Glutamine, Glutamate, and GABA in Human Diseases
Elling Kvamme in Glutamine and Glutamate in Mammals, 1988
Ammonia which has not been disposed of normally in the urea cycle is “detoxified” by conversion into glutamine. Ammonia is first reacted with α-ketoglutarate (2-oxoglutarate) derived from the tricarboxylic acid (TCA) cycle to form glutamate. This reaction is catalyzed by glutamate dehydrogenase. The second step, catalyzed by glutamine synthetase, reacts further ammonia with glutamate to form glutamine. In the genetically determined urea cycle metabolic defects, levels of ammonia and glutamine in physiological fluids and the brain are usually highest in patients with carbamoyl phosphate synthetase deficiency and ornithine carbamoyl transferase deficiency and lower in defects later in the urea cycle such as argi- ninosuccinate lyase deficiency and arginase deficiency.18
Consideration of Glutamine Synthetase as a Multifunctional Protein
James F. Kane in Multifunctional Proteins: Catalytic/Structural and Regulatory, 2019
The summation of binding sites for metals, substrates, and feedback inhibitors seems extraordinarily large for each 50,000 dalton subunit. Then, in addition, the presence of the AMP modification site adds a dimension not seen with many other proteins. Within the framework of considering glutamine synthetase as a multifunctional protein, the adenylylation process is of particular interest. During the adenylylation and deadenylylation process, glutamine synthetase is, in essence, serving as a substrate for another enzyme reaction. The modification process in turn has a large effect on the conformation of glutamine synthetase and changes the binding of many other effectors. In this regard, glutamine synthetase binds and responds to several effectors, has its own important catalytic activity, and has a site that serves as a substrate for the adenyl transferase enzyme. These aspects alone make glutamine synthetase a complicated multifaceted enzyme, but in addition to these features is the consideration of whether glutamine synthetase can function as a regulator of protein synthesis.
ENTRIES A–Z
Philip Winn in Dictionary of Biological Psychology, 2003
see glutamine glutamine Glutamine is the precursor of the neurotransmitter GLUTAMATE; GLUTAMINASE is the enzyme that catalyses the conversion of glutamine to glutamate (see CATALYST). Curiously, glutamine is synthesized from glutamate, a reaction catalysed by the enzyme GLUTAMINE SYNTHETASE. Why should it be possible to use glutamate to make glutamine, which is then used to make glutamate? The likeliest explanation is that glutamine is stored in NEURONS and glia as an inactive form of glutamate—a reservoir that can be called on if required. It is possible that the conversion of glutamine to glutamate can occur in neurons, though it can certainly occur in astrocytes (see GLIAL CELLS). Astrocytes appear able to transport glutamate across membranes into the neurons they support.
Oral glutamine supplementation increases seizure severity in a rodent model of mesial temporal lobe epilepsy
Published in Nutritional Neuroscience, 2022
Roni Dhaher, Eric C. Chen, Edgar Perez, Amedeo Rapuano, Mani Ratnesh S. Sandhu, Shaun E. Gruenbaum, Ketaki Deshpande, Feng Dai, Hitten P. Zaveri, Tore Eid
Glutamine synthetase (GS, also known as glutamate-ammonia-ligase, GLUL) catalyzes the formation of glutamate and ammonia to glutamine and is the only enzyme known to synthesize significant amounts of glutamine in mammals [1]. Glutamine is critical for several biological processes such as synthesis of the excitatory and inhibitor neurotransmitters glutamate and gamma-aminobutyric acid (GABA) [2] and ammonia detoxification [3]. Not surprisingly, loss-of-function mutations of the GS gene are associated with considerable mortality and morbidity, and the small number of humans reported with such mutations have suffered from multi-organ failure, encephalopathy, and epilepsy [4]. However, in one case study in which glutamine was enterically supplemented to an infant with GS deficiency, glutamine normalized the EEG, suggesting that the amino acid might prevent GS-associated seizures [5].
Dysregulated metabolism: A friend-to-foe skewer of macrophages
Published in International Reviews of Immunology, 2023
Keywan Mortezaee, Jamal Majidpoor
Increasing the production of succinate is important for regulation of macrophage polarization. Succinate is a known regulator of pro-inflammatory responses, mediated through HIF-1α stabilization and suppression of anti-inflammatory gene expression profile. Glutamine synthetase is an enzyme related to acid-base homeostasis and nitrogen metabolism. M2 macrophages under starvation induce the activity of glutamine synthase for production of glutamine. Blockade of glutamine synthase causes M2-to-M1 skewing of macrophages and the resultant tumor regression. Incubation of M2 macrophages with the glutamine synthase inhibitor methionine sulfoximine causes succinate accumulation and increased glucose utilization, thereby promoting metabolic rewiring toward attaining M1-like phenotype. Succinate is contributed to HIF-1α stabilization, so it is expected that blockade of glutamine synthase will cause HIF-1α activation, as it is attested [84]. Due to the interference between PKM2 activity with succinate accumulation and glycolysis for M1 polarization, a suggested strategy could be targeting PKM2.
Polyphenol-rich Spondias mombin leaf extract abates cerebral ischemia/reperfusion-induced disturbed glutamate-ammonia metabolism and multiorgan toxicity in rats
Published in Biomarkers, 2023
Olubukola Benedicta Ojo, Abigail Oladunni Olajide, Grace Boluwatife Olagunju, Comfort Olowu, Sunday Solomon Josiah, Zainab Abiola Amoo, Mary Tolulope Olaleye, Afolabi Clement Akinmoladun
Glutamate regulatory enzymes modulate glutamate metabolism and play a major role in stroke outcomes by contributing to neuronal cell death and neurological deficits (Ruban et al.2020). Glutamine synthetase (GS) is a key regulator of nitrogen metabolism which catalyses the ATP-dependent condensation of glutamate with ammonia to glutamine which enters the bloodstream and is transported to the liver (Castegna and Menga 2018). GS is predominantly expressed in glutamine-consuming organs such as the brain, liver, and kidney (Hakvoort et al.2017). Glutamine, the most abundant free amino acid in the blood, is converted to glutamate in the mitochondria, which is converted back to alpha-ketoglutarate by oxidative deamination by the tricarboxylic acid cycle (TCA) for energy generation (Liang et al.2021). Glutamine is synthesised in the central nervous system (CNS) to scavenge glutamate, in the kidney to control ammonia production needed to counteract metabolic acidosis, and in the liver to detoxify ammonia to urea (Hakvoort et al.2017). A high amount of ammonia is produced by intestinal bacteria through the action of urease and the degradation of proteins and amino acids contributes to ammonia accumulation (Castegna and Menga 2018).
Related Knowledge Centers
- Adenosine Diphosphate
- Ammonia
- Enzyme
- Glutamic Acid
- Glutamine
- Photorespiration
- Metabolism
- Amino Acid
- Nitrogen
- Adenosine Triphosphate