scholarly journals Production of tricarballylic acid by rumen microorganisms and its potential toxicity in ruminant tissue metabolism

1986 ◽  
Vol 56 (1) ◽  
pp. 153-162 ◽  
Author(s):  
James B. Russell ◽  
Neil Forsberg
Keyword(s):  
Citric Acid ◽  
Citric Acid Cycle ◽  
Competitive Inhibitor ◽  
Rumen Microorganisms ◽  
Aconitate Hydratase ◽  
Factors Affecting ◽  
Acid Cycle ◽  
Rat Liver Cells ◽  
High Concentrations

1. Rumen microorganisms convert trans-aconitate to tricarballylate. The following experiments describe factors affecting the yield of tricarballylate, its absorption from the rumen into blood and its effect on mammalian citric acid cycle activity in vitro.2. When mixed rumen microorganisms were incubated in vitro with Timothy hay (Phleum praiense L.) and 6.7 mM-trans-aconitate, 64 % of the trans-aconitate was converted to tricarballylate. Chloroform and nirate treatments inhibited methane production and increased the yield of tricarballylate to 82 and 75% respectively.3. Sheep given gelatin capsules filled with 20 g trans-aconitate absorbed tricarballylate and the plasma concentration ranged from 0.3 to 0.5 mM 9 h after administration. Feeding an additional 40 g potassium chloride had little effect on plasma tricarballylate concentrations. Between 9 and 36 h there was a nearly linear decline in plasma tricarballylate.4. Tricarballylate was a competitive inhibitor of the enzyme, aconitate hydratase (aconitase; EC 4.2.1.3), and the inhibitor constant, KI, was 0.52 mM. This KIvalue was similar to the Michaelis-Menten constant (Km) of the enzyme for citrate.5. When liver slices from sheep were incubated with increasing concentrations of tricarballylate, [I4C]acetate oxidation decreased. However, even at relatively high concentrations (8 mM), oxidation was still greater than 80% of the maximum. Oxidation of [I4C]acetate by isolated rat liver cells was inhibited to a greater extent by tricarballylate. Concentrations as low as 0.5 mM caused a 30% inhibition of citric acid cycle activity.

Studies on the Citric Acid Cycle and its Portion of Glucose Breakdown by Calf and Bovine Lenses in vitro

1971 ◽  
Vol 2 (3-4) ◽  
pp. 143-148 ◽  
Author(s):  
O. Hockwin ◽  
G. Blum ◽  
I. Korte ◽  
T. Murata ◽  
W. Radetzki ◽  
...  
Keyword(s):  
Citric Acid ◽  
Citric Acid Cycle ◽  
Acid Cycle

scholarly journals Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates

2006 ◽  
Vol 282 (7) ◽  
pp. 4524-4532 ◽  
Author(s):  
Peppi Koivunen ◽  
Maija Hirsilä ◽  
Anne M. Remes ◽  
Ilmo E. Hassinen ◽  
Kari I. Kivirikko ◽  
...  
Keyword(s):  
Citric Acid ◽  
Transcriptional Activity ◽  
Citric Acid Cycle ◽  
Dimethyl Ester ◽  
Hypoxia Inducible Factor ◽  
Fumarate Hydratase ◽  
High Concentration ◽  
Cultured Fibroblasts ◽  
Acid Cycle

The stability and transcriptional activity of the hypoxia-inducible factors (HIFs) are regulated by two oxygen-dependent events that are catalyzed by three HIF prolyl 4-hydroxylases (HIF-P4Hs) and one HIF asparaginyl hydroxylase (FIH). We have studied possible links between metabolic pathways and HIF hydroxylases by analyzing the abilities of citric acid cycle intermediates to inhibit purified human HIF-P4Hs and FIH. Fumarate and succinate were identified as in vitro inhibitors of all three HIF-P4Hs, fumarate having Ki values of 50–80 μm and succinate 350–460 μm, whereas neither inhibited FIH. Oxaloacetate was an additional inhibitor of all three HIF-P4Hs with Ki values of 400–1000 μm and citrate of HIF-P4H-3, citrate being the most effective inhibitor of FIH with a Ki of 110 μm. Culturing of cells with fumarate diethyl or dimethyl ester, or a high concentration of monoethyl ester, stabilized HIF-1α and increased production of vascular endothelial growth factor and erythropoietin. Similar, although much smaller, changes were found in cultured fibroblasts from a patient with fumarate hydratase (FH) deficiency and upon silencing FH using small interfering RNA. No such effects were seen upon culturing of cells with succinate diethyl or dimethyl ester. As FIH was not inhibited by fumarate, our data indicate that the transcriptional activity of HIF is quite high even when binding of the coactivator p300 is prevented. Our data also support recent suggestions that the increased fumarate and succinate levels present in the FH and succinate dehydrogenase-deficient tumors, respectively, can inhibit the HIF-P4Hs with consequent stabilization of HIF-αs and effects on tumor pathology.

Differential effects of heptanoate and hexanoate on myocardial citric acid cycle intermediates following ischemia-reperfusion

2006 ◽  
Vol 100 (1) ◽  
pp. 76-82 ◽  
Author(s):  
Isidore C. Okere ◽  
Tracy A. McElfresh ◽  
Daniel Z. Brunengraber ◽  
Wenjun Martini ◽  
Joseph P. Sterk ◽  
...  
Keyword(s):  
Citric Acid ◽  
Citric Acid Cycle ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Negative Control ◽  
Saline Control ◽  
Acid Cycle ◽  
Treatment Groups ◽  
Reversible Ischemia

In the normal heart, there is loss of citric acid cycle (CAC) intermediates that is matched by the entry of intermediates from outside the cycle, a process termed anaplerosis. Previous in vitro studies suggest that supplementation with anaplerotic substrates improves cardiac function during myocardial ischemia and/or reperfusion. The present investigation assessed whether treatment with the anaplerotic medium-chain fatty acid heptanoate improves contractile function during ischemia and reperfusion. The left anterior descending coronary artery of anesthetized pigs was subjected to 60 min of 60% flow reduction and 30 min of reperfusion. Three treatment groups were studied: saline control, heptanoate (0.4 mM), or hexanoate as a negative control (0.4 mM). Treatment was initiated after 30 min of ischemia and continued through reperfusion. Myocardial CAC intermediate content was not affected by ischemia-reperfusion; however, treatment with heptanoate resulted in a more than twofold increase in fumarate and malate, with no change in citrate and succinate, while treatment with hexanoate did not increase fumarate or malate but increased succinate by 1.8-fold. There were no differences among groups in lactate exchange, glucose oxidation, oxygen consumption, and contractile power. In conclusion, despite a significant increase in the content of carbon-4 CAC intermediates, treatment with heptanoate did not result in improved mechanical function of the heart in this model of reversible ischemia-reperfusion. This suggests that reduced anaplerosis and CAC dysfunction do not play a major role in contractile and metabolic derangements observed with a 60% decrease in coronary flow followed by reperfusion.

scholarly journals Control of the citric acid cycle by glyoxylate. The mechanism of inhibition of oxoglutarate dehydrogenase, isocitrate dehydrogenase and aconitate hydratase

1969 ◽  
Vol 114 (3) ◽  
pp. 513-518 ◽  
Author(s):  
A. Adinolfi ◽  
R. Moratti ◽  
S. Olezza ◽  
A. Ruffo
Keyword(s):  
Citric Acid ◽  
Isocitrate Dehydrogenase ◽  
Citric Acid Cycle ◽  
Direct Interaction ◽  
Inhibitory Effect ◽  
Aconitate Hydratase ◽  
Acid Cycle ◽  
Mechanism Of Inhibition ◽  
Oxoglutarate Dehydrogenase ◽  
Thiamin Pyrophosphate

1. The effects of glyoxylate on partially purified preparations of aconitate hydratase, isocitrate dehydrogenase and oxoglutarate dehydrogenase were compared with those of oxalomalate and hydroxyoxoglutarate (obtained by condensation of glyoxylate with oxaloacetate and pyruvate respectively). 2. Glyoxylate (1mm) did not affect aconitate hydratase and isocitrate dehydrogenase, whereas oxalomalate (1mm) inhibited the enzyme activities completely. 3. Glyoxylate (0·025mm) inhibited oxoglutarate dehydrogenase irreversibly, whereas the same concentrations of oxalomalate and hydroxyoxoglutarate were ineffective. This inhibitory effect was prevented if oxoglutarate, pyruvate or oxaloacetate was mixed with the enzyme before the glyoxylate. 4. Incubation of oxoglutarate dehydrogenase with radioactive glyoxylate produced radioactive carbon dioxide; radioactivity was also recovered in the portion of the enzyme identified with thiamin pyrophosphate. 5. The behaviour of glyoxylate in producing multiple inhibitions of the citric acid cycle, either by direct interaction with oxoglutarate dehydrogenase, or by means of its condensation compounds which inhibit aconitate hydratase and isocitrate dehydrogenase, is discussed.

Effect of growth substrate on enzymes of the citric and glyoxylic acid cycles in Thiobacillus novellus

1971 ◽  
Vol 17 (5) ◽  
pp. 617-624 ◽  
Author(s):  
A. Michael Charles
Keyword(s):  
Citric Acid ◽  
High Speed ◽  
Citric Acid Cycle ◽  
Nadh Oxidase ◽  
Specific Activity ◽  
Glyoxylic Acid ◽  
Growth Substrate ◽  
Malic Dehydrogenase ◽  
Aconitate Hydratase ◽  
Acid Cycle

A quantitative study was conducted of enzymes involved in the citric acid cycle and associated systems of the facultative autotroph Thiobacillus novellus grown on five different substrates. Irrespective of the growth substrate the organism possessed complete citric and glyoxylic acid cycles and the specific activity of α-ketoglutarate dehydrogenase was always quite low. Also, the activities of the enzymes of both cycles were usually lowest in extracts from autotrophic cells, and highest in extracts from acetate-grown cells. The three remaining extracts had activities that were between the two extremes with those from glucose-grown cells generally lower than those from pyruvate and succinate. Several exceptions should be noted among these generalizations. For example, the activity of aconitate hydratase and malic dehydrogenase was lowest in extracts from glucose-grown cells while that of isocitric dehydrogenase was lowest in extracts from pyruvate-grown cells. Transhydrogenase activity was virtually absent from extracts of pyruvate- and succinate-grown cells while NADH oxidase, which was identical in these two extracts, was also relatively low. Of interest is the large amount of cytochrome c found in high-speed supernatants. In extracts from autotrophic cells this was about 2.3% of the soluble protein and is suggestive of a significant role being played by the electron-transport system during growth of the organism.

Pyruvate and citric acid cycle carbon requirements in isolated skeletal muscle mitochondria

2004 ◽  
Vol 286 (3) ◽  
pp. C565-C572 ◽  
Author(s):  
Jeffrey I. Messer ◽  
Matthew R. Jackman ◽  
Wayne T. Willis
Keyword(s):  
Skeletal Muscle ◽  
Citric Acid ◽  
Citric Acid Cycle ◽  
Thermodynamic Force ◽  
Glycogen Depletion ◽  
Acid Cycle ◽  
Physiological Range ◽  
Skeletal Muscle Mitochondria

Carbohydrate depletion precipitates fatigue in skeletal muscle, but, because pyruvate provides both acetyl-CoA for mainline oxidation and anaplerotic carbon to the citric acid cycle (CAC), the mechanism remains obscure. Thus pyruvate and CAC kinetic parameters were independently quantified in mitochondria isolated from rat mixed skeletal muscle. Mitochondrial oxygen consumption rate ( Jo) was measured polarographically while either pyruvate or malate was added stepwise in the presence of a saturating concentration of the other substrate. These substrate titrations were carried out across a physiological range of fixed extramitochondrial ATP free energy states (ΔGP), established with a creatine kinase energy clamp, and also at saturating [ADP]. The apparent Km,malate for mitochondrial Jo ranged from 21 to 32 μM, and the apparent Km,pyruvate ranged from 12 to 26 μM, with both substrate Km values increasing as ΔGP declined. Vmax for both substrates also increased as ΔGP fell, reflecting thermodynamic control of Jo. Reported in vivo skeletal muscle [malate] are >10-fold greater than the Km,malate determined in this study. In marked contrast, the Km,pyruvate determined is near the [pyruvate] reported in muscle approaching exhaustion associated with glycogen depletion. When data were evaluated in the context of a linear thermodynamic force-flow (ΔGP- Jo) relationship, the ΔGP- Jo slope was essentially insensitive to changes in [malate] in the range observed in vivo but decreased markedly with declining [pyruvate] across the physiological range. Mitochondrial respiration is particularly sensitive to variations in [pyruvate] in the physiological range. In contrast, physiological [malate] exerts very little, if any, influence on mitochondrial pyruvate oxidation measured in vitro.

scholarly journals In vitro evidence that d-serine disturbs the citric acid cycle through inhibition of citrate synthase activity in rat cerebral cortex

2009 ◽  
Vol 1298 ◽  
pp. 186-193 ◽  
Author(s):  
Ângela Zanatta ◽  
Patrícia Fernanda Schuck ◽  
Carolina Maso Viegas ◽  
Lisiane Aurélio Knebel ◽  
Estela Natacha Brandt Busanello ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Citric Acid ◽  
Citric Acid Cycle ◽  
Citrate Synthase ◽  
Rat Cerebral Cortex ◽  
Acid Cycle
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