Chemistry:Cyclic guanosine monophosphate–adenosine monophosphate

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Short description: Chemical compound
Cyclic guanosine monophosphate–adenosine monophosphate
Names
Other names
cGAMP; cyclic GMP-AMP; cGAMP(2'-5'); cyclic Gp(2'-5')Ap(3'-5')
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
UNII
Properties
C20H24N10O13P2
Molar mass 674.417 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references
Tracking categories (test):

Cyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP-AMP, cGAMP) is the first cyclic di-nucleotide found in metazoa.[1] In mammalian cells, cGAMP is synthesized by cyclic GMP-AMP synthase (cGAS) from ATP and GTP upon cytosolic DNA stimulation.[2][3]

Biosynthesis and function

The enzyme cyclic GMP-AMP synthase catalyses a chemical reaction that produces a specific isomer of cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) from the components guanosine triphosphate (GTP) and adenosine triphosphate (ATP), with two units of pyrophosphate (PPi) as a byproduct:

  1. REDIRECT Template:Chemical reaction

The cyclic product has a bond between the 2'-OH of GMP and the 5'-phosphate of AMP and another between the 3'-OH of AMP and 5'-phosphate of GMP.[3] This molecule, referred to as 2′3′-cGAMP (cyclic [G(2',5')pA(3',5')p]), functions as an endogenous second messenger inducing STING-dependent type I interferon response.[1][4][5][6] cGAMP has also been shown to be an effective adjuvant that boosts the production of antigen-specific antibodies and T cell responses in mice.[7] cGAMP exercises antiviral functions in the cell where it is produced, but can also transfer to neighboring cells through gap junctions.[5] It may even be packaged into lentivirus (such as HIV-1), poxvirus and herpes virus, and under cell culture conditions has been found to transmit an antiviral signal to the cells infected with these viruses; however, there is reason to think that at least HIV is capable of evading this mechanism by some means.[8] [9] cGAMP can also be exported into the extracellular space, where it can act as an intercellular signaling molecule.[10] Export is at least partly mediated by the ATP-binding cassette transporter ABCC1, which transports cGAMP directly in an ATP-dependent manner.[11] Additional export mechanisms remain to be identified. Extracellular cGAMP can be imported into cells by several transporters and channels, including SLC19A1[12][13], SLC46A2[14], and LRRC8 channels.[15][16] Extracellular cGAMP is hydrolyzed primarily by ENPP1,[17][10] with its paralog ENPP3 also contributing to cGAMP degradation.[18]

cGAMP signalling has been identified in prokaryotes including Vibrio cholerae which express a bacterial analogue of cGAS. In these organisms, cGAS is encoded as part of an operon alongside cGAMP-activated phospholipases (e.g. CapV in V. cholerae). During infection by bacteriophage, cGAS is activated and cGAMP is synthesised, activating CapV which degrades the cell's membrane and triggers cell death before the phage can complete its replicatory cycle.[19]

References

  1. ↑ 1.0 1.1 Wu, J; Sun, L; Chen, X; Du, F; Shi, H; Chen, C; Chen, ZJ (Dec 20, 2012). "Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA.". Science 339 (6121): 826–30. doi:10.1126/science.1229963. PMID 23258412. 
  2. ↑ Sun, L; Wu, J; Du, F; Chen, X; Chen, ZJ (Dec 20, 2012). "Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway". Science 339 (6121): 786–91. doi:10.1126/science.1232458. PMID 23258413. 
  3. ↑ 3.0 3.1 Zhang, X; Shi, H; Wu, J; Zhang, X; Sun, L; Chen, C; Chen, ZJ (Jun 3, 2013). "Cyclic GMP-AMP Containing Mixed Phosphodiester Linkages Is An Endogenous High-Affinity Ligand for STING". Molecular Cell 51 (2): 226–235. doi:10.1016/j.molcel.2013.05.022. PMID 23747010. 
  4. ↑ Gao, P et al. (May 3, 2013). "Cyclic [G(2′,5′)pA(3′,5′)p Is the Metazoan Second Messenger Produced by DNA-Activated Cyclic GMP-AMP Synthase"]. Cell 153 (5): 1094–1107. doi:10.1016/j.cell.2013.04.046. PMID 23647843. 
  5. ↑ 5.0 5.1 Ablasser, A; Goldeck, M; Cavlar, T; Deimling, T; Witte, G; Röhl, I; Hopfner, KP; Ludwig, J et al. (Jun 20, 2013). "cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING". Nature 498 (7454): 380–384. doi:10.1038/nature12306. PMID 23722158. 
  6. ↑ Diner, EJ; Burdette, DL; Wilson, SC; Monroe, KM; Kellenberger, CA; Hyodo, M; Hayakawa, Y; Hammond, MC et al. (May 23, 2013). "The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING". Cell Reports 3 (5): 1355–61. doi:10.1016/j.celrep.2013.05.009. PMID 23707065. 
  7. ↑ Li, XD; Wu, J; Gao, D; Wang, H; Sun, L; Chen, ZJ (Sep 20, 2013). "Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects". Science 341 (6152): 1390–4. doi:10.1126/science.1244040. PMID 23989956. 
  8. ↑ John W. Schoggins (2015-09-11). "Viruses carry antiviral cargo". Science 349 (6253): 1186–1187. doi:10.1126/science.aad0942. PMID 26359389. 
  9. ↑ Andrea Ablasser (2013-09-29). "Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP". Nature 503 (7477): 530–534. doi:10.1038/nature12640. PMID 24077100. 
  10. ↑ 10.0 10.1 Carozza, Jacqueline A.; Böhnert, Volker; Nguyen, Khanh C.; Skariah, Gemini; Shaw, Kelsey E.; Brown, Jenifer A.; Rafat, Marjan; von Eyben, Rie et al. (24 February 2020). "Extracellular cGAMP is a cancer-cell-produced immunotransmitter involved in radiation-induced anticancer immunity" (in en). Nature Cancer (Nature Publishing Group) 1 (2): 184–196. doi:10.1038/s43018-020-0028-4. ISSN 2662-1347. PMID 33768207. PMC 7990037. https://www.nature.com/articles/s43018-020-0028-4. 
  11. ↑ Maltbaek, Joanna H.; Cambier, Stephanie; Snyder, Jessica M.; Stetson, Daniel B. (2022-10-11). "ABCC1 transporter exports the immunostimulatory cyclic dinucleotide cGAMP". Immunity 55 (10): 1799–1812.e4. doi:10.1016/j.immuni.2022.08.006. ISSN 1097-4180. PMID 36070769. PMC 9561016. https://pubmed.ncbi.nlm.nih.gov/36070769. 
  12. ↑ Ritchie, Christopher; Cordova, Anthony F.; Hess, Gaelen T.; Bassik, Michael C.; Li, Lingyin (July 2019). "SLC19A1 Is an Importer of the Immunotransmitter cGAMP". Molecular Cell 75 (2): 372–381.e5. doi:10.1016/j.molcel.2019.05.006. ISSN 1097-2765. PMID 31126740. PMC 6711396. https://linkinghub.elsevier.com/retrieve/pii/S1097276519303594. 
  13. ↑ Luteijn, Rutger D.; Zaver, Shivam A.; Gowen, Benjamin G.; Wyman, Stacia K.; Garelis, Nick E.; Onia, Liberty; McWhirter, Sarah M.; Katibah, George E. et al. (2019-09-19). "SLC19A1 transports immunoreactive cyclic dinucleotides" (in en). Nature 573 (7774): 434–438. doi:10.1038/s41586-019-1553-0. ISSN 0028-0836. PMID 31511694. PMC 6785039. https://www.nature.com/articles/s41586-019-1553-0. 
  14. ↑ Cordova, Anthony F.; Ritchie, Christopher; Böhnert, Volker; Li, Lingyin (2021-06-23). "Human SLC46A2 Is the Dominant cGAMP Importer in Extracellular cGAMP-Sensing Macrophages and Monocytes" (in en). ACS Central Science 7 (6): 1073–1088. doi:10.1021/acscentsci.1c00440. ISSN 2374-7943. PMID 34235268. PMC 8228594. https://pubs.acs.org/doi/10.1021/acscentsci.1c00440. 
  15. ↑ Lahey, Lauren J.; Mardjuki, Rachel E.; Wen, Xianlan; Hess, Gaelen T.; Ritchie, Christopher; Carozza, Jacqueline A.; Böhnert, Volker; Maduke, Merritt et al. (9 November 2020). "LRRC8A:C/E Heteromeric Channels Are Ubiquitous Transporters of cGAMP" (in en). Molecular Cell 80 (4): 578–591.e5. doi:10.1016/j.molcel.2020.10.021. PMID 33171122. PMC 12629894. https://linkinghub.elsevier.com/retrieve/pii/S1097276520307280. 
  16. ↑ Zhou, Chun; Chen, Xia; Planells-Cases, Rosa; Chu, Jiachen; Wang, Li; Cao, Limin; Li, Zhihong; López-Cayuqueo, Karen I. et al. (2020-05-19). "Transfer of cGAMP into Bystander Cells via LRRC8 Volume-Regulated Anion Channels Augments STING-Mediated Interferon Responses and Anti-viral Immunity". Immunity 52 (5): 767–781.e6. doi:10.1016/j.immuni.2020.03.016. ISSN 1097-4180. PMID 32277911. https://pubmed.ncbi.nlm.nih.gov/32277911. 
  17. ↑ Li, Lingyin; Yin, Qian; Kuss, Pia; Maliga, Zoltan; Millán, José L.; Wu, Hao; Mitchison, Timothy J. (December 2014). "Hydrolysis of 2′3′-cGAMP by ENPP1 and design of nonhydrolyzable analogs" (in en). Nature Chemical Biology (Nature Publishing Group) 10 (12): 1043–1048. doi:10.1038/nchembio.1661. ISSN 1552-4469. PMID 25344812. PMC 4232468. https://www.nature.com/articles/nchembio.1661. 
  18. ↑ Mardjuki, Rachel; Wang, Songnan; Carozza, Jacqueline; Zirak, Bahar; Subramanyam, Vishvak; Abhiraman, Gita; Lyu, Xuchao; Goodarzi, Hani et al. (14 May 2024). "Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint". Cell Reports 43 (5). doi:10.1016/j.celrep.2024.114209. ISSN 2211-1247. PMID 38749434. PMC 13268100. https://linkinghub.elsevier.com/retrieve/pii/S2211124724005370. 
  19. ↑ Cohen, Daniel; Melamed, Sarah; Millman, Adi; Shulman, Gabriela; Oppenheimer-Shaanan, Yaara; Kacen, Assaf; Doron, Shany; Amitai, Gil et al. (October 2019). "Cyclic GMP–AMP signalling protects bacteria against viral infection" (in en). Nature 574 (7780): 691–695. doi:10.1038/s41586-019-1605-5. ISSN 1476-4687. PMID 31533127. https://www.nature.com/articles/s41586-019-1605-5. 



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