N-Arachidonylglycine

N-Arachidonylglycine (NAGly) is a carboxylic metabolite of the endocannabinoid anandamide (AEA).[1][2] Since it was first synthesized in 1996,[3] NAGly has been a primary focus of the relatively contemporary field of lipidomics due to its wide range of signaling targets in the brain, the immune system and throughout various other bodily systems. In combination with 2‐arachidonoyl glycerol (2‐AG), NAGly has enabled the identification of a family of lipids often referred to as endocannabinoids.[4] Recently, NAGly has been found to bind to G-protein coupled receptor 18 (GPR18), the putative abnormal cannabidiol receptor.[5][6] NaGly is an endogenous inhibitor of fatty acid amide hydrolase (FAAH) and thereby increases the ethanolamide endocannabinoids AEA, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) levels.[7] NaGly is found throughout the body and research on its explicit functions is ongoing.

N-Arachidonylglycine
Names
IUPAC name
(5Z,8Z,11Z,14Z)-N-Icosa-5,8,11,14-tetraenoylamino-acetic acid
Other names
N-Arachidonylglycine
Arachidonoyl glycine
NA-glycine
Identifiers
3D model (JSmol)
7652004
ChEBI
ChEMBL
ChemSpider
MeSH Anandamide
Properties
C22H35NO3
Molar mass 361.526 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)
Infobox references

Synthesis

The exact biosynthesis of NaGly is not completely understood, but there are two proposed pathways found in vitro for its biosynthesis: 1) enzymatically regulated conjugation of arachidonic acid and glycine and 2) the oxidative metabolism of the endogenous cannabinoid anandamide.[8][9] In the first pathway, Cytochrome c catalyzes the in vitro synthesis of NaGly from arachidonoyl coenzyme A and glycine in the presence of hydrogen peroxide.[10] In the second pathway, alcohol dehydrogenase catalyzes the oxidation of anandamide into N-arachidonoyl glycine.[9]

Research

Effects on the nervous system

NAGly has been hypothesized to have a neurophysiological function of pain suppression, supported by evidence that it suppresses formalin-induced pain behavior in rats.[11] In particular, peripherally administered NAGly inhibited phase 2 pain behavior, suggesting either a direct suppression of nociceptive afferents on the nerve or an indirect modulation of the afferents' interstitial environment.[11] In either case, these findings hold promise for NAGly as a means of mitigating postoperative or chronic pain. NAGly is also effective in acute pain models, reducing mechanical allodynia and thermal hyperalgesia induced by intraplantar injection of Fruend's complete adjuvant.[12] Similar mechanical allydonia induced by partial ligation of the sciatic nerve was also reduced by NaGly.[13] Other arachidonic acid-amino acid conjugates did not have the same effects and the actions of NaGly were not affected by cannabinoid receptor agonists in either study, suggesting a novel non-cannabinoid receptor mediated approach to alleviate inflammatory pain.[12][13]

NaGly was shown to be endogenous ligand for the G-protein couple receptor GPR92 along with farnesyl pyrophosphate.[14] In the dorsal root ganglia (DRG), where GPR92 was found to be localized NaGly increased intracellular calcium levels in DRG neurons, indicating a role of NaGly in the sensory nervous system through the activation of GPR92.[14]

Effects on the immune system

NAGly has been the focus of research on the immune system because of its antinociceptive effects and inhibitory action on components of the immune system. Specifically, it significantly inhibited TNFα and IFNγ production, and it shows potential as a therapeutic treatment for chronic inflammation.[15] Moreover, NAGly has been shown to act as a substrate for cyclooxygenase-2 (COX-2), the enzyme primarily known for producing prostaglandins associated with increases in inflammation and hyperalgesia. In many mammalian tissues that express COX-2, significant levels of NAGly are naturally present, and in these tissues COX-2 selectively metabolizes NAGly prostaglandin (PG) H2 glycine and HETE-Gly.[16]

Cell migration

NAGly has been hypothesized to induce cell migration in BV-2 microglia cells.[5] The same research suggests that this migration occurs through GPR18. This was verified using GPR18 transfected HEK-293 cells. The same migration wasn't witnessed using non-transfected and GPR55 transfected HEK-293.[5] Additionally, tetrahydrocannabinol and NaGly are full agonists at the GPR18 receptors and induce migration in human endometrial HEC-1B cells.[17] Understanding functions of NaGly in such structures provides a promising future in helping treat diseases such as endometriosis.

Other targets

Insulin secretion

NaGly was identified as a novel insulin secretagogue and was shown to increase intracellular calcium concentration through stimulation of voltage dependent calcium channels.[18] Additionally, this action was dependent on extracellular glucose level.[18]

Additional biochemical interactions

NaGly has been shown to inhibit the glycine transporter GLYT2a in a non-competitive fashion with arachidonic acids and secondary messenger systems of GLYT2a, suggesting a novel recognition site for the N-arachodnoyl amino acids, especially because other conjugated amino acids had similar effects.[19]

References
  1. Burstein SH, Huang SM, Petros TJ, Rossetti RG, Walker JM, Zurier RB (October 2002). "Regulation of anandamide tissue levels by N-arachidonylglycine". Biochemical Pharmacology. 64 (7): 1147–50. doi:10.1016/S0006-2952(02)01301-1. PMID 12234618.
  2. Bradshaw HB, Rimmerman N, Hu SS, Benton VM, Stuart JM, Masuda K, Cravatt BF, O'Dell DK, Walker JM (May 2009). "The endocannabinoid anandamide is a precursor for the signaling lipid N-arachidonoyl glycine by two distinct pathways". BMC Biochemistry. 10: 14. doi:10.1186/1471-2091-10-14. PMC 2689249. PMID 19460156.
  3. Sheskin T, Hanus L, Slager J, Vogel Z, Mechoulam R (February 1997). "Structural requirements for binding of anandamide-type compounds to the brain cannabinoid receptor". Journal of Medicinal Chemistry. 40 (5): 659–67. doi:10.1021/jm960752x. PMID 9057852.
  4. Bradshaw HB, Rimmerman N, Hu SS, Burstein S, Walker JM (2009). "Novel endogenous N-acyl glycines identification and characterization". Vitamins and Hormones. Vitamins & Hormones. 81: 191–205. doi:10.1016/S0083-6729(09)81008-X. ISBN 9780123747822. PMID 19647113.
  5. McHugh D, Hu SS, Rimmerman N, Juknat A, Vogel Z, Walker JM, Bradshaw HB (March 2010). "N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor". BMC Neuroscience. 11 (1): 44. doi:10.1186/1471-2202-11-44. PMC 2865488. PMID 20346144.
  6. Kohno M, Hasegawa H, Inoue A, Muraoka M, Miyazaki T, Oka K, Yasukawa M (September 2006). "Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18". Biochemical and Biophysical Research Communications. 347 (3): 827–32. doi:10.1016/j.bbrc.2006.06.175. PMID 16844083.
  7. Tegeder I (February 2016). "Endocannabinoids as Guardians of Metastasis". International Journal of Molecular Sciences. 17 (2): 230. doi:10.3390/ijms17020230. PMC 4783962. PMID 26875980.
  8. Bradshaw HB, Rimmerman N, Hu SS, Benton VM, Stuart JM, Masuda K, Cravatt BF, O'Dell DK, Walker JM (May 2009). "The endocannabinoid anandamide is a precursor for the signaling lipid N-arachidonoyl glycine by two distinct pathways". BMC Biochemistry. 10 (1): 14. doi:10.1186/1471-2091-10-14. PMC 2689249. PMID 19460156.
  9. Aneetha H, O'Dell DK, Tan B, Walker JM, Hurley TD (January 2009). "Alcohol dehydrogenase-catalyzed in vitro oxidation of anandamide to N-arachidonoyl glycine, a lipid mediator: synthesis of N-acyl glycinals". Bioorganic & Medicinal Chemistry Letters. 19 (1): 237–41. doi:10.1016/j.bmcl.2008.10.087. PMC 2798806. PMID 19013794.
  10. McCue JM, Driscoll WJ, Mueller GP (January 2008). "Cytochrome c catalyzes the in vitro synthesis of arachidonoyl glycine". Biochemical and Biophysical Research Communications. 365 (2): 322–7. doi:10.1016/j.bbrc.2007.10.175. PMID 17986381.
  11. Huang SM, Bisogno T, Petros TJ, Chang SY, Zavitsanos PA, Zipkin RE, Sivakumar R, Coop A, Maeda DY, De Petrocellis L, Burstein S, Di Marzo V, Walker JM (November 2001). "Identification of a new class of molecules, the arachidonyl amino acids, and characterization of one member that inhibits pain". The Journal of Biological Chemistry. 276 (46): 42639–44. doi:10.1074/jbc.M107351200. PMID 11518719.
  12. Succar R, Mitchell VA, Vaughan CW (August 2007). "Actions of N-arachidonyl-glycine in a rat inflammatory pain model". Molecular Pain. 3 (1): 24. doi:10.1186/1744-8069-3-24. PMC 2042976. PMID 17727733.
  13. Vuong LA, Mitchell VA, Vaughan CW (January 2008). "Actions of N-arachidonyl-glycine in a rat neuropathic pain model". Neuropharmacology. 54 (1): 189–93. doi:10.1016/j.neuropharm.2007.05.004. PMID 17588618.
  14. Oh DY, Yoon JM, Moon MJ, Hwang JI, Choe H, Lee JY, Kim JI, Kim S, Rhim H, O'Dell DK, Walker JM, Na HS, Lee MG, Kwon HB, Kim K, Seong JY (July 2008). "Identification of farnesyl pyrophosphate and N-arachidonylglycine as endogenous ligands for GPR92". The Journal of Biological Chemistry. 283 (30): 21054–64. doi:10.1074/jbc.M708908200. PMC 2475705. PMID 18499677.
  15. WO application 9738688, Ferrante A, Poulos A, Pitt M, Easton C, Sleigh M, Rathjen D, Widmer F, "Methods of Treating Immunopathologies Using Polyunsaturated Fatty Acids", published 23 October 1997, assigned to Peptide Technology Pty Ltd. and Women's and Children's Hospital Adelaide
  16. Prusakiewicz JJ, Kingsley PJ, Kozak KR, Marnett LJ (August 2002). "Selective oxygenation of N-arachidonylglycine by cyclooxygenase-2". Biochemical and Biophysical Research Communications. 296 (3): 612–7. doi:10.1016/s0006-291x(02)00915-4. PMID 12176025.
  17. McHugh D, Page J, Dunn E, Bradshaw HB (April 2012). "Δ(9) -Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells". British Journal of Pharmacology. 165 (8): 2414–24. doi:10.1111/j.1476-5381.2011.01497.x. PMC 3423258. PMID 21595653.
  18. Ikeda Y, Iguchi H, Nakata M, Ioka RX, Tanaka T, Iwasaki S, Magoori K, Takayasu S, Yamamoto TT, Kodama T, Yada T, Sakurai T, Yanagisawa M, Sakai J (August 2005). "Identification of N-arachidonylglycine, U18666A, and 4-androstene-3,17-dione as novel insulin Secretagogues". Biochemical and Biophysical Research Communications. 333 (3): 778–86. doi:10.1016/j.bbrc.2005.06.005. PMID 15967412.
  19. Wiles AL, Pearlman RJ, Rosvall M, Aubrey KR, Vandenberg RJ (November 2006). "N-Arachidonyl-glycine inhibits the glycine transporter, GLYT2a". Journal of Neurochemistry. 99 (3): 781–6. doi:10.1111/j.1471-4159.2006.04107.x. PMID 16899062.
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