Neurotransmitters: N-acetylaspartylglutamate (NAAG)

NAAG2Overview of transmitter
CHEM218 Seminar

Neurotransmitters are chemicals that enable the communication of signals between nerve cells and other cells. They act as “signal bearers”, leaping across the synaptic cleft, exiting the axonic surface of one neuron and attaching to receptor proteins on the dendritic surface of another neuron.

Neurotransmitters also enable nerves to communicate with muscle cells, gland cells, and various other tissues types throughout the body. Typically residing in synaptic vesicles, the neurotransmitter N-acetylaspartylglutamate (NAAG) is the most concentrated peptide in the brain, being the 3rd most prevalent neurotransmitter, and is found throughout the central nervous system (CNS).[1][2] Research supports its role as a regulator of synaptic release at central synapses, a co-transmitter at the vertebrate neuro-muscular junction (NMJ), and a unique biomarker for cognitive function.[2][3]

NAAG may contribute up to ~25% of the acetate signal that is usually ascribed to N-acetylaspartate (NAA) which is of relevance in cognitive development [2], while coinciding drops of NAAG and NAA are possibly linked to multiple brain disorders, such as Multiple Sclerosis (MS).[2][3]

N-acetylaspartylglutamate or NAAG: The above figure depicts NAAG’s molecular structure in a ball and stick fashion. Below it is depicted again, but this time the individual atoms are labelled to highlight the actual organic groups within the structure. As you can see the molecule has multiple organic functional groups present:


  1. The two types of functional groups are circled in yellow in figure-1
  2. The structures labeled 1, 2, and 3 in are carboxylic acid groups, consisting of a ketone and alcohol group at the terminal end of a carbon chain.
  3. The structures labeled 4, and 5 are amide groups, consisting of an amine situated next to a ketone.

Physical & Chemical Properties: NAAG, is a neuron-specific dipeptide[2] falling under the classification of organic peptides. Some physical attributes are as follows:

  • Molecular formula: C11H16N2O8
  • Molecular weight: 304.25334 g/mol
  • Water solubility: 3.29 mg/mL
  • Refractivity: 64.06 m3·mol-1
  • Hydrogen Bond Donor Count: 5
  • Hydrogen Bond Acceptor Count: 8
  • Rotatable Bond Count: 9
  • Heavy Atom Count: 21
  • Formal Charge : 0

Synonyms for NAAG:

  • a-Spaglumic acid
  • Acetyl-a-L-aspartylglutamic acid
  • Acetyl-alpha-L-aspartylglutamic acid
  • alpha-Spaglumic acid
  • Isospaglumic acid
  • N-(N-Acetylaspartyl)glutamic acid
  • N-Acetyl-a-aspartylglutamic acid
  • N-Acetyl-a-L-aspartyl-L-glutamic acid
  • N-Acetyl-alpha-aspartylglutamic acid
  • N-Acetyl-alpha-L-aspartyl-L-glutamic acid
  • N-Acetyl-L-aspartyl-L-glutamic acid

NAAG is primarily located in the CNS and neurons produce NAAG using NAAG synthetase I (NAAGS I as there is an NAAGS 2 and NAAG 2 molecule[4]), an enzyme that controls the synthesis of NAAG.

NAAG is typically co-released with a primary transmitter, (i.e. glutamate) under conditions of elevated neuronal activity. The primary transmitter is released into the immediate synaptic space, and the peptide is released perisynaptically where it activates presynaptic and glial type 3 metabotropic glutamate receptors (mGluR3) its primary receptor.[1][2][3]

NAAG is inactivated by two different eznymes: glutamate carboxypeptidases II (GCPII) and III (GCPIII), forming N-acetylaspartate (NAA) and glutamate (Glu), which are transported to glial cells (grey matter).

NAAG’s prevalence and usage tends to be associated with Laboratory chemicals, and the manufacture of substances.[5] It has also found use as a anti-allergic medication (NAAXIA) in eye drops and nasal preparations.[6]

NAAG is available for purchase through typical chemical vendors, and is biologically prevalent, found to be present in mammalian cerebrospinal fluid (CSF), blood, and urine.




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