A jack of all trades: the multiple roles of the unique essential second messenger cyclic di-AMP

Mol Microbiol. 2015 Jul;97(2):189-204. doi: 10.1111/mmi.13026. Epub 2015 May 9.


Second messengers are key components of many signal transduction pathways. In addition to cyclic AMP, ppGpp and cyclic di-GMP, many bacteria use also cyclic di-AMP as a second messenger. This molecule is synthesized by distinct classes of diadenylate cyclases and degraded by phosphodiesterases. The control of the intracellular c-di-AMP pool is very important since both a lack of this molecule and its accumulation can inhibit growth of the bacteria. In many firmicutes, c-di-AMP is essential, making it the only known essential second messenger. Cyclic di-AMP is implicated in a variety of functions in the cell, including cell wall metabolism, potassium homeostasis, DNA repair and the control of gene expression. To understand the molecular mechanisms behind these functions, targets of c-di-AMP have been identified and characterized. Interestingly, c-di-AMP can bind both proteins and RNA molecules. Several proteins that interact with c-di-AMP are required to control the intracellular potassium concentration. In Bacillus subtilis, c-di-AMP also binds a riboswitch that controls the expression of a potassium transporter. Thus, c-di-AMP is the only known second messenger that controls a biological process by interacting with both a protein and the riboswitch that regulates its expression. Moreover, in Listeria monocytogenes c-di-AMP controls the activity of pyruvate carboxylase, an enzyme that is required to replenish the citric acid cycle. Here, we review the components of the c-di-AMP signaling system.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Bacteria / enzymology
  • Bacteria / metabolism
  • Bacterial Proteins / metabolism
  • Dinucleoside Phosphates / metabolism*
  • Phosphoric Diester Hydrolases / metabolism
  • Pyruvate Carboxylase / metabolism
  • Riboswitch
  • Second Messenger Systems*


  • Bacterial Proteins
  • Dinucleoside Phosphates
  • Riboswitch
  • cyclic diadenosine phosphate
  • Phosphoric Diester Hydrolases
  • Pyruvate Carboxylase