Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Dec 7;201(1):e00462-18.
doi: 10.1128/JB.00462-18. Print 2019 Jan 1.

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

Fabian M Commichau  1 , Jana L Heidemann  2 , Ralf Ficner  2 , Jörg Stülke  3
Affiliations
Review

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

Fabian M Commichau et al. J Bacteriol. .

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 Bacillus subtilis, 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 diadenylate cyclase (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 an HD domain. Recent findings on the occurrence, domain organization, activity control, and structural features of diadenylate cyclases and phosphodiesterases are discussed in this review.

Keywords: diadenylate cyclase; phosphodiesterase; second messenger; signal transduction.

PubMed Disclaimer

Figures

FIG 1
FIG 1
Targets that are presumed and known to be regulated by c-di-AMP. (A) Diadenylate cyclases and phosphodiesterases, their localization, and catalyzed reactions. All diadenylate cyclases (blue) use two molecules of ATP to produce c-di-AMP with the concomitant release of two molecules of pyrophosphate. The phosphodiesterases of the PgpH and GdpP families (gold) cleave c-di-AMP to generate the linear dinucleotide pApA. The DhhP-type phosphodiesterases (gray) generate pApA, and many of the enzymes are capable of cleaving pApA to the final product AMP. For all enzymes with pApA as the final product, a nano-RNase (NrnA, green) is required to degrade the pApA to two molecules of AMP. The cell wall-anchored phosphodiesterase CdnP degrades extracellular c-di-AMP to AMP. (B) The expression of the ktrAB and kimA genes is controlled by the c-di-AMP-dependent ydaO riboswitch in B. subtilis (17, 18). c-di-AMP directly binds to the KtrC subunit and the KdpD sensor kinase of the KtrCD and KdpFABC potassium uptake systems, respectively, of S. aureus (16, 109). c-di-AMP simulates the activity of the S. aureus potassium exporter CpaA. The transport activity of the Opu osmolyte uptake system in S. aureus and L. monocytogenes is controlled by c-di-AMP (23, 24). In lactic acid bacteria, transcriptional repression of the busAB genes encoding an osmoprotectant transporter is mediated by BusR, which requires c-di-AMP for DNA binding (25, 35). The pyruvate carboxylase PycA of L. monocytogenes is inhibited by c-di-AMP (24). CbpA and CbpB from L. monocytogenes and DarA, which is conserved in several Gram-positive bacteria, are c-di-AMP targets of unknown function (16, 24, 38).
FIG 2
FIG 2
Organization of diadenylate cyclases. (A) Domain structure of the different classes of diadenylate cyclases. The different domains are characterized by a color code. DAC, diadenylate cyclase domain; HhH, helix-hinge-helix domain; TM, transmembrane helix; CC, coiled-coil domain; PYK, pyruvate kinase-like domain; YbbR, YbbR domain (the unit domain of CdaR); EIIFru, PTS EII-like domain; PAS, Per-Arnt-Sim domain; PAC, PAS C-terminal domain. (B) Structures of the DAC domains of CdaA (blue, L. monocytogenes; PDB ID 4RV7), DisA (gray, T. maritima; PDB ID 3C21), and CdaS (green, B. cereus; PDB ID 2FB5), as well as an overlay of the three DAC domain structures with its bound reaction product c-di-AMP depicted in stick model. Conserved residues involved in ATP binding are highlighted in red. (C) Structure of a catalytic DAC dimer of DisA from T. maritima (PDB ID 3C21) with bound c-di-AMP depicted as a stick model. Conserved residues in the active site are shown in red.
FIG 3
FIG 3
Organization of c-di-AMP-degrading phosphodiesterases. (A) Domain structure of the four classes of phosphodiesterases. The different domains are characterized by a color code. TM, transmembrane helix; PAS, Per-Arnt-Sim domain; GGDEF, (degenerated) GGDEF domain; DHH, DHH domain; DHHA1, DHHA1 domain; 7TMR-HDED, seven-transmembrane helix-HDED domain; HD, HD domain; MP, metallophosphatase domain; NT, 5′-nucleotidase domain; LPxTG, surface localization motif. (B) Structures of GdpP from S. aureus (PDB ID 5XSN), the DhhP-type phosphodiesterase of T. maritima (PDB ID 5O25), and PgpH from L. monocytogenes (PDB ID 4S1B). The DHH domain (red) and the smaller DHHA1 domain (light gray) of the GdpP-type phosphodiesterases are colored as in Fig. 2A. Bound molecules are depicted in the stick model.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Gomelsky M. 2011. cAMP, c-di-GMP, c-di-AMP, and now cGMP: bacteria use them all! Mol Microbiol 79:562–565. doi:10.1111/j.1365-2958.2010.07514.x. - DOI - PMC - PubMed
    1. Görke B, Stülke J. 2008. Carbon catabolite repression in bacteria: many ways to make the most out of nutrients. Nat Rev Microbiol 6:613–624. doi:10.1038/nrmicro1932. - DOI - PubMed
    1. Hauryliuk V, Atkinson GC, Murakami KS, Tenson T, Gerdes K. 2015. Recent functional insights into the role of (p) ppGpp in bacterial physiology. Nat Rev Microbiol 13:298–309. doi:10.1038/nrmicro3448. - DOI - PMC - PubMed
    1. Hengge R, Gründling A, Jenal U, Ryan R, Yildiz F. 2015. Bacterial signal transduction by c-di-GMP and other nucleotide second messengers. J Bacteriol 197:e00331-15. doi:10.1128/JB.00331-15. - DOI - PMC - PubMed
    1. Witte G, Hartung S, Büttner K, Hopfner KP. 2008. Structural biochemistry of a bacterial checkpoint protein reveals diadenylate cyclase activity regulated by DNA recombination intermediates. Mol Cell 30:167–178. doi:10.1016/j.molcel.2008.02.020. - DOI - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources