# The World of Cyclic Dinucleotides in Bacterial Behavior
The c-di-AMP molecule regulates processes such as osmoprotection [23; 24], cell-wall homeostasis [25], potassium ion channel expression and function [26], DNA repair to maintain genomic integrity [3], diverse gene expression [27; 28], biofilm formation [29; 30], sporulation [31], antibiotic resistance [32], and metabolism [33]. Another CDN, 3'-5' cGAMP modulates chemotaxis, virulence and exoelectrogenesis (the use of insoluble extracellular terminal electron acceptors) [34]. 3'-5' cGAMP and also c-UAMP activate the phospholipase activity of patatin-like lipase enzymes [6; 35]. As described above, c-di-GMP molecule is synthesized by GGDEF domain-containing proteins [36; 37; 38] and degraded into pGpG or GMP by phosphodiesterase proteins containing HD-GYP or EAL domains, respectively. The released pGpG can then be degraded by an oligoribonuclease Orn [39; 40]. A divergent GGDEF family enzyme synthesizes not only c-di-GMP but also 3'-5' cGAMP molecules [41; 42]. Bacteria synthesize 3'-5' cGAMP mainly by the activity of proteins containing SMODS domains (Second Messenger Oligonucleotide or Dinucleotide Synthease) [4; 5], while eukaryotic cells synthesize cGAMP with a mixed 2'-5' and 3'-5' phosphodisester linkage (2'-3' cGAMP) by GMP-AMP synthase (cGAS) enzymes [43; 44; 45]. cGAS are structurally similar to SMODS and they belong to cGAS/DncV-like nucleotidyltransferase (CD-NTases) enzymes superfamily [4; 5]. The best characterized enzyme containing SMODS domain is DncV (a _Vibrio cholerae_ dinucleotide cyclase), with its orthologues being able to synthesize different cyclic nucleotides, including 3'-5' cGAMP, cUAMP, c-di-UMP, and cAAGMP, respectively produced by DncV, DncE, _Lp_CdnE02, and _Ec_CdnD02 proteins [6]. Bacterial CD-NTase enzymes also synthesize, as minor products, c-di-GMP, c-di-AMP, cUGMP, and cCUMP [6]. This diverse array of products synthesized by this group of enzymes is thought to be related to a low energetic barrier at the catalytic site for altering product specificity [6]. The c-di-AMP molecules are synthesized by di-adenylyl cyclase (DAC) proteins and hydrolyzed into pApA or AMP by specific phosphodiesterase (PDE) that contain DHH-DHHA1 or HD (His-Asp) domains [46; 47]. _Listeria monocytogenes_ encodes two PDEs: PdeA and PgpH [47]. Remarkably, the hydrolysis activity of PgpH is inhibited by the alarmone ppGpp, suggesting a crosstalk between c-di-AMP signaling and stringent response [47]. Three classes of DAC proteins have been identified, DisA, CdaA, and CdaS. All of them contain DGA and RHR motifs that are important in the catalysis [48; 49]. Bacteria sense second messenger molecules in different ways and respond to them in different manners. The c-di-GMP, c-di-AMP and cGAMP molecules are sensed by both proteins and RNAs. Some examples of c-di-GMP effectors are mRNA riboswitches [50], transcription factors [9; 51; 52], and different classes of protein domains such as PiLZ [53; 54; 55], degenerate GGDEF domains, degenerate EAL domains [56], and AAA+ ATPases domains [11; 12; 57] (see Table 1 for more details in the cyclic dinucleotide receptors section). When binding to its receptors, c-di-GMP can regulate bacterial physiology by altering gene transcription, protein expression and protein function, thus allowing the bacteria to respond to environmental stimuli at different speeds, be it a fast response, achieved by directly regulating protein activity, or a slower one, by regulating gene expression. Moreover, c-di-GMP can regulate the same physiological process in different ways, as seen for bacterial motility, when both flagellar gene expression and the flagellar motor function are regulated by c-di-GMP molecules [53; 58]. Some examples of c-di-AMP effectors are proteins containing RCK domain [59], the universal stress protein (USP) domain [60], and PstA proteins [61]. In contrast, almost nothing is known about bacterial cGAMP receptors; one example is the CapV phospholipase from _V. cholerae_[35].