mmol/kg dry wt, respectively). However, the net increase in muscle TCAI during the first minute of exercise was higher (P </= 0.05) in the DCA trial vs. Con (3.05 +/- 0.45 vs. 2.44 +/- 0.55 mmol. min(-1). kg dry wt(-1), respectively), and consequently, the SigmaTCAI was not different between trials during exercise. We conclude that DCA reduced TCAI pool size at rest by increasing the flux through PDH and diverting pyruvate away from anaplerotic pathways. The reason for the similar absolute increase in TCAI during exercise is not clear but may be related to 1) an initial mismatch between glycolytic flux and PDH flux that provided sufficient pyruvate for anaplerosis in both trials; or 2) a transient inhibition of PDH flux during the DCA trial due to an elevated resting acetyl-CoA-to-CoASH ratio, which augmented the anaplerotic flux of carbon during the rest-to-work transition.

Adult↗
PubMed2003

Short-term training attenuates muscle TCA cycle expansion during exercise in women.

Muscle glycogenolytic flux and lactate accumulation during exercise are lower after 3-7 days of "short-term" aerobic training (STT) in men (e.g., Green HJ, Helyar R, Ball-Burnett M, Kowalchuk N, Symon S, and Farrance B. J Appl Physiol 72: 484-491, 1992). We hypothesized that 5 days of STT would attenuate pyruvate production and the increase in muscle tricarboxylic acid cycle intermediates (TCAI) during exercise, because of reduced flux through the reaction catalyzed by alanine aminotransferase (AAT; pyruvate + glutamate <--> 2-oxoglutarate + alanine). Eight women [22 +/- 1 yr, peak oxygen uptake (Vo2 peak) = 40.3 +/- 4.6 ml. kg-1. min-1] performed seven 45-min bouts of cycle exercise at 70% Vo2 peak over 9 days (1 bout/day; rest only on days 2 and 8). During the first and last bouts, biopsies (vastus lateralis) were obtained at rest and after 5 and 45 min of exercise. Muscle glycogen concentration was approximately 50% higher at rest after STT (493 +/- 38 vs. 330 +/- 20 mmol/kg dry wt; P <or= 0.05), and net glycogenolysis and lactate accumulation were reduced after 5 min of exercise by 59 and 49%, respectively (P <or= 0.05). The net increase in four measured TCAI was approximately 40% lower (P <or= 0.05) during exercise after training (1.68 +/- 0.60 vs. 2.71 +/- 0.44 mmol/kg dry wt), and the net decrease in glutamate concentration was attenuated (P <or= 0.05). We conclude that 1). the contraction-induced increase in flux through AAT is reduced after 5 days of aerobic training and 2). the muscle glycogenolytic response during exercise after STT in women is similar to that in men.

Adult↗
PubMed1993

Utilization of glutamine and of TCA cycle constituents as precursors for transmitter glutamate and GABA.

In the present review evidence is presented that (1) glutamine synthesis in astrocytes is essential for synthesis of GABA in neurons; (2) alpha-ketoglutarate in the presence of alanine (as an amino group donor) can replace glutamine as a precursor for synthesis of transmitter glutamate, but maybe not as a precursor for transmitter GABA; (3) differences exist in the intraneuronal metabolic pathways for utilization of alpha-ketoglutarate plus alanine and of glutamine, and (4) alanine also functions as a substrate for oxidative metabolism in glutamatergic neurons. It should be emphasized that the supply of precursors for transmitter glutamate and GABA in glutamatergic and GABAergic neurons depends on metabolic processes in astrocytes regardless whether glutamine or alpha-ketoglutarate plus L-alanine function as the transmitter precursors. The key reason that an interaction with astrocytes is essential is that both pyruvate carboxylase, the major enzyme in the brain for net synthesis of tricarboxylic acid cycle intermediates, and glutamine synthetase, the enzyme forming glutamine from glutamate, are specifically located in astrocytes, but not in neurons.

Animals↗
PubMed1981

Activities of enzymes required for the conversion of 4-carbon TCA cycle compounds to 3-carbon glycolytic compounds in human diploid fibroblasts.

Phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate carboxylase activities were localized in the mitochondrial (particulate) fraction of human diploid fibroblasts (HDF). Malic enzyme, malate dehydrogenase (MDH) and glutamate oxalacetate transaminase (GOT) were distributed between the mitochondrial and cytosolic (soluble) fractions, the latter two enzymes being more equally distributed than malic enzyme, which was largely cytosolic. The specific activities of mitochondrial PEPCK and cytosolic malic enzyme, MDH and GOT increased during cell growth. The results support an active conversion of 4-carbon tricarboxylic acid cycle intermediates to 3-carbon glycolytic intermediates in HDF.

Aspartate Aminotransferases↗
PubMed2003

Therapeutic effect of Semecarpus anacardium Linn. nut milk extract on carbohydrate metabolizing and mitochondrial TCA cycle and respiratory chain enzymes in mammary carcinoma rats.

Semecarpus anacardium Linn. of the family Anacardiaceae has many applications in the Ayurvedic and Siddha systems of medicine. We have evaluated the effect of S. anacardium nut milk extract on carbohydrate metabolizing enzymes and mitochondrial tricarboxylic acid cycle and respiratory enzymes in liver and kidney mitochondria of dimethyl benzanthracene-induced mammary carcinoma in Sprague-Dawley rats. Mammary carcinoma-bearing rats showed a significant rise in glycolytic enzymes (hexokinase, phosphoglucoisomerase and aldolase) and a simultaneous fall in gluconeogenic enzymes (glucose-6-phosphatase and fructose 1,6-diphosphatase). The activities of mitochondrial enzymes isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, NADH-dehydrogenase and cytochrome C oxidase were significantly lowered in mammary carcinoma-bearing rats when compared with control rats. S. anacardium nut extract administration to tumour-induced animals significantly lowered the glycolytic enzyme activities (hexokinase, phosphoglucoisomerase and aldolase) and there was a rise in gluconeogenic enzymes (glucose-6-phosphatase and fructose 1,6-diphosphatase), which indicated an antitumour and anticancer effect. Comparison of normal control rats and rats administered S. anacardium only as drug control animals showed no significant variations in enzyme activities. S. anacardium nut extract administration to dimethyl benzanthracene-tumour-induced animals significantly increased the activities of mitochondrial enzymes, thereby suggesting its role in mitochondrial energy production.

9,10-Dimethyl-1,2-benzanthracene↗