Metabolism of signalling nucleotides

Parent categories	2. Metabolism 2.5. Nucleotide metabolism
Neighbouring categories	2.5.1. Utilization of nucleotides 2.5.2. Biosynthesis/ acquisition of nucleotides 2.5.3. Metabolism of signalling nucleotides 2.5.4. Nucleotide metabolism/ other
Related categories	DAC domain EAL domain GGDEF domain
Overview on the categories (Excel file) All genes and their categories (Excel file)

Genes in this functional category

ppGpp synthesis and degradation

• RelA
• SasA
• SasB

c-di-AMP synthesis

• DisA
• CdaA
• CdaS

Control of c-di-AMP synthesis

• CdaR controls CdaA activity PubMed
• RadA controls DisA activity PubMed

Note that c-di-AMP is essential for the growth of B. subtilis, but accumulation of the nucleotide is detrimental as well PubMed

c-di-AMP degradation

• GdpP
• PgpH
• YfkN

Protein potentially involved in c-di-GMP metabolism and signalling

Proteins containing a GGDEF domain (potential diguanylate cyclases)

• DgcK, has cyclase activity
• DgcW, has cyclase activity, contains both a GGDEF and an EAL domain
• DgcP, has cyclase activity
• YdaK, no activity, degenerate GGDEF domain
• GdpP, no diguanylate cyclase activity, is c-di-AMP specific phosphodiesterase (see above), degenerate GGDEF domain

Proteins containing an EAL domain (potential c-di-GMP phosphodiesterases)

• PdeH, has phosphodiesterase activity
• YkuI, no phosphodiesterase activity
• DgcW, phosphodiesterase activity not demonstrated, contains both a GGDEF and an EAL domain

Targets of signalling nucleotides

• ppGpp targets
  • DnaG
  • GdpP
  • Gmk
  • GuaB
  • HprT
  • RbgA
  • Era
  • YnbA

• c-di-GMP targets
  • DgrA (contains a PilZ domain)

• other c-di-GMP-binding proteins
  • YdaK
  • YkuI

• c-di-AMP targets
  • DarA PubMed
  • KtrC (binds c-di-AMP in vivo) PubMed
  • the ydaO riboswitch PubMed

Important original publications

Fabian M Commichau, Johannes Gibhardt, Sven Halbedel, Jan Gundlach, Jörg Stülke
A Delicate Connection: c-di-AMP Affects Cell Integrity by Controlling Osmolyte Transport.
Trends Microbiol: 2018, 26(3);175-185
[PubMed:28965724] [WorldCat.org] [DOI] (I p)

Rebecca M Corrigan, Lauren E Bellows, Alison Wood, Angelika Gründling
ppGpp negatively impacts ribosome assembly affecting growth and antimicrobial tolerance in Gram-positive bacteria.
Proc Natl Acad Sci U S A: 2016, 113(12);E1710-9
[PubMed:26951678] [WorldCat.org] [DOI] (I p)

Anthony O Gaca, Cristina Colomer-Winter, José A Lemos
Many means to a common end: the intricacies of (p)ppGpp metabolism and its control of bacterial homeostasis.
J Bacteriol: 2015, 197(7);1146-56
[PubMed:25605304] [WorldCat.org] [DOI] (I p)

Jan Gundlach, Achim Dickmanns, Kathrin Schröder-Tittmann, Piotr Neumann, Jan Kaesler, Jan Kampf, Christina Herzberg, Elke Hammer, Frank Schwede, Volkhard Kaever, Kai Tittmann, Jörg Stülke, Ralf Ficner
Identification, characterization, and structure analysis of the cyclic di-AMP-binding PII-like signal transduction protein DarA.
J Biol Chem: 2015, 290(5);3069-80
[PubMed:25433025] [WorldCat.org] [DOI] (I p)

Allison Kriel, Shaun R Brinsmade, Jessica L Tse, Ashley K Tehranchi, Alycia N Bittner, Abraham L Sonenshein, Jue D Wang
GTP dysregulation in Bacillus subtilis cells lacking (p)ppGpp results in phenotypic amino acid auxotrophy and failure to adapt to nutrient downshift and regulate biosynthesis genes.
J Bacteriol: 2014, 196(1);189-201
[PubMed:24163341] [WorldCat.org] [DOI] (I p)

James W Nelson, Narasimhan Sudarsan, Kazuhiro Furukawa, Zasha Weinberg, Joy X Wang, Ronald R Breaker
Riboswitches in eubacteria sense the second messenger c-di-AMP.
Nat Chem Biol: 2013, 9(12);834-9
[PubMed:24141192] [WorldCat.org] [DOI] (I p)

Xiaohui Gao, Sampriti Mukherjee, Paige M Matthews, Loubna A Hammad, Daniel B Kearns, Charles E Dann
Functional characterization of core components of the Bacillus subtilis cyclic-di-GMP signaling pathway.
J Bacteriol: 2013, 195(21);4782-92
[PubMed:23893111] [WorldCat.org] [DOI] (I p)

Rebecca M Corrigan, Ivan Campeotto, Tharshika Jeganathan, Kevin G Roelofs, Vincent T Lee, Angelika Gründling
Systematic identification of conserved bacterial c-di-AMP receptor proteins.
Proc Natl Acad Sci U S A: 2013, 110(22);9084-9
[PubMed:23671116] [WorldCat.org] [DOI] (I p)

Felix M P Mehne, Katrin Gunka, Hinnerk Eilers, Christina Herzberg, Volkhard Kaever, Jörg Stülke
Cyclic di-AMP homeostasis in bacillus subtilis: both lack and high level accumulation of the nucleotide are detrimental for cell growth.
J Biol Chem: 2013, 288(3);2004-17
[PubMed:23192352] [WorldCat.org] [DOI] (I p)

Allison Kriel, Alycia N Bittner, Sok Ho Kim, Kuanqing Liu, Ashley K Tehranchi, Winnie Y Zou, Samantha Rendon, Rui Chen, Benjamin P Tu, Jue D Wang
Direct regulation of GTP homeostasis by (p)ppGpp: a critical component of viability and stress resistance.
Mol Cell: 2012, 48(2);231-41
[PubMed:22981860] [WorldCat.org] [DOI] (I p)

Yun Chen, Yunrong Chai, Jian-hua Guo, Richard Losick
Evidence for cyclic Di-GMP-mediated signaling in Bacillus subtilis.
J Bacteriol: 2012, 194(18);5080-90
[PubMed:22821967] [WorldCat.org] [DOI] (I p)

Yaara Oppenheimer-Shaanan, Ezequiel Wexselblatt, Jehoshua Katzhendler, Eylon Yavin, Sigal Ben-Yehuda
c-di-AMP reports DNA integrity during sporulation in Bacillus subtilis.
EMBO Rep: 2011, 12(6);594-601
[PubMed:21566650] [WorldCat.org] [DOI] (I p)

Important reviews

Erin B Purcell, Rita Tamayo
Cyclic diguanylate signaling in Gram-positive bacteria.
FEMS Microbiol Rev: 2016, 40(5);753-73
[PubMed:27354347] [WorldCat.org] [DOI] (I p)

Wieland Steinchen, Gert Bange
The magic dance of the alarmones (p)ppGpp.
Mol Microbiol: 2016, 101(4);531-44
[PubMed:27149325] [WorldCat.org] [DOI] (I p)

TuAnh Ngoc Huynh, Joshua J Woodward
Too much of a good thing: regulated depletion of c-di-AMP in the bacterial cytoplasm.
Curr Opin Microbiol: 2016, 30;22-29
[PubMed:26773214] [WorldCat.org] [DOI] (I p)

Fabian M Commichau, Achim Dickmanns, Jan Gundlach, Ralf Ficner, Jörg Stülke
A jack of all trades: the multiple roles of the unique essential second messenger cyclic di-AMP.
Mol Microbiol: 2015, 97(2);189-204
[PubMed:25869574] [WorldCat.org] [DOI] (I p)

Kuanqing Liu, Alycia N Bittner, Jue D Wang
Diversity in (p)ppGpp metabolism and effectors.
Curr Opin Microbiol: 2015, 24;72-9
[PubMed:25636134] [WorldCat.org] [DOI] (I p)

Rebecca M Corrigan, Angelika Gründling
Cyclic di-AMP: another second messenger enters the fray.
Nat Rev Microbiol: 2013, 11(8);513-24
[PubMed:23812326] [WorldCat.org] [DOI] (I p)

Dimpy Kalia, Gökçe Merey, Shizuka Nakayama, Yue Zheng, Jie Zhou, Yiling Luo, Min Guo, Benjamin T Roembke, Herman O Sintim
Nucleotide, c-di-GMP, c-di-AMP, cGMP, cAMP, (p)ppGpp signaling in bacteria and implications in pathogenesis.
Chem Soc Rev: 2013, 42(1);305-41
[PubMed:23023210] [WorldCat.org] [DOI] (I p)

Mark Gomelsky
cAMP, c-di-GMP, c-di-AMP and now cGMP: bacteria use them all!
Mol Microbiol: 2011, 79(3);562-5
[PubMed:21255104] [WorldCat.org] [DOI] (I p)

Tilman Schirmer, Urs Jenal
Structural and mechanistic determinants of c-di-GMP signalling.
Nat Rev Microbiol: 2009, 7(10);724-35
[PubMed:19756011] [WorldCat.org] [DOI] (I p)

Regine Hengge
Principles of c-di-GMP signalling in bacteria.
Nat Rev Microbiol: 2009, 7(4);263-73
[PubMed:19287449] [WorldCat.org] [DOI] (I p)

Ute Römling
Great times for small molecules: c-di-AMP, a second messenger candidate in Bacteria and Archaea.
Sci Signal: 2008, 1(33);pe39
[PubMed:18714086] [WorldCat.org] [DOI] (I e)

Peggy A Cotter, Scott Stibitz
c-di-GMP-mediated regulation of virulence and biofilm formation.
Curr Opin Microbiol: 2007, 10(1);17-23
[PubMed:17208514] [WorldCat.org] [DOI] (P p)

Ute Römling, Mark Gomelsky, Michael Y Galperin
C-di-GMP: the dawning of a novel bacterial signalling system.
Mol Microbiol: 2005, 57(3);629-39
[PubMed:16045609] [WorldCat.org] [DOI] (P p)