Disorders of glutamate metabolism

Kelly, Andrea; Stanley, Charles A.

doi:10.1002/mrdd.1040

Cited by 89 publications

(84 citation statements)

References 74 publications

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“…In agreement with this finding, the results of a previous study indicate that sepsis induces significant decreases in the lung concentrations of glutamine (37%), glutamate (21%), 2-oxoglutarate (65%), and AMP (18%) in rats (34). Disruptions of glutamate metabolism have been implicated in several clinical disorders in brain, liver, and pancreas (35).…”

Section: Mitochondrial Proteinssupporting

confidence: 77%

Impact of Low and High Tidal Volumes on the Rat Alveolar Epithelial Type II Cell Proteome

Hirsch¹,

Hansen²,

Sapru³

et al. 2007

Am J Respir Crit Care Med

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Rationale: Mechanical ventilation with high tidal volumes leads to increased permeability, generation of inflammatory mediators, and damage to alveolar epithelial cells (ATII). Objectives: To identify changes in the ATII proteome after two different ventilation strategies in rats. Methods: Rats (n ϭ 6) were ventilated for 5 hours with high-and low tidal volumes (VTs) (high VT: 20 ml/kg; low VT: 6 ml/kg). Pooled nonventilated rats served as control animals. ATII cells were isolated and lysed, and proteins were tryptically cleaved into peptides. Cellular protein content was evaluated by peptide labeling of the ventilated groups with 18 O. Samples were fractionated by cation exchange chromatography and identified using electrospray tandem mass spectrometry. Proteins identified by 15 or more peptides were statistically compared using t tests corrected for the false discovery rate. Measurements and Main Results: High VT resulted in a significant increase in airspace neutrophils without an increase in extravascular lung water. Compared with low-VT samples, high-VT samples showed a 32% decrease in the inositol 1,4,5-trisphosphate 3 receptor (p Ͻ 0.01), a 34% decrease in Na ϩ , K ϩ -ATPase (p Ͻ 0.01), and a significantly decreased content in ATP synthase chains. Even low-VT samples displayed significant changes, including a 66% decrease in heat shock protein 90-␤ (p Ͻ 0.01) and a 67% increase in mitochondrial pyruvate carboxylase (p Ͻ 0.01). Significant differences were found in membrane, acute phase, structural, and mitochondrial proteins. Conclusions: After short-term exposure to high-VT ventilation, significant reductions in membrane receptors, ion channel proteins, enzymes of the mitochondrial energy system, and structural proteins in ATII cells were present. The data supports the two-hit concept that an unfavorable ventilatory strategy may make the lung more vulnerable to an additional insult.Keywords: acute lung injury; alveolar epithelium; corticosterone Acute lung injury is a major cause of morbidity (1) and mortality, and mechanical ventilation is critical to survival of most patients with acute lung injury. However, mechanical ventilation with high tidal volumes (Vts) is known to have deleterious side effects. The importance of ventilator-induced lung injury caused by mechanical ventilation has been established by several experimental and clinical studies (2, 3). Avoidance of excessive Vts Mechanical ventilation with high tidal volumes leads to increased permeability, generation of inflammatory mediators, and damage to alveolar epithelial cells that may contribute to ventilator-induced lung injury. What This Study Adds to the FieldUsing a proteomic approach, significant reductions of key proteins in alveolar type II cells from rats were identified after short-term positive-pressure ventilation.during mechanical ventilation reduces the risk of ventilatorinduced injury, and application of a lower Vt strategy to ventilate patients with acute respiratory distress syndrome has been shown to lead to a greater than 2...

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Section: Mitochondrial Proteinssupporting

confidence: 77%

Impact of Low and High Tidal Volumes on the Rat Alveolar Epithelial Type II Cell Proteome

Hirsch¹,

Hansen²,

Sapru³

et al. 2007

Am J Respir Crit Care Med

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“…GPT2 and highly related GPT are among several transaminases that regulate critical metabolic processes, including amino acid metabolism and the tricarboxylic acid (TCA) cycle. Glutamate is also a substrate in the synthesis of glutathione, an important antioxidant in cells (4). We show that GPT2 is localized to mitochondria and is expressed at increasing levels in brain during early postnatal development corresponding to periods of circuit development.…”

Section: Significancementioning

confidence: 82%

Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features

Ouyang

Nakayama

Baytaş

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Mutations that cause neurological phenotypes are highly informative with regard to mechanisms governing human brain function and disease. We report autosomal recessive mutations in the enzyme glutamate pyruvate transaminase 2 (GPT2) in large kindreds initially ascertained for intellectual and developmental disability (IDD). GPT2 [also known as alanine transaminase 2 (ALT2)] is one of two related transaminases that catalyze the reversible addition of an amino group from glutamate to pyruvate, yielding alanine and α-ketoglutarate. In addition to IDD, all affected individuals show postnatal microcephaly and ∼80% of those followed over time show progressive motor symptoms, a spastic paraplegia. Homozygous nonsense p.Arg404* and missense p.Pro272Leu mutations are shown biochemically to be loss of function. The GPT2 gene demonstrates increasing expression in brain in the early postnatal period, and GPT2 protein localizes to mitochondria. Akin to the human phenotype, Gpt2-null mice exhibit reduced brain growth. Through metabolomics and direct isotope tracing experiments, we find a number of metabolic abnormalities associated with loss of Gpt2. These include defects in amino acid metabolism such as low alanine levels and elevated essential amino acids. Also, we find defects in anaplerosis, the metabolic process involved in replenishing TCA cycle intermediates. Finally, mutant brains demonstrate misregulated metabolites in pathways implicated in neuroprotective mechanisms previously associated with neurodegenerative disorders. Overall, our data reveal an important role for the GPT2 enzyme in mitochondrial metabolism with relevance to developmental as well as potentially to neurodegenerative mechanisms.GPT2 | intellectual and developmental disability | mitochondria | metabolomics | spastic paraplegia

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“…Glutamate is associated with processes such as protein synthesis/degradation, ammonia disposal, energy production and neurotransmission [3], thus glutamate plays a significant role in fundamental metabolic processes. As a result, glutamate is present in many cells such as skeletal muscle, liver, intestine and kidneys.…”

Section: Introductionmentioning

confidence: 99%

A novel reagentless glutamate microband biosensor for real-time cell toxicity monitoring

Hughes

Pemberton

Fielden

et al. 2016

Analytica Chimica Acta

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Disclaimer UWE has obtained warranties from all depositors as to their title in the material deposited and as to their right to deposit such material. UWE makes no representation or warranties of commercial utility, title, or fitness for a particular purpose or any other warranty, express or implied in respect of any material deposited. UWE makes no representation that the use of the materials will not infringe any patent, copyright, trademark or other property or proprietary rights. UWE accepts no liability for any infringement of intellectual property rights in any material deposited but will remove such material from public view pending investigation in the event of an allegation of any such infringement. A mixture of the enzyme glutamate dehydrogenase (GLDH), cofactor nicotinamide adenine dinucleotide (NAD + ) and the biopolymer chitosan (CHIT) were drop-coated onto the surface of the transducer (MB-SPCE) in a simple one step fabrication process.The reagentless biosensor was used with amperometry in stirred solution at an applied potential of +0.1 V (vs. Ag/AgCl). All experiments were carried out at the following conditions: pH 7, temperature 37ºC, atmosphere 5% CO 2 .The linear range of the device was found to be 25 -125 μM in phosphate buffer (75 mM, containing 0.05 M NaCl) and 25 -150 μM in cell culture medium. The limits of detection (LOD) were found to be 1.2 µM and 4.2 µM based on three times signal to noise, using PBS and culture medium respectively. The sensitivity was calculated to be 106 nA µM -1 cm -2 and 210 nA µM -1 cm -2 in PBS and cell medium respectively. The response time was ~60s in an agitated solution.HepG2 cells were exposed to various concentrations of paracetamol (1 mM, 5 mM and 10 mM) in order to investigate the drug-induced release of glutamate into the culture medium in real time. Two toxicity studies were investigated using different methods of exposure and analysis.The first method consisted of a single measurement of the glutamate concentration, using the method of standard addition, after 24 hours incubation. The concentrations of glutamate were 3 found to be 52µM, 93µM and 177µM, released on exposure to 1mM, 5mM and 10mM paracetamol respectively.The second method involved the continuous monitoring of glutamate released from HepG2 cells upon exposure to paracetamol over 8 hours. The concentrations of glutamate released in the presence of 1mM, 5mM and 10mM paracetamol, increased in proportion to the drug concentration, ie: 16µM, 28µM and 62µM respectively. This result demonstrates the feasibility of using this approach to monitor early metabolic changes after exposure to a model toxic compound.

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Disorders of glutamate metabolism

Cited by 89 publications

References 74 publications

Impact of Low and High Tidal Volumes on the Rat Alveolar Epithelial Type II Cell Proteome

Impact of Low and High Tidal Volumes on the Rat Alveolar Epithelial Type II Cell Proteome

Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features

A novel reagentless glutamate microband biosensor for real-time cell toxicity monitoring

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