Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Nverify (what is YN ?)
Infobox references
Biosynthesis and degradationedit
The biosynthesis and degradation of NaGly is not completely understood. Using biochemical approaches, two proposed pathways include: 1) enzymatic conjugation of arachidonic acid and glycine and 2) the oxidative metabolism of the endogenous cannabinoid anandamide.[8][9] In support of the former "direct" pathway of arachidonic acid and glycine conjugation and hydrolysis, the secreted enzyme PM20D1 and the intracellular amidase FAAH has been identified as enzymatic regulators of NAGly metabolism in mice.[10][11]
Researchedit
Effects on the nervous systemedit
NAGly has been hypothesized to have a neurophysiological function of pain suppression, supported by evidence that it suppresses formalin-induced pain behavior in rats.[12] 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.[12] 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.[13] Similar mechanical allydonia induced by partial ligation of the sciatic nerve was also reduced by NaGly.[14] 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.[13][14]
NaGly was shown to be endogenous ligand for the G-protein couple receptor GPR92 along with farnesyl pyrophosphate.[15] 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.[15]
Effects on the immune systemedit
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.[16] 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.[17]
Cell migrationedit
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.[18] Understanding functions of NaGly in such structures provides a promising future in helping treat diseases such as endometriosis.
Cellular respirationedit
NAGly powerfully stimulates oxygen consumption in multiple cell lines, including murine C2C12 myoblasts and human HEK293T cells.[19] This respiratory bioactivity of NAGly is by increased uncoupled (state4u) mitochondrial respiration and depends on the presence of fatty acid desaturation.[20] NAGly respiration bioactivity can be also abrogated in the presence of serum albumin, which functions as an NAGly carrier in murine blood plasma.[21]
Other targetsedit
Insulin secretionedit
NaGly was identified as a novel insulinsecretagogue and was shown to increase intracellular calcium concentration through stimulation of voltage dependent calcium channels.[22] Additionally, this action was dependent on extracellular glucose level.[22]
Additional biochemical interactionsedit
NaGly has been shown to inhibit the glycine transporter GLYT2a in a non-competitive fashion with arachidonic acid and secondary messenger systems of GLYT2a, suggesting a novel recognition site for the N-arachidonyl amino acids, especially because other conjugated amino acids had similar effects.[23]
^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. PMC2689249. PMID 19460156.
^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.
^Bradshaw HB, Rimmerman N, Hu SS, Burstein S, Walker JM (2009). Novel endogenous N-acyl glycines identification and characterization. Vitamins & Hormones. Vol. 81. pp. 191–205. doi:10.1016/S0083-6729(09)81008-X. ISBN 9780123747822. PMID 19647113.
^ abcMcHugh 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. PMC2865488. PMID 20346144.
^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.
^Tegeder I (February 2016). "Endocannabinoids as Guardians of Metastasis". International Journal of Molecular Sciences. 17 (2): 230. doi:10.3390/ijms17020230. PMC4783962. PMID 26875980.
^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. PMC2689249. PMID 19460156.
^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. PMC2798806. PMID 19013794.
^Long JZ, Roche AM, Berdan CA, Louie SM, Roberts AJ, Svensson KJ, Dou FY, Bateman LA, Mina AI, Deng Z, Jedrychowski MP, Lin H, Kamenecka TM, Asara JM, Griffin PR, Banks AS, Nomura DK, Spiegelman BM (July 2018). "Ablation of PM20D1 reveals N-acyl amino acid control of metabolism and nociception". Proc Natl Acad Sci U S A. 115 (29): E6937–45. Bibcode:2018PNAS..115E6937L. doi:10.1073/pnas.1803389115. PMC6055169. PMID 29967167.
^Kim JT, Terrell SM, Li VL, Wei W, Fischer CR, Long JZ (April 2020). "Cooperative enzymatic control of N-acyl amino acids by PM20D1 and FAAH". eLife. 9: e552115. doi:10.7554/eLife.55211. PMC7145423. PMID 32271712.
^ abHuang 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.
^ abSuccar R, Mitchell VA, Vaughan CW (August 2007). "Actions of N-arachidonyl-glycine in a rat inflammatory pain model". Molecular Pain. 3 (1): 1744-8069–3-24. doi:10.1186/1744-8069-3-24. PMC2042976. PMID 17727733.
^ abVuong 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. S2CID 35178601.
^ abOh 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. PMC2475705. PMID 18499677.
^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
^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.
^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. PMC3423258. PMID 21595653.