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Cited by 223Amino Acid Enzymes and MetabolismNeuroscience and Neuropharmacology ResearchMetabolism and Genetic Disorders

Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain

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Cooper, Arthur, Jeitner, Thomas·2016·Biomolecules
DOI 10.3390/biom6020016PMC PMC4919911
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Abstract

Glutamate is present in the brain at an average concentration—typically 10–12 mM—far in excess of those of other amino acids. In glutamate-containing vesicles in the brain, the concentration of glutamate may even exceed 100 mM. Yet because glutamate is a major excitatory neurotransmitter, the concentration of this amino acid in the cerebral extracellular fluid must be kept low—typically µM. The remarkable gradient of glutamate in the different cerebral compartments: vesicles > cytosol/mitochondria > extracellular fluid attests to the extraordinary effectiveness of glutamate transporters and the strict control of enzymes of glutamate catabolism and synthesis in well-defined cellular and subcellular compartments in the brain. A major route for glutamate and ammonia removal is via the glutamine synthetase (glutamate ammonia ligase) reaction. Glutamate is also removed by conversion to the inhibitory neurotransmitter γ-aminobutyrate (GABA) via the action of glutamate decarboxylase. On the other hand, cerebral glutamate levels are maintained by the action of glutaminase and by various α-ketoglutarate-linked aminotransferases (especially aspartate aminotransferase and the mitochondrial and cytosolic forms of the branched-chain aminotransferases). Although the glutamate dehydrogenase reaction is freely reversible, owing to rapid removal of ammonia as glutamine amide, the direction of the glutamate dehydrogenase reaction in the brain in vivo is mainly toward glutamate catabolism rather than toward the net synthesis of glutamate, even under hyperammonemia conditions. During hyperammonemia, there is a large increase in cerebral glutamine content, but only small changes in the levels of glutamate and α-ketoglutarate. Thus, the channeling of glutamate toward glutamine during hyperammonemia results in the net synthesis of 5-carbon units. This increase in 5-carbon units is accomplished in part by the ammonia-induced stimulation of the anaplerotic enzyme pyruvate carboxylase. Here, we suggest that glutamate may constitute a buffer or bulwark against changes in cerebral amine and ammonia nitrogen. Although the glutamate transporters are briefly discussed, the major emphasis of the present review is on the enzymology contributing to the maintenance of glutamate levels under normal and hyperammonemic conditions. Emphasis will also be placed on the central role of glutamate in the glutamine-glutamate and glutamine-GABA neurotransmitter cycles between neurons and astrocytes. Finally, we provide a brief and selective discussion of neuropathology associated with altered cerebral glutamate levels.

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  • Glutamate and glutamine are the most abundant amino acids in the human brain.

    “Glutamate and glutamine are the most abundant amino acids in the human brain [129].”

    From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [129]

    The Introduction identifies glutamate as the most abundant common protein-coded amino acid in the brain and says glutamine is present at millimolar concentrations. It does not establish that glutamine is the second most abundant amino acid in human brain tissue; its separate comparison of glutamine with other amino acids concerns human cerebrospinal fluid, not brain tissue. (LLM, conf=0.78)

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Research works printed but not linked: 1

  1. [1]Lajtha A.B. Maker H.S. Clarke D.D. Chapter 17. Metabolism and transport of carbohydrates and amino acids Basic Neurochemistry 3rd ed. Siegel D.J. Albers R.W. Agranoff B.W. Katzman R. Little, Brown and Company Boston, MA, USA 1981 329 353

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Authors
Cooper, A., & Jeitner, T.
Affiliations
New York Medical College (US)
Corresponding author
Cooper, Arthur
ORCID
Venue
Biomolecules
Publisher
MDPI AG
Published
2016-03-26
Volume
6
Issue
2
Pages
16
ISSN
2218-273X (ISSN-L)
DOI
10.3390/biom6020016
PMC
PMC4919911
OpenAlex
W2311283174
Cited by
223
References
199
Citations by year
2026: 14 · 2025: 23 · 2024: 13 · 2023: 15 · 2022: 27 · 2021: 45 · 2020: 20 · 2019: 10 · 2018: 20 · 2017: 21 · 2016: 15
FWCI
2.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomolecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Touro Scholar (Touro College) (submittedVersion, cc-by)
  • Touro Scholar (Touro College) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK016739)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
nitrogen homeostasis, hyperammonemia, glutamine synthetase, glutamic acid decarboxylase, glutaminase, glutamate dehydrogenase, glutamate transporters, pyruvate carboxylase, aspartate aminotransferase, branched-chain amino acid aminotransferase, alpha-ketoglutarate, glutamine, ammonia
MeSH terms
Transaminases, Blood-Brain Barrier, Brain, Glutaminase, Humans, Nitrogen, Glutamic Acid, Hyperammonemia

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