| Revision as of 13:19, 24 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{chembox}} taken from revid 454451664 of page N-Acetylaspartylglutamic_acid for the Chem/Drugbox validation project (updated: 'ChEMBL', 'CASNo'). |
Latest revision as of 21:23, 19 August 2024 edit 96.241.107.52 (talk)No edit summaryTag: Visual edit |
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{{short description|Peptide neurotransmitter}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|chembox}}) taken from revid of page ] with values updated to verified values.}} |
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{{DISPLAYTITLE:''N''-Acetylaspartylglutamic acid}} |
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| verifiedrevid = 453508811 |
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|Name=''N''-Acetylaspartylglutamic acid |
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| verifiedrevid = 462256775 |
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|ImageFile=Acetylaspartylglutamic acid.png |
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| Name = ''N''-Acetylaspartylglutamic acid |
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|ImageSize=200px |
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| ImageFile = Acetylaspartylglutamic acid.png |
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|IUPACName=(2''S'')-2-<nowiki>amino]pentanedioic acid |
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| ImageFile_Ref = {{chemboximage|correct|??}} |
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|OtherNames=''N''-Acetyl-1-aspartylglutamic acid; NAAG; Spaglumic acid |
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| ImageSize = 160 |
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|Section1= {{Chembox Identifiers |
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| ImageName = Stereo, skeletal formula of N-acetylaspartylglutamic acid |
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| CASNo = <!-- blanked - oldvalue: 4910-46-7 --> |
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| SystematicName = (2''S'')-2-pentanedioic acid |
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| PubChem= 188803 |
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| OtherNames = {{unbulleted list|''N''-Acetyl-<small>L</small>-α-aspartyl-<small>L</small>-glutamic acid|''N''-Acetyl-1-aspartylglutamic acid{{citation needed|reason=What is the systematic basis for the '1' (numeral one)? Should it be a lower-case ell or small-caps ell?|date=March 2018}}|Isospaglumic acid|Spaglumic acid<ref name=drugs.com>, drugs.com</ref><ref name="isomeric naming">This is a misnomer: "spaglumic acid" is the β-aspartyl isomer whereas "isospaglumic acid" is the α-aspartyl isomer. See ] entry for "".</ref> |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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}} |
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| ChEMBL = <!-- blanked - oldvalue: 1329032 --> |
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|Section1={{Chembox Identifiers |
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| IUPHAR_ligand = 1405 |
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| Abbreviations = NAAG |
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| SMILES= CC(=O)N(CC(=O)O)C(=O)N(CCC(=O)O)C(=O)O |
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| CASNo_Ref = {{cascite|changed|??}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| CASNo = 3106-85-2 |
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| PubChem = 188803 |
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| ChemSpiderID = 164080 |
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| ChemSpiderID = 164080 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| InChI = 1/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 |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| InChIKey = OPVPGKGADVGKTG-BQBZGAKWBZ |
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| UNII = 1W8M12WXYL |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| MeSHName = N-acetyl-1-aspartylglutamic+acid |
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| SMILES = CC(=O)N(CC(O)=O)C(=O)N(CCC(O)=O)C(O)=O |
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| StdInChI = 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 |
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| StdInChI = 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 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = OPVPGKGADVGKTG-BQBZGAKWSA-N |
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| StdInChIKey = OPVPGKGADVGKTG-BQBZGAKWSA-N |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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|Section2= {{Chembox Properties |
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|Section2={{Chembox Properties |
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| Formula=C<sub>11</sub>H<sub>16</sub>N<sub>2</sub>O<sub>8</sub> |
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| C=11 | H=16 | N=2 | O=8 |
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| MolarMass=304.25 g/mol |
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|Section3= {{Chembox Hazards |
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|Section6={{Chembox Pharmacology |
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| ATCCode_prefix = R01 |
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| ATCCode_suffix = AC05 |
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| ATC_Supplemental = {{ATC|S01|GX03}} |
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'''''N''-Acetylaspartylglutamic acid''' ('''''N''-acetylaspartylglutamate''' or '''NAAG''') is a ] ] and the third-most-prevalent neurotransmitter in the mammalian nervous system. NAAG consists of ] (NAA) and ] coupled via a peptide bond. |
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NAAG was discovered as a nervous system-specific peptide in 1965 by Curatolo and colleagues<ref>{{cite journal |vauthors=CURATOLO A, D ARCANGELO P, LINO A, BRANCATI A |title=Distribution Of N-Acetyl-Aspartic And N-Acetyl-Aspartyl-Glutamic Acids In Nervous Tissue |journal=J. Neurochem. |volume=12 |issue= 4|pages=339–42 |year=1965 |pmid=14340686 |doi=10.1111/j.1471-4159.1965.tb06771.x|s2cid=29248053 }}</ref> but initially disregarded as a neurotransmitter and not extensively studied. However it meets the criteria for a ], including being concentrated in ]s, packed in synaptic vesicles, released in a calcium-dependent manner, and hydrolyzed in the synaptic space by enzymatic activity. |
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NAAG activates a specific receptor, the metabotropic glutamate receptor type 3. It is synthesized enzymatically from its two precursors and catabolized by ]s in the synapse. The inhibition of the latter enzymes has potentially important therapeutic effects in animal models of several neurologic conditions and disorders. |
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Under the ] '''spaglumic acid''',<ref name=drugs.com/><ref name="isomeric naming"/> NAAG is used as an ] medication in eye drops and nasal preparations. |
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==Research history== |
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<!--the following are facts or are they opinions?-->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 ]s in a manner relevant to physiology is controversial, its primary receptor was long believed to be the ]. Its interaction with the mGluR3 causes an activation of G proteins that reduce the concentration of the second messengers ] and ] 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.<ref>{{cite journal| author=Coyle, J.T. |title=The nagging question of the function of N-acetylaspartylglutamate |journal=Neurobiology of Disease |volume= 4 |year=1997 |pages=231–8| doi=10.1006/nbdi.1997.0153| pmid=9361299| issue=3–4|s2cid=35316779 }}</ref><ref>{{cite journal| author=Neale, J.H.| author2=Bzdega, T.| author3=Wroblewska, B. |title=N-Acetylaspartylglutamate: The Most Abundant Peptide Neurotransmitter in the Mammalian Central Nervous System |journal=Journal of Neurochemistry |volume=75 |year=2000 |pages=443–452|pmid=10899918| doi=10.1046/j.1471-4159.2000.0750443.x| issue=2| s2cid=24983894}}</ref> Stimulation of the mGluR3 by NAAG has been, however, questioned, finding relevant glutamate contamination in commercially available NAAG.<ref>{{cite journal| author=Fricker, A.-C.| author2=Mok, M.H.S.| author3=de la Flor, R.| author4=Shah, A.J.| author5=Woolley, M.| author6=Dawson, L.A.| author7=Kew, J.N.C. |title=Effects of N-acetylaspartylglutamate (NAAG) at group II mGluRs and NMDAR |journal=Neuropharmacology |volume= 56| issue=6–7 |year=2009 |pages=1060–67| pmid=19285517| doi=10.1016/j.neuropharm.2009.03.002| s2cid=35139256}}</ref><ref>{{cite journal| author=Chopra, M.| author2=Yao, Y.| author3=Blake, T.J.| author4=Hampson, D.R.| author5=Johnson, E.C. |title=The neuroactive peptide N-acetylaspartylglutamate is not an agonist at the metabotropic glutamate receptor subtype 3 of metabotropic glutamate receptor |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=330| issue=1 |year=2009 |pages=212–19| pmid=19389924| doi=10.1124/jpet.109.152553| s2cid=16838369}}</ref> |
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According to one publication, NAAG can be differentiated from NAA ] by MR spectroscopy at 3 Tesla.<ref>{{cite journal |vauthors=Edden RA, Pomper MG, Barker PB |title=In vivo differentiation of N-acetyl aspartyl glutamate from N-acetyl aspartate at 3 Tesla |journal=Magnetic Resonance in Medicine |volume=57 |issue=6 |pages=977–82 |year=2007 |pmid=17534922 |doi=10.1002/mrm.21234|s2cid=30929036 |doi-access=free }}</ref> |
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==Biosynthesis== |
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] activity mediates the biosynthesis of NAAG from glutamate and NAA, but little is known about the mechanism or regulation of this enzyme, and no NAAG synthetase activity has been isolated in cell-free preparations. Since other neuropeptides and nearly all vertebrate peptides are synthesized by post-translational processing, NAAG synthetase activity is relatively unique. As with NAA, the synthesis of NAAG is primarily restricted to neurons, although ] 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 ] cells, it has been shown that a ] (PKA) activator will increase the quantity of NAAG, while a ] (PKC) activator will decrease its concentration. This finding suggests that PKA and PKC have opposing regulatory effects on the NAAG synthetase enzyme.<ref>{{cite journal |author=Gehl, Laura |author2=Omar Saab |author3=Tomasz Bzdega |author4=Barbara Wroblewska |author5=Joseph Neale |name-list-style=amp |title=Biosynthesis of NAAG by an enzyme-mediate process in rat central nervous neurons and glia |journal=Journal of Neurochemistry | volume=90 |year=2004 |pages=989–997 |doi=10.1111/j.1471-4159.2004.02578.x |pmid=15287905 |issue=4|doi-access=free }}</ref><ref>{{cite journal | author=Arun, P. | author2=Madhavarao, C.N. | author3=Moffett, J.R. | author4=Namboodiri, M.A.A. |title=Regulation of N-acetylaspartate and N-acetylaspartylglutamate biosynthesis by protein kinase activators |journal=Journal of Neurochemistry |volume=98 |year=2006| pages=2034–2042 | doi=10.1111/j.1471-4159.2006.04068.x | pmid=16945114 | issue=6| s2cid=4464084 }}</ref> |
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==Catabolism== |
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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 ]-based analogs of NAAG, including ZJ43, ZJ17, and ZJ11. In rat models, ZJ43 and 2-PMPA reduce perception of inflammatory and neuropathic pain when administered systemically, intracerebrally, or locally, suggesting that NAAG modulates neurotransmission in pain circuits via mGlu3 receptors. The inhibition of NAAG hydrolysis increases the concentration of NAAG in the synaptic space analogous to the effects of MAOIs in increasing the concentration of serotonin. This elevated NAAG gives greater activation of presynaptic mGluR3 receptors, which decrease release of transmitter (glutamate) in the pain signaling pathways of the spinal cord and brain. In the case of ], the injection of a NAAG peptidase inhibitor reduces neuron and ] death in the ] nearest the site of the injury. In a mouse model of ] (ALS), the chronic inhibition of NAAG peptidase activity delayed the onset of ALS symptoms and slowed the progress of the neuronal death. To model ], animals were injected with ] (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.<ref>{{cite journal |author=Riveros, N. |author2=Orrego, F. |title=A study of possible excitatory effects of N-acetylaspartylglutamate in different in vivo and in vitro brain preparations |journal=Brain Research |volume=299 |year=1984 |pages=393–395 |doi=10.1016/0006-8993(84)90727-3 |pmid=6145497 |issue=2|s2cid=33135015 }}</ref><ref>{{cite journal |author=Yamamoto, T. |author2=Saito, O. |author3=Aoe, T. |author4=Bartolozzi, A. |author5=Sarva, J. |author6=Kozikowski, A. |author7=Wroblewska, B. |author8=Bzdega, T. |author9=Neale, J. H. |name-list-style=amp |title=Local Administration of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibitors Is Analgesic in Peripheral Pain |journal=European Journal of Neuroscience |volume=25 |year=2007 |pages=147–158 |doi=10.1111/j.1460-9568.2006.05272.x |pmid=17241276 |issue=1|s2cid=8951718 }}</ref><ref>{{cite journal| author=Zhou, J| author2=Neale, J.H| author3=Pomper, M.G.| author4=Kozikowski, A.P |title=NAAG Peptidase Inhibitors and their Potential for Diagnosis and Therapy |journal=Nature Reviews Drug Discovery |volume=4 |year = 2005 |pages =1015–1026| doi=10.1038/nrd1903| pmid=16341066| issue=12| s2cid=21807952}}</ref><ref>{{cite journal |author = Neale, J.H. |author2 = Olszewski, R.T. |author3 = Gehl, L.M. |author4 = Wroblewska, B. |author5 = Bzdega, T. |title=The neurotransmitter N-acetylaspartyl-glutamate in models of pain, ALS, diabetic neuropathy, CNS injury and schizophrenia |journal=Trends in Pharmacological Sciences |volume=26 |year = 2005| pages =477–484 |pmid = 16055199 |issue = 9 |doi = 10.1016/j.tips.2005.07.004}}</ref><ref>{{cite journal | author=Olszewski, R.T. | author2=Wegorzewska, M.M. | author3=Monteiro, A.C. | author4=Krolikowski, K.A. | author5=Zhou, J. | author6=Kozikowski, A.P. | author7=Long, K. | author8=Mastropaolo, J. | author9=Deutsch, S.I. | author10=Neale, J.H. | name-list-style=amp |title=Phencyclidine and Dizocilpine Induced Behaviors Reduced by N-acetylaspartylglutamate Peptidase Inhibition via Metabotropic Glutamate Receptors |journal = Biological Psychiatry | year = 2007|doi=10.1016/j.biopsych.2007.04.016 | volume=63 | issue=1 | pages=86–91 | pmid=17597589 | pmc=2185547}}</ref><sup></sup> |
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==See also== |
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* ] |
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* ] |
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==References== |
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{{Reflist|2}}16. Neale JH, Olszewski R. (2019) "A role for N-acetylaspartylglutamate (NAAG) and mGluR3 in cognition" Neurobiol Learn Mem. 2019 Feb;158:9-13. doi: 10.1016/j.nlm.2019.01.006. PMID: 30630041. |
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17. Neale JH, Yamamoto T. (2020) "N-acetylaspartylglutamate (NAAG) and glutamate carboxypeptidase II: An abundant peptide neurotransmitter-enzyme system with multiple clinical applications" Prog Neurobiol.184:101722. doi: 10.1016/j.pneurobio.2019.101722. PMID: 31730793{{Neurotransmitters}} |
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{{Glutamatergics}} |
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{{DEFAULTSORT:Acetylaspartylglutamic acid, N-}} |
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