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
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

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, modified GGDEF domain
• GdpP, no diguanylate cyclase activity, is c-di-AMP specific phosphodiesterase (see above), modified 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

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)

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)

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)