Compartmentation of glutamate metabolism in brain. Evidence for the existence of two different tricarboxylic acid cycles in brain

1. 14C from [1−14C]glucose injected intraperitoneally into mice is incorporated into glutamate, aspartate and glutamine in the brain to a much greater extent than 14C from [2−14C]glucose. This difference for [1−14C]glucose and [2−14C]glucose increases with time. The amount of 14C in C-1 of glutamate increases steadily with time with both precursors. It is suggested that a large part of the glutamate and aspartate pools in brain are in close contact with intermediates of a fast-turning tricarboxylic acid cycle. 2. 14C from [1−14C]acetate and [2−14C]acetate is incorporated to a much larger extent into glutamine than into glutamate. An examination of the time-course of 14C incorporated into glutamine and glutamate reveals that glutamine is not formed from the glutamate pool, labelled extensively by glucose, but from a small glutamate pool. This small glutamate pool is not derived from an intermediate of a fast-turning tricarboxylic acid cycle. 3. It is proposed that two different tricarboxylic acid cycles exist in brain.

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Effects of sevoflurane anesthesia and abdominal surgery on the systemic metabolome: a prospective observational study

BMC Anesthesiology ◽

10.1186/s12871-021-01301-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yiyong Wei ◽

Donghang Zhang ◽

Jin Liu ◽

Mengchan Ou ◽

Peng Liang ◽

...

Keyword(s):

Abdominal Surgery ◽

General Anesthesia ◽

Tricarboxylic Acid Cycle ◽

Tricarboxylic Acid ◽

Metabolic Changes ◽

Sevoflurane Anesthesia ◽

Glutamate Metabolism ◽

Acid Cycle ◽

Link Type ◽

The Mean

Abstract Background Metabolic status can be impacted by general anesthesia and surgery. However, the exact effects of general anesthesia and surgery on systemic metabolome remain unclear, which might contribute to postoperative outcomes. Methods Five hundred patients who underwent abdominal surgery were included. General anesthesia was mainly maintained with sevoflurane. The end-tidal sevoflurane concentration (ETsevo) was adjusted to maintain BIS (Bispectral index) value between 40 and 60. The mean ETsevo from 20 min after endotracheal intubation to 2 h after the beginning of surgery was calculated for each patient. The patients were further divided into low ETsevo group (mean − SD) and high ETsevo group (mean + SD) to investigate the possible metabolic changes relevant to the amount of sevoflurane exposure. Results The mean ETsevo of the 500 patients was 1.60% ± 0.34%. Patients with low ETsevo (n = 55) and high ETsevo (n = 59) were selected for metabolomic analysis (1.06% ± 0.13% vs. 2.17% ± 0.16%, P < 0.001). Sevoflurane and abdominal surgery disturbed the tricarboxylic acid cycle as identified by increased citrate and cis-aconitate levels and impacted glycometabolism as identified by increased sucrose and D-glucose levels in these 114 patients. Glutamate metabolism was also impacted by sevoflurane and abdominal surgery in all the patients. In the patients with high ETsevo, levels of L-glutamine, pyroglutamic acid, sphinganine and L-selenocysteine after sevoflurane anesthesia and abdominal surgery were significantly higher than those of the patients with low ETsevo, suggesting that these metabolic changes might be relevant to the amount of sevoflurane exposure. Conclusions Sevoflurane anesthesia and abdominal surgery can impact principal metabolic pathways in clinical patients including tricarboxylic acid cycle, glycometabolism and glutamate metabolism. This study may provide a resource data for future studies about metabolism relevant to general anaesthesia and surgeries. Trial registration www.chictr.org.cn. identifier: ChiCTR1800014327.

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METABOLIC COMPARTMENTATION IN THE BRAIN: METABOLISM OF A TRICARBOXYLIC ACID CYCLE INTERMEDIATE, [1,4-14C] SUCCINATE, AFTER INTRACEREBRAL ADMINISTRATION

Journal of Neurochemistry ◽

10.1111/j.1471-4159.1974.tb12228.x ◽

1974 ◽

Vol 23 (6) ◽

pp. 1281-1289 ◽

Cited By ~ 16

Author(s):

H. Mouhler. ◽

A. J. Patel ◽

R. Balaazs

Keyword(s):

Brain Metabolism ◽

Tricarboxylic Acid Cycle ◽

Tricarboxylic Acid ◽

Acid Cycle ◽

Metabolic Compartmentation ◽

Intracerebral Administration ◽

The Brain

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Effects of tamoxifen on tricarboxylic acid cycle enzymes in the brain of rats submitted to an animal model of mania induced by amphetamine

Psychiatry Research ◽

10.1016/j.psychres.2013.11.016 ◽

2014 ◽

Vol 215 (2) ◽

pp. 483-487 ◽

Cited By ~ 6

Author(s):

Samira S. Valvassori ◽

Daniela V. Bavaresco ◽

Josiane Budni ◽

Tamara S. Bobsin ◽

Cinara L. Gonçalves ◽

...

Keyword(s):

Animal Model ◽

Tricarboxylic Acid Cycle ◽

Tricarboxylic Acid ◽

Acid Cycle ◽

The Brain

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Dual metabolomic profiling uncovers Toxoplasma manipulation of the host metabolome and the discovery of a novel parasite metabolic capability

10.1101/463075 ◽

2018 ◽

Cited By ~ 1

Author(s):

William J. Olson ◽

David Stevenson ◽

Daniel Amador-Noguez ◽

Laura J. Knoll

Keyword(s):

Pentose Phosphate Pathway ◽

Time Course ◽

Tricarboxylic Acid Cycle ◽

Tricarboxylic Acid ◽

Pentose Phosphate ◽

Acid Cycle ◽

Obligate Intracellular ◽

Host Parasite ◽

Host Metabolism ◽

Sedoheptulose Bisphosphatase

AbstractThe obligate intracellular parasite Toxoplasma gondii is auxotrophic for several key metabolites and must scavenge these from the host. It is unclear how Toxoplasma manipulates host metabolism for its overall growth rate and non-essential metabolites. To address this question, we measured changes in the joint host-parasite metabolome over a time course of infection. Host and parasite transcriptomes were simultaneously generated to determine potential changes in metabolic enzyme levels. Toxoplasma infection increased activity in multiple metabolic pathways, including the tricarboxylic acid cycle, the pentose phosphate pathway, glycolysis, amino acid synthesis, and nucleotide metabolism. Our analysis indicated that changes in some pathways, such as the tricarboxylic acid cycle, derive from the parasite, while changes in others, like the pentose phosphate pathway, were host and parasite driven. Further experiments led to the discovery of a Toxoplasma enzyme, sedoheptulose bisphosphatase, which funnels carbon from glycolysis into ribose synthesis through a energetically driven dephosphorylation reaction. This second route for ribose synthesis resolves a conflict between the Toxoplasma tricarboxylic acid cycle and pentose phosphate pathway, which are both NADP+ dependent. During periods of high energetic and ribose need, the competition for NADP+ could result in lethal redox imbalances. Sedoheptulose bisphosphatase represents a novel step in Toxoplasma central carbon metabolism that allows Toxoplasma to satisfy its ribose demand without using NADP+. Sedoheptulose bisphosphatase is not present in humans, highlighting its potential as a drug target.Author SummaryThe obligate intracellular parasite Toxoplasma is commonly found among human populations worldwide and poses severe health risks to fetuses and individuals with AIDS. While some treatments are available they are limited in scope. A possible target for new therapies is Toxoplasma’s limited metabolism, which makes it heavily reliant in its host. In this study, we generated a joint host/parasite metabolome to better understand host manipulation by the parasite and to discover unique aspects of Toxoplasma metabolism that could serve as the next generation of drug targets. Metabolomic analysis of Toxoplasma during an infection time course found broad activation of host metabolism by the parasite in both energetic and biosynthetic pathways. We discovered a new Toxoplasma enzyme, sedoheptulose bisphosphatase, which redirects carbon from glycolysis into ribose synthesis. Humans lack sedoheptulose bisphosphatase, making it a potential drug target. The wholesale remodeling of host metabolism for optimal parasite growth is also of interest, although the mechanisms behind this host manipulation must be further studied before therapeutic targets can be identified.

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The operation of the γ-aminobutyrate bypath of the tricarboxylic acid cycle in brain tissue in vitro

Biochemical Journal ◽

10.1042/bj1160445 ◽

1970 ◽

Vol 116 (3) ◽

pp. 445-461 ◽

Cited By ~ 253

Author(s):

B. J. Hammond ◽

R. Balázs ◽

Y. Machiyama ◽

T. Julian ◽

D. Richter

Keyword(s):

Amino Acids ◽

Brain Tissue ◽

Time Course ◽

Tricarboxylic Acid Cycle ◽

Specific Radioactivity ◽

Tricarboxylic Acid ◽

Minor Importance ◽

Acid Cycle ◽

Metabolic Compartmentation ◽

High Specific Radioactivity

1. Cerebral-cortex slices prelabelled with γ-amino[1-14C]butyrate (GABA) were incubated in a glucose–saline medium. After the initial rapid uptake there was no appreciable re-entry of 14C into the GABA pool, either from the medium or from labelled metabolites formed in the tissue. The kinetic constants of GABA metabolism were determined by computer simulation of the experimental results by using mathematical procedures. The GABA flux was estimated to be 0.03μmol per min/g, or about 8% of the total flux through the tricarboxylic acid cycle. It was found that the assumption of compartmentation did not greatly affect the estimates of the GABA flux. 2. The time-course of incorporation of 14C into amino acids associated with the tricarboxylic acid cycle was followed with [1-14C]GABA and [U-14C]-glucose as labelled substrates. The results were consistent with the utilization of GABA via succinate. This was confirmed by determining the position of 14C in the carbon skeletons of aspartate and glutamate formed after the oxidation of [1-14C]GABA. These results also indicated that under the experimental conditions the reversal of reactions catalysed by α-oxoglutarate dehydrogenase and glutamate decarboxylase respectively was negligible. The conversion of [14C]GABA into γ-hydroxybutyrate was probably also of minor importance, but decarboxylation of oxaloacetate did occur at a relatively slow rate. 3. When [1-14C]GABA was the labelled substrate there was evidence of a metabolic compartmentation of glutamate since, even before the peak of the incorporation of 14C into glutamate had been reached, the glutamine/glutamate specific-radioactivity ratio was greater than unity. When [U-14C]glucose was oxidized this ratio was less than unity. The heterogeneity of the glutamate pool was indicated also by the relatively high specific radioactivity of GABA, which was comparable with that of aspartate during the whole incubation time (40min). The rates of equilibration of labelled amino acids between slice and medium gave evidence that the permeability properties of the glutamate compartments labelled as a result of oxidation of [1-14C]GABA were different from those labelled by the metabolism of [14C]glucose. The results showed therefore that in brain tissue incubated under the conditions used, the organization underlying metabolic compartmentation was preserved. The observed concentration ratios of amino acids between tissue and medium were also similar to those obtaining in vivo. These ratios decreased in the order: GABA>acidic acids>neutral amino acids>glutamine. 4. The approximate pool sizes of the amino acids in the different metabolic compartments were calculated. The glutamate content of the pool responsible for most of the labelling of glutamine during oxidation of [1-14C]GABA was estimated to be not more than 30% of the total tissue glutamate. The GABA content of the ‘transmitter pool’ was estimated to be 25–30% of the total GABA in the tissue. The structural correlates of metabolic compartmentation were considered.

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