Description
2′,3′-cGAMP (CAS 1441190-66-4) is an endogenous STING (stimulator of interferon genes) agonist.1?Produced from ATP and GTP via the action of cGMP-AMP synthase (cGAS) which acts as a cytosolic DNA sensor.2,3?Induces autophagy which is a mechanism for clearance of DNA and viruses in the cytosol.4?DNA damage stimulates 2’,3’-cGAMP which stimulates an inflammatory response.5
Chemical Properties
White to colorless lyophilized solid.
Uses
2′,3′-cGAMP sodium salt has been used to identify small compounds capable of binding human stimulator of interferon genes (STING). It is also used to study type I interferon response to cytosolic DNA.
Definition
ChEBI:2'-3'-cGAMP is a cyclic purine dinucleotide that consists of AMP and GMP units cyclised via 3',5'- and 2',5'-linkages respectively. It is a cyclic purine dinucleotide, a guanyl ribonucleotide and an adenyl ribonucleotide. It is functionally related to a Gp[2'-5']Ap[3']. It is a conjugate acid of a 2'-3'-cGAMP(2-).
Biochem/physiol Actions
2′,3′-cGAMP (cyclic [G(2′,5′)pA(3′,5′)p]) is the natural agonist for the STING (STimulator of INterferon Genes) pathway, discovered to be a pathway for antiviral innate immunity. 2′3′-cGAMP is a second messenger produced in mammalian cells by the cytosolic DNA sensor cGAS (cGAMP synthase) to activate innate immune responses by binding to STING and initiating an interferon response. The affinity of 2′3′-cGAMP for human STING is much higher than that of the bacterial 3′3′-cyclic dinucleotides (CDNs), with a Kd of 4.59 nM compared to >1 μM for bacterial 3′3′-CDNs.
Mode of action
2’3’-cGAMP (cyclic [G(2’,5’)pA(3’,5’)p]) is produced in mammalian cells by cGAS (cGAMP synthase) in response to double-stranded DNA in the cytoplasm. Similar to the canonical 3’3’-cGAMP, 2’3’-cGAMP serves as a second messenger to activate innate immune responses by binding to and activating STING. Upon activation, STING induces type I IFNs via the TANK-binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) pathway [1], and pro-inflammatory cytokines via the NF-κB pathway [1, 2]. Structural and functional studies have revealed that 2’3’-cGAMP is distinct from the canonical 3’3’-cGAMP produced by bacteria [3, 4]. 2'3'-cGAMP binds to STING with a much greater affinity than 3'3'-cGAMP does [1]. Interestingly, certain variants of STING are able to distinguish between noncanonical and canonical cGAMP [3].
References
1) Zhang?et al.?(2015), Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING; Mol. Cell?51?226
2) Wu?et al.?(2013), Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA; Science?339?826
3) Sun?et al.?(2013), Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway; Science?339?786
4) Gui?et al.?(2019),?Autophagy induction via STING trafficking is a primordial function of the cGAS pathway;??Nature,?567?262
5) Li and Chen (2018),?The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence and cancer;??J. Exp. Med.,?215?1287
