Through production of cyclic di-nucleotides as second messengers, di-nucleotide cyclases in bacteria and more recently in mammalian cells have been found to play important roles in modulating a wide range of cellular processes1. During infection of Vibrio cholerae (V. cholerae), di-nucleotide cyclase Vibrio (DncV) is required for efficient intestinal colonization by V. cholerae and downregulates hyperinfectivity-associated V. cholerae chemotaxis through generation of a regulatory molecule cyclic GMP-AMP (cGAMP)2.

In eukaryotes, cGAMP synthase (cGAS) was identified as a cytoplasmic DNA sensor that activates the type I interferon pathway by synthesizing the second messenger cGAMP3,4. Structural, biochemical and cellular studies reveal that upon dsDNA binding, cGAS is activated through formation of a catalytically competent conformation5,6. dsDNA binding can be disrupted by ablation of interactions with two or three successive phosphodiesters in either DNA strand, which results in impaired or completely abrogated cGAS function and in turn negatively impacts type I interferon production6. Similar to the formation of c-di-GMP, cGAMP is likely to be generated in a stepwise manner, involving an initial formation of G(2′,5′)pA linkage followed by A(3′,5′)pG generation. These sequential reactions lead to the formation of the pair of phosphodiester linkages with two molecules of pyrophosphate released as byproducts5,6.

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