In addition to well-characterized bacterial nucleotide second messengers such as 3',5'-cGMP, cyclic di-AMP or ppGpp, an expanding repertoire of linear and cyclic nucleotide players has been discovered during the past years: ppApp[1-5], AP4A[8-10], 2',3'-cNMPs[11-13] or dITP[14] (Tab. 1).
Bacteria utilize a remarkably diverse set of nucleotide-based second messengers to regulate growth, stress adaptation, motility, biofilm formation, and antiviral defense pathways[1-20].
Knowledge gained from analyzing these pathways enables manipulation of bacterial behavior, and is thus valuable for biotechnology and medical applications.
| Inosine- based |
Guanosine- based |
Adenosine- based |
Cytosine- based |
Uridine- based |
|
|---|---|---|---|---|---|
| Linear second messenger | |||||
| Nucleoside triphosphates | dITP[14] | ||||
| Nucleoside polyphosphates | ppGpp[1-7] | ppApp[1-5] | |||
| pppGpp[1-7] | pppApp[1-5] | ||||
| Dinucleoside polyphosphates | AP4A-Solution[8-10] AP4A-Solid[8-10] |
||||
| Cyclic second messenger | |||||
| Cyclic nucleotide monophosphates | 3‘,5‘-cGMP[16] 2‘,3‘-cGMP[11-13] |
3‘,5‘-cAMP[16] 2‘,3‘-cAMP[11-13] |
2‘,3‘-cCMP[11-13] | 2‘,3‘-cUMP[11-13] | |
| Cyclic dinucleotides | c-diGMP[16,17] | c-diAMP[16,17] | |||
| 3‘,3‘-cGAMP[16-18] 2‘,3‘-cGAMP[18,19] |
|||||
| Cyclic trinucleotides | c-triAMP[16,18] | ||||
| 3‘,3‘,3‘-cAAG[16,18] | |||||
Check out our complete portfolio of cyclic nucleotides and nucleoside & dinucleoside polyphosphates as well!
Please contact Barbara with all questions or inquiries you may have!
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[1] Ahmad et al. (2019) An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp. Nature 575: 674.
[2] Jimmy et al. (2020) A widespread toxin-antitoxin system exploiting growth control via alarmone signaling. Proc. Natl. Acad. Sci. U.S.A. 117: 10500.
[3] Anderson et al. (2021) Regulatory Themes and Variations by the Stress-Signaling Nucleotide Alarmones (p)ppGpp in Bacteria. Annu Rev Genet. 55: 115.
[4] Chau et al. (2021) Emerging and divergent roles of pyrophosphorylated nucleotides in bacterial physiology and pathogenesis. PLOS Pathogens 17(5): e1009532.
[5] Steinchen et al. (2021) Dual Role of a (p)ppGpp‐and (p)ppApp‐degrading Enzyme in Biofilm Formation and Interbacterial Antagonism. Molecular Microbiology 115(6): 1339.
[6] Hauryliuk et al. (2015) Recent functional insights into the role of (p)ppGpp in bacterial physiology. Nature Reviews Microbiology.
[7] Dalebroux et al. (2012) ppGpp: magic beyond RNA polymerase. Nature Reviews Microbiology 10 (3):203.
[8] Giammarinaro et al. (2022) Diadenosine tetraphosphate regulates biosynthesis of GTP in Bacillus subtilis. Nat Microbiol 7:1442
[9] Young et al. (2024) From dusty shelves toward the spotlight: growing evidence for Ap4A as an alarmone in maintaining RNA stability and proteostasis. Current Opinion in Microbiology 81:102536.
[10] Zegarra et al. (2023) The mysterious diadenosine tetraphosphate (AP4A). microLife 4: https://doi.org/10.1093/femsml/uqad016
[11] Marotta et al. (2023) Insights into the metabolism, signaling, and physiological effects of 2’,3’-cyclic nucleotide monophosphates in bacteria. Critical Reviews in Biochemistry and Molecular Biology. 58(2-6):118.
[12] Chauhan et al. (2022) Binding of 2′,3′-Cyclic Nucleotide Monophosphates to Bacterial Ribosomes Inhibits Translation. ACS Cent. Sci. 8(11):1518.
[13] Duggal et al. (2022) Cellular Effects of 2′,3′-Cyclic Nucleotide Monophosphates in Gram-Negative Bacteria. ACS Cent. Sci. 204(1):e00208-21.
[14] Zeng et al. (2025) Base-modified nucleotides mediate immune signaling in bacteria. Science : https://doi.org/10.1126/science.ads6055
[15] Barańska et al. (2025) Prokaryotic homeostasis – a solution to thrive and survive. Front. Mol. Biosci.12: https://doi.org/10.3389/fmolb.2025.1704789
[16] Wenzl et al. (2024) How enzyme-centered approaches are advancing research on cyclic oligo-nucleotides. FEBS Lett.598(8): 839.
[17] Yoon et al. (2021) The ever-expanding world of bacterial cyclic oligonucleotide second messengers. Curr Opin Microbiol.60: 96.
[18] Whiteley et al. (2019) Bacterial cGAS-like enzymes synthesize diverse nucleotide signals. Nature567(7747): 194.
[19] Tak et al. (2023) Bacterial cGAS-like enzymes produce 2‘,3‘-cGAMP to activate an ion channel that restricts phage replication. bioRxiv: https://doi.org/10.1101/2023.07.24.550367
[20] Hengge (2023) The symbolic power of nucleotide second messengers – or how prokaryotes link sensing and responding to their outside world. microLife 4: https://doi.org/10.1093/femsml/uqad036
