Current Genetics

, Volume 64, Issue 1, pp 191–195 | Cite as

Perspective of ions and messengers: an intricate link between potassium, glutamate, and cyclic di-AMP

  • Jan Gundlach
  • Fabian M. Commichau
  • Jörg Stülke


Potassium and glutamate are the most abundant ions in every living cell. Whereas potassium plays a major role to keep the cellular turgor and to buffer the negative charges of the nucleic acids, the major function of glutamate is to serve as the universal amino group donor. In addition, both ions are involved in osmoprotection in bacterial cells. Here, we discuss how bacterial cells maintain the homeostasis of both ions and how adaptive evolution allows them to live even at extreme potassium limitation. Interestingly, positively charged amino acids are able to partially replace potassium, likely by buffering the negative charge of DNA. A major factor involved in the control of potassium homeostasis in Gram-positive bacteria is the essential second messenger cyclic di-AMP. This nucleotide is synthesized in response to the potassium concentration and in turn controls the expression and activity of potassium transporters. We discuss the link between the two major ions, DNA and the second messenger c-di-AMP.


Bacillus subtilis Escherichia coli PH homeostasis Cyclic di-AMP Potassium 



We are grateful to Christina Herzberg for helpful discussions. This work was supported by the Deutsche Forschungsgemeinschaft (STU 214/16-1 and CO 1139/2-1) (to JS and FMC, respectively).


  1. Bai Y, Yang J, Zarella TM, Zhang Y, Metzger DW, Bai G (2014) Cyclic di-AMP impairs potassium uptake mediated by a cyclic di-AMP binding protein in Streptococcus pneumoniae. J Bacteriol 196:614–623CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bennett BD, Kimball EH, Gao M, Osterhout R, van Dien SJ, Rabinowitz JD (2009) Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli. Nat Chem Biol 5:593–599CrossRefPubMedPubMedCentralGoogle Scholar
  3. Blötz C, Treffon K, Kaever V, Schwede F, Hammer E, Stülke J (2017) Identification of the components involved in cyclic di-AMP signaling in Mycoplasma pneumoniae. Front Microbiol 8:1328CrossRefPubMedPubMedCentralGoogle Scholar
  4. Brill J, Hoffmann T, Bleisteiner M, Bremer E (2011) Osmotically controlled synthesis of the compatible solute proline is critical for cellular defense of Bacillus subtilis against high osmolarity. J Bacteriol 193:5335–5346CrossRefPubMedPubMedCentralGoogle Scholar
  5. Commichau FM, Gunka K, Landmann JJ, Stülke J (2008) Glutamate metabolism in Bacillus subtilis: gene expression and enzyme activities evolved to avoid futile cycles and to allow rapid responses to perturbations in the system. J Bacteriol 190:3557–3564CrossRefPubMedPubMedCentralGoogle Scholar
  6. Commichau FM, Dickmanns A, Gundlach J, Ficner R, Stülke J (2015) A jack of all trades: the multiple roles of the unique essential second messenger cyclic di-AMP. Mol Microbiol 97:189–204CrossRefPubMedGoogle Scholar
  7. Corrigan RM, Gründling A (2013) Cyclic di-AMP: another second messenger enters the fray. Nat Rev Microbiol 11:513–524CrossRefPubMedGoogle Scholar
  8. Corrigan RM, Campeotto I, Jeganathan T, Roelofs KG, Lee VT, Gründling A (2013) Systematic identification of conserved bacterial c-di-AMP receptor proteins. Proc Natl Acad Sci USA 110:9084–9089CrossRefPubMedPubMedCentralGoogle Scholar
  9. Csonka LN, Ikeda TP, Fletcher SA, Kustu S (1994) The accumulation of glutamate is necessary for optimal growth of Salmonella typhimurium in media of high osmolality but not induction of the proU operon. J Bacteriol 176:6324–6333CrossRefPubMedPubMedCentralGoogle Scholar
  10. Epstein W (2003) The roles and regulation of potassium in bacteria. Prog Nucleic Acids Res Mol Biol 75:293–320CrossRefGoogle Scholar
  11. Gralla JD, Vargas DR (2006) Potassium glutamate as a transcriptional inhibitor during bacterial osmoregulation. EMBO J 25:1515–1521CrossRefPubMedPubMedCentralGoogle Scholar
  12. Gundlach J, Mehne FMP, Herzberg C, Kampf J, Valerius O, Kaever V, Stülke J (2015) An essential poison: synthesis and degradation of cyclic di-AMP in Bacillus subtilis. J Bacteriol 197:3265–3274CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gundlach J, Herzberg C, Hertel D, Thürmer A, Daniel R, Link H, Stülke J (2017a) Adaptation of Bacillus subtilis to life at extreme potassium limitation. mBio 8:e00861–17CrossRefPubMedPubMedCentralGoogle Scholar
  14. Gundlach J, Herzberg C, Kaever V, Gunka K, Hoffmann T, Weiß M, Gibhardt J, Thürmer A, Hertel D, Daniel R, Bremer E, Commichau FM, Stülke J (2017b) Control of potassium homeostasis is an essential function of the second messenger cyclic di-AMP in Bacillus subtilis. Sci Signal 10:eaal3011CrossRefPubMedGoogle Scholar
  15. Gunka K, Commichau FM (2012) Control of glutamate homeostasis in Bacillus subtilis: a complex interplay between ammonium assimilation, glutamate biosynthesis and degradation. Mol Microbiol 85:213–224CrossRefPubMedGoogle Scholar
  16. Gunka K, Newman J, Commichau FM, Herzberg C, Rodrigues C, Hewitt L, Lewis RJ, Stülke J (2010) Functional dissection of a trigger enzyme: mutations of the Bacillus subtilis glutamate dehydrogenase RocG that affect catalytic activity and regulatory properties differentially. J Mol Biol 400:815–827CrossRefPubMedGoogle Scholar
  17. Holtmann G, Bakker EP, Uozumi N, Bremer E (2003) KtrAB and KtrCD: two K+ uptake systems in Bacillus subtilis and their role in adaptation to hypertonicity. J Bacteriol 185:1289–1298CrossRefPubMedPubMedCentralGoogle Scholar
  18. Huynh TN, Woodward JJ (2016) Too much of a good thing: regulated depletion of c-di-AMP in the bacterial cytoplasm. Curr Opin Microbiol 30:22–29CrossRefPubMedPubMedCentralGoogle Scholar
  19. Laermann V, Ćudić E, Kipschull K, Zimmann P, Altendorf K (2013) The sensor kinase KdpD of Escherichia coli senses external K+. Mol Microbiol 88:1194–1204CrossRefPubMedGoogle Scholar
  20. Luo Y, Helmann JD (2012) Analysis of the role of Bacillus subtilis σM in β-lactam resistance reveals an essential role for c-di-AMP in peptidoglycan homeostasis. Mol Microbiol 83:623–639CrossRefPubMedPubMedCentralGoogle Scholar
  21. Lüttmann D, Heermann R, Zimmer B, Hillmann A, Rampp IS, Jung K, Görke B (2009) Stimulation of the potassium sensor KdpD kinase activity by interaction with the phosphotransferase protein IIA(Ntr) in Escherichia coli. Mol Microbiol 72:978–994CrossRefPubMedGoogle Scholar
  22. McLaggan D, Naprstek J, Buurman ET, Epstein W (1994) Interdependence of K+ and glutamate accumulation during osmotic adaptation of Escherichia coli. J Biol Chem 269:1911–1917PubMedGoogle Scholar
  23. Mehne FMP, Gunka K, Eilers H, Herzberg C, Kaever V, Stülke J (2013) Cyclic-di-AMP homeostasis in Bacillus subtilis: both lack and high-level accumulation of the nucleotide are detrimental for cell growth. J Biol Chem 288:2004–2017CrossRefPubMedGoogle Scholar
  24. Meyer FM, Gerwig J, Hammer E, Herzberg C, Commichau FM, Völker U, Stülke J (2011) Physical interactions between tricarboxylic acid cycle enzymes in Bacillus subtilis: evidence for a metabolon. Metab Eng 13:18–27CrossRefPubMedGoogle Scholar
  25. Mörk-Mörkenstein M, Heermann R, Göpel Y, Jung K, Görke B (2017) Non-canonical activation of histidine kinase KdpD by phosphotransferase protein PtsN through interaction with the transmitter domain. Mol Microbiol. doi: 10.1111/mmi.13751 PubMedGoogle Scholar
  26. Moscoso JA, Schramke H, Zhang Y, Tosi T, Dehbi A, Jung K, Gründling A (2015) Binding of cyclic di-AMP to the Staphylococcus aureus sensor kinase KdpD occurs via the universal stress protein domain and downregulates the expression of the Kdp potassium transporter. J Bacteriol 198:98–110CrossRefPubMedPubMedCentralGoogle Scholar
  27. Nelson JW, Sudarsan N, Furukawa K, Weingerg Z, Wang JX, Breaker RR (2013) Riboswitches in eubacteria sense the second messenger cyclic di-AMP. Nat Chem Biol 9:834–839CrossRefPubMedPubMedCentralGoogle Scholar
  28. Nissen P, Hansen J, Ban N, Moore PB, Steitz TA (2000) The structural basis of ribosome activity in peptide bond synthesis. Science 289:920–930CrossRefPubMedGoogle Scholar
  29. Oh YK, Palsson B, Park SM, Schilling CH, Mahadevan R (2007) Genome-scale reconstruction of metabolic network in Bacillus subtilis based on high-throughput phenotyping and gene essentiality data. J Biol Chem 282:28791–28799CrossRefPubMedGoogle Scholar
  30. Pham TH, Liang ZX, Marcellin E, Turner MS (2016) Replenishing the cyclic-di-AMP pool: regulation of diadenylate cyclase activity in bacteria. Curr Genet 62:125–128CrossRefGoogle Scholar
  31. Radchenko MV, Tanaka K, Waditee R, Oshimi S, Matsuzaki Y, Fukuhara M, Kobayashi H, Takabe T, Nakamura T (2006a) Potassium/proton antiport system of Escherichia coli. J Biol Chem 281:19822–19829CrossRefPubMedGoogle Scholar
  32. Radchenko MV, Waditee R, Oshimi S, Fukuhara M, Takabe T, Nakamura T (2006b) Cloning, functional expression and primary characterization of Vibrio parahaemolyticus K+/H+ antiporter genes in Escherichia coli. Mol Microbiol 59:651–663CrossRefPubMedGoogle Scholar
  33. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbor Laboratory, New YorkGoogle Scholar
  34. Saum SH, Sydow JF, Palm P, Pfeiffer F, Oesterhelt D, Müller V (2006) Biochemical and molecular characterization of the biosynthesis of glutamine and glutamate, two major compatible solutes in the moderately halophilic bacterium Halobacillus halophilus. J Bacteriol 188:6808–6815CrossRefPubMedPubMedCentralGoogle Scholar
  35. Surmann K, Laermann V, Zimmann P, Altendorf K, Hammer E (2014) Absolute quantification of the Kdp subunits of Escherichia coli by multiple reaction monitoring. Proteomics 14:1630–1638CrossRefPubMedGoogle Scholar
  36. Van Heeswijk WC, Westerhoff HV, Boogerd FC (2013) Nitrogen assimilation in Escherichia coli: putting molecular data into a systems perspective. Microbiol Mol Bio Rev 77:628–695CrossRefGoogle Scholar
  37. 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 30:167–178CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Department of General MicrobiologyGeorg-August-University GöttingenGöttingenGermany

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