N-Acetylaspartate as a reservoir for glutamate

Joseph F. Clark, Amos Doepke, Jessica Andrea Filosa, Robert L. Wardle, Aigang Lu, Timothy J. Meeker, Gail J. Pyne-Geithman

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

N-acetylaspartate (NAA) is an intermediary metabolite that is found in relatively high concentrations in the human brain. More specifically, NAA is so concentrated in the neurons that it generates one of the most visible peaks in nuclear magnetic resonance (NMR) spectra, thus allowing NAA to serve as "a neuronal marker". However, to date there is no generally accepted physiological (primary) role for NAA. Another molecule that is found at similar concentrations in the brain is glutamate. Glutamate is an amino acid and neurotransmitter with numerous functions in the brain. We propose that NAA, a six-carbon amino acid derivative, is converted to glutamate (five carbons) in an energetically favorable set of reactions. This set of reactions starts when aspartoacylase converts the six carbons of NAA to aspartate and acetate, which are subsequently converted to oxaloacetate and acetyl CoA, respectively. Aspartylacylase is found in astrocytes and oligodendrocytes. In the mitochondria, oxaloacetate and acetyl CoA are combined to form citrate. Requiring two steps, the citrate is oxidized in the Kreb's cycle to α-ketoglutarate, producing NADH. Finally, α-ketoglutarate is readily converted to glutamate by transaminating the α-keto to an amine. The resulting glutamate can be used by multiple cells types to provide optimal brain functional and structural needs. Thus, the abundant NAA in neuronal tissue can serve as a large reservoir for replenishing glutamate in times of rapid or dynamic signaling demands and stress. This is beneficial in that proper levels of glutamate serve critical functions for neurons, astrocytes, and oligodendrocytes including their survival. In conclusion, we hypothesize that NAA conversion to glutamate is a logical and favorable use of this highly concentrated metabolite. It is important for normal brain function because of the brain's relatively unique metabolic demands and metabolite fluxes. Knowing that NAA is converted to glutamate will be important for better understanding myriad neurodegenerative diseases such as Canavan's Disease and Multiple Sclerosis, to name a few. Future studies to demonstrate the chemical, metabolic and pathological links between NAA and glutamate will support this hypothesis.

Original languageEnglish (US)
Pages (from-to)506-512
Number of pages7
JournalMedical Hypotheses
Volume67
Issue number3
DOIs
StatePublished - Jun 28 2006
Externally publishedYes

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Glutamic Acid
Brain
Oxaloacetic Acid
Acetyl Coenzyme A
Carbon
Oligodendroglia
Citric Acid
Astrocytes
Canavan Disease
N-acetylaspartate
Neurons
Amino Acids
Aspartic Acid
Neurodegenerative Diseases
NAD
Multiple Sclerosis
Names
Amines
Neurotransmitter Agents
Mitochondria

ASJC Scopus subject areas

  • Developmental Biology
  • Medicine(all)
  • Drug Discovery

Cite this

Clark, J. F., Doepke, A., Filosa, J. A., Wardle, R. L., Lu, A., Meeker, T. J., & Pyne-Geithman, G. J. (2006). N-Acetylaspartate as a reservoir for glutamate. Medical Hypotheses, 67(3), 506-512. https://doi.org/10.1016/j.mehy.2006.02.047

N-Acetylaspartate as a reservoir for glutamate. / Clark, Joseph F.; Doepke, Amos; Filosa, Jessica Andrea; Wardle, Robert L.; Lu, Aigang; Meeker, Timothy J.; Pyne-Geithman, Gail J.

In: Medical Hypotheses, Vol. 67, No. 3, 28.06.2006, p. 506-512.

Research output: Contribution to journalArticle

Clark, JF, Doepke, A, Filosa, JA, Wardle, RL, Lu, A, Meeker, TJ & Pyne-Geithman, GJ 2006, 'N-Acetylaspartate as a reservoir for glutamate', Medical Hypotheses, vol. 67, no. 3, pp. 506-512. https://doi.org/10.1016/j.mehy.2006.02.047
Clark JF, Doepke A, Filosa JA, Wardle RL, Lu A, Meeker TJ et al. N-Acetylaspartate as a reservoir for glutamate. Medical Hypotheses. 2006 Jun 28;67(3):506-512. https://doi.org/10.1016/j.mehy.2006.02.047
Clark, Joseph F. ; Doepke, Amos ; Filosa, Jessica Andrea ; Wardle, Robert L. ; Lu, Aigang ; Meeker, Timothy J. ; Pyne-Geithman, Gail J. / N-Acetylaspartate as a reservoir for glutamate. In: Medical Hypotheses. 2006 ; Vol. 67, No. 3. pp. 506-512.
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