N-Acetylaspartylglutamic acid

Source: Wikipedia, the free encyclopedia.
(Redirected from
Spaglumic acid
)
N-Acetylaspartylglutamic acid
Stereo, skeletal formula of N-acetylaspartylglutamic acid
Names
Systematic IUPAC name
(2S)-2-[(2S)-2-Acetamido-3-carboxypropanamido]pentanedioic acid
Other names
  • N-Acetyl-L-α-aspartyl-L-glutamic acid
  • N-Acetyl-1-aspartylglutamic acid[citation needed]
  • Isospaglumic acid
  • Spaglumic acid[1][2]
Identifiers
3D model (
JSmol
)
Abbreviations NAAG
ChemSpider
ECHA InfoCard
 100.163.604 Edit this at Wikidata
MeSH N-acetyl-1-aspartylglutamic+acid
UNII
  • InChI=1S/C11H16N2O8/c1-5(14)12-7(4-9(17)18)10(19)13-6(11(20)21)2-3-8(15)16/h6-7H,2-4H2,1H3,(H,12,14)(H,13,19)(H,15,16)(H,17,18)(H,20,21)/t6-,7-/m0/s1 checkY
    Key: OPVPGKGADVGKTG-BQBZGAKWSA-N checkY
  • CC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O
Properties
C11H16N2O8
Molar mass 304.255 g·mol−1
Pharmacology
R01AC05 (WHO) S01GX03 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

N-Acetylaspartylglutamic acid (N-acetylaspartylglutamate or NAAG) is a peptide neurotransmitter and the third-most-prevalent neurotransmitter in the mammalian nervous system. NAAG consists of N-acetylaspartic acid (NAA) and glutamic acid coupled via a peptide bond.

NAAG was discovered as a nervous system-specific peptide in 1965 by Curatolo and colleagues[3] but initially disregarded as a neurotransmitter and not extensively studied. However it meets the criteria for a neurotransmitter, including being concentrated in neurons, packed in synaptic vesicles, released in a calcium-dependent manner, and hydrolyzed in the synaptic space by enzymatic activity.

NAAG activates a specific receptor, the metabotropic glutamate receptor type 3. It is synthesized enzymatically from its two precursors and catabolized by

NAAG peptidases
in the synapse. The inhibition of the latter enzymes has potentially important therapeutic effects in animal models of several neurologic conditions and disorders.

Under the

INN spaglumic acid,[1][2] NAAG is used as an antiallergic
medication in eye drops and nasal preparations.

Research history

After its discovery in 1965, NAAG was disregarded as a neurotransmitter for several reasons. First, neuropeptides were not considered neurotransmitters until years later. Second, it did not seem to directly affect membrane potential, so it was classified as a metabolic intermediate. The importance of brain peptides became clearer with the discovery of endogenous opioids. Whereas the ability of NAAG to interact with NMDA receptors in a manner relevant to physiology is controversial, its primary receptor was long believed to be the mGluR3. Its interaction with the mGluR3 causes an activation of G proteins that reduce the concentration of the second messengers cAMP and cGMP in both the nerve cells and glia. This can lead to several changes in the cellular activity, including regulation of gene expression, reduction in the release of transmitter, and inhibition of long-term potentiation.[4][5] Stimulation of the mGluR3 by NAAG has been, however, questioned, finding relevant glutamate contamination in commercially available NAAG.[6][7]

According to one publication, NAAG can be differentiated from NAA in vivo by MR spectroscopy at 3 Tesla.[8]

Biosynthesis

glial cells also contain and synthesize this peptide. In vitro, NAAG synthesis appears to be regulated by the availability of its precursor, NAA. In addition, during differentiation of neuroblastoma cells, it has been shown that a protein kinase A (PKA) activator will increase the quantity of NAAG, while a protein kinase C (PKC) activator will decrease its concentration. This finding suggests that PKA and PKC have opposing regulatory effects on the NAAG synthetase enzyme.[9][10]

Catabolism

NAAG is catabolized via NAAG peptidase activity. Two enzymes with NAAG peptidase activity have been cloned, glutamate carboxypeptidase II and glutamate carboxypeptidase III. These enzymes mediate the hydrolysis of NAAG to NAA and glutamate. Their inhibition can produce therapeutic benefits. Two main types of inhibitors of this enzyme are known: compounds related to 2-(phosphonomethyl)pentanedioic acid (2-PMPA) and

amyotrophic lateral sclerosis (ALS), the chronic inhibition of NAAG peptidase activity delayed the onset of ALS symptoms and slowed the progress of the neuronal death. To model schizophrenia, animals were injected with phencyclidine (PCP) and, therefore, exhibited symptoms of the disorder, such as social withdrawal and motor responses. Upon injection with ZJ43, these behaviors were decreased, suggesting that an increase in NAAG in the synapse — and its subsequent activation of mGluR3 receptors — has potential as a co-therapy for schizophrenia. In these cases, NAAG peptidase inhibition reduces the adverse effects in these disorders. Future research focuses on the role of NAAG in pain perception, brain injury, and schizophrenia while developing NAAG peptidase inhibitors with even greater ability to cross the blood–brain barrier.[11][12][13][14][15]

See also

  • Aspartate
  • Glutamate

References

  1. ^ a b Spaglumic Acid, drugs.com
  2. ^ a b This is a misnomer: "spaglumic acid" is the β-aspartyl isomer whereas "isospaglumic acid" is the α-aspartyl isomer. See PubChem entry for "spaglumic acid".
  3. S2CID 29248053
    .
  4. S2CID 35316779
    .
  5. S2CID 24983894
    .
  6. S2CID 35139256
    .
  7. S2CID 16838369
    .
  8. S2CID 30929036
    .
  9. PMID 15287905
    .
  10. S2CID 4464084
    .
  11. S2CID 33135015
    .
  12. S2CID 8951718
    .
  13. S2CID 21807952
    .
  14. PMID 16055199
    .
  15. PMID 17597589
    .