# The World of Cyclic Dinucleotides in Bacterial Behavior
In the case of the 3'-5' cGAMP receptors, genes are located adjacent to CD-NTase genes in the genome encode nucleotide receptors and act as effectors in biological conflicts, such as phospholipases, nucleases, and pore-forming agents [4; 35]. The CD-NTase genes and the cyclic nucleotide receptors are generally found on mobile genetic elements, while genes encoding GGDEF domains are widespread in the chromosomes of different bacteria and c-di-GMP receptors do not show a tendency to be located close to genes encoding proteins containing GGDEF domains. CDNs are probably present in almost all kinds of bacteria and their impact on an organism's physiology is probably determined by their concentration and the type of the second messenger. Interestingly, eukaryotic host cells evolved ways to sense some bacterial CDNs as a strategy to detect the presence of a pathogen and thus trigger a counterattack to avoid or fight invasion. The stimulator of interferon genes (STING) protein binds bacterial CDNs 3'-5' cGAMP, 3'-5' c-di-AMP and 3'-5' c-di-GMP molecules, as well as eukaryotic 2'-3' cGAMP molecules. Binding of STING to these cyclic dinucleotides activates expression of type I interferon in infected cells and initiates the innate immunity response for successful pathogen elimination [62]. On the other hand, cUAMP and cAAGMP are not recognized by STING proteins but are a ligand of mammalian CDN sensor reductase controlling NF-kB (RECON) [6]. Binding of c-di-AMP, cUAMP or cAAGMP to RECON inhibits its enzymatic activity, leading to increased activation of the proinflammatory transcription factor NF-kB, redirecting the cellular response toward an antibacterial reaction [6]. These new discoveries suggest that different classes of cyclic oligonucleotides molecules may have a larger role in bacterial signaling and pathogen recognition than previously thought. Consequently, STING could be a target for new drugs for the treatment of bacterial infections [1]. Additionally, it is noteworthy that STING is currently being explored as a candidate stimulant for anticancer immune activity [63]. In this review, we focus on recent advances in relation to the enzymes involved in the production of bacterial CDNs. We describe the conserved residues important to perform the catalysis of proteins containing GGDEF, SMODS, or DAC domains. Some bacterial CDN receptors that had their structure solved in complex with the ligand are also presented, with a focus on the residues involved in ligand recognition. We also highlight the conformation of the CDNs inside of the protein binding pocket. Surprisingly, different kinds of receptors bind CDNs with similar conformations. Additional observations, based on genomic data, suggest different CDN second messenger systems tend to coexist in many organisms showing the complexity and the importance of bacterial CDN signaling networks. We explore these resources and present an organization of our current knowledge on this expanding research topic. GGDEF, SMODS, and DAC Domains Do Not Share Structural Similarities and Probably Perform the Nucleotide Cyclization Catalysis by Different Mechanisms  
At the moment, three different classes of prokaryotic proteins are known to synthesize CDN molecules: (i) proteins containing GGDEF domains (Pfam family: PF00990); (ii) CD-NTases enzymes that have the catalytic domain known as SMODS (PF18144) [4]; and (iii) DAC proteins that have a catalytic domain called DAC domain (DisA_N domain, PF2457). Proteins containing GGDEF domains synthesize mainly 3'-5' c-di-GMP (c-di-GMP) molecules, while proteins containing SMODS domain synthesize preferentially 3'-5' cGAMP (cGAMP) molecules and proteins containing DAC domain synthesize mainly 3'-5' c-di-AMP (c-di-AMP) molecules. Even though CDN molecules are mainly synthesized by prokaryotic cells, eukaryotic cells also synthesize CDNs such as 2'-3' cGAMP by cGAS enzymes. These three classes of CDN synthetases do not share structural similarities, have different residues involved in substrate binding, and possess different catalytic mechanisms.