Making and Breaking of an Essential Poison: the Cyclases and Phosphodiesterases That Produce and Degrade the Essential Second Messenger Cyclic di-AMP in Bacteria

Abstract

Cyclic di-AMP is a second messenger nucleotide that is produced by many bacteria and some archaea. Recent work has shown that c-di-AMP is unique among the signaling nucleotides, as this molecule is in many bacteria both essential on one hand and toxic upon accumulation on the other. Moreover, in bacteria like , c-di-AMP controls a biological process, potassium homeostasis, by binding both potassium transporters and riboswitch molecules in the mRNAs that encode the potassium transporters. In addition to the control of potassium homeostasis, c-di-AMP has been implicated in many cellular activities including DNA repair, cell wall homeostasis, osmotic adaptation, biofilm formation, central metabolism, and virulence. C-di-AMP is synthesized and degraded by diadenylate cyclases and phosphodiesterases, respectively. In the diadenylate cyclases, one type of catalytic domain, the DAC domain, is coupled to various other domains that control the localization, the protein-protein interactions, and the regulation of the enzymes. The phosphodiesterases have a catalytic core that consists either of a DHH/DHHA1 or of a HD domain. Recent findings on the occurrence, domain organization, activity control and structural features of diadenylate cyclases and phosphodiesterases are discussed in this review.

Cyclic nucleotides in archaea: Cyclic di‐AMP in the archaeonHaloferax volcaniiand its putative role

“…A phylogenetic analysis of the DAC domain of proteins related to DacZ from H. volcanii showed that homologs are presents in almost all euryarchaea and in some bacteria and that, remarkably, structure prediction methods revealed that the N ‐terminal domain has, despite low sequence homology, a fold that resembles the pyruvate kinase C‐terminal alpha/beta domain (PK_C) fold. This domain is also found in DAC representatives of the DacY/CdaZ class (Commichau et al, ; Corrigan & Gründling, ) suggesting that the archaeal DAC classes DacZ and DacY/CdaZ form one large family that is not exclusively found in archaea but also in some bacteria (Figure ). The PK_C fold was initially identified to bind fructose‐1,6‐bisphosphate to allosterically regulate the activity of pyruvate kinase.…”

“…Homologs were identified in most euryarchaeal species, but no DACs were identified in crenarchaeota. Proteins of the DacY/CdaZ class, like CdaZ from M. jannaschii , contain an N ‐terminal pyruvate kinase C‐terminal alpha/beta domain (PK_C) (Commichau et al, ; Corrigan & Gründling, ). Remarkably, although the conservation of the N ‐terminal primary sequence of DacZ proteins was very low, homology modeling of the 3D structure of the N ‐termini of these proteins indicated that members of the DacZ class and of the identified bacterial close homologs have a predicted fold similar to the N ‐terminus of members of the DacY/CdaZ class.…”

“…All c‐di‐AMP‐producing DACs share a conserved DAC domain (also known as DisA_N) that catalyzes the reaction of two ATP to form c‐di‐AMP. Several different families of DACs have been identified, which all differ in their additional regulatory domain (Commichau et al, ; Corrigan & Gründling, ). So far, members of four bacterial DAC classes have been characterized in more detail: DisA (Witte et al, ), DacA/CdaA (Rosenberg et al, ), DacB/CdaS (Mehne et al, ), and CdaM (Blötz et al, ).…”

“…In vivo, c‐di‐AMP is synthesized from two molecules of adenosine triphosphate (ATP) by diadenylate cyclases (DACs) (Witte et al, ), and is degraded to two molecules of adenosine monophosphate (AMP) by phosphodiesterases (PDEs) (Manikandan et al, ). Phylogenetic analysis has revealed several classes of DACs, all of which contain a conserved DAC domain (also called DisA_N domain [Pfam: PF02457]) in addition to several other functionally different domains (Commichau, Heidemann, Ficner, & Stülke, ; Corrigan & Gründling, ). Hypothetical proteins containing predicted DAC domains are present in diverse bacterial but also some archaeal species of the phylum Euryarchaeota, in which a previous study identified five unique putative DAC classes (DacV–DacZ) (Corrigan & Gründling, ).…”

“…Hypothetical proteins containing predicted DAC domains are present in diverse bacterial but also some archaeal species of the phylum Euryarchaeota, in which a previous study identified five unique putative DAC classes (DacV–DacZ) (Corrigan & Gründling, ). For the archaeal DacY class (also referred to as CdaZ class (Commichau et al, )) it has been shown that a representative of this class, CdaZ from Methanocaldococcus jannaschii , exhibits DAC activity when expressed in a heterologous host (Commichau et al, ; Kellenberger, Chen, Whiteley, Portnoy, & Hammond, ). However, the actual production of c‐di‐AMP in vivo has not been reported for any archaeal species so far.…”