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Discovery of small alarmone synthetases and their inhibitors as toxin-antitoxin loci

Steffi Jimmy, Chayan Kumar Saha, Constantine Stavropoulos, Abel Garcia-Pino, Vasili Hauryliuk, Gemma C. Atkinson
doi: https://doi.org/10.1101/575399
Steffi Jimmy
1Department of Molecular Biology, Umeå University, Building 6K, 6L University Hospital Area, 901 87 Umeå, Sweden
2Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Building 6K and 6L, University Hospital Area, SE-901 87 Umeå, Sweden
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Chayan Kumar Saha
1Department of Molecular Biology, Umeå University, Building 6K, 6L University Hospital Area, 901 87 Umeå, Sweden
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Constantine Stavropoulos
1Department of Molecular Biology, Umeå University, Building 6K, 6L University Hospital Area, 901 87 Umeå, Sweden
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Abel Garcia-Pino
3Cellular and Molecular Microbiology, Faculté des Sciences, Université Libre de Bruxelles, 12 rue des Professeurs Jeener et Brachet, 6041 Gosselies, Belgium
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Vasili Hauryliuk
1Department of Molecular Biology, Umeå University, Building 6K, 6L University Hospital Area, 901 87 Umeå, Sweden
2Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Building 6K and 6L, University Hospital Area, SE-901 87 Umeå, Sweden
4University of Tartu, Institute of Technology, 50411 Tartu, Estonia
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  • For correspondence: vasili.hauryliuk@umu.se gemma.atkinson@umu.se
Gemma C. Atkinson
1Department of Molecular Biology, Umeå University, Building 6K, 6L University Hospital Area, 901 87 Umeå, Sweden
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  • For correspondence: vasili.hauryliuk@umu.se gemma.atkinson@umu.se
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Summary

Under stressful conditions, bacterial RelA-SpoT Homologue (RSH) enzymes synthesise the alarmone (p)ppGpp, a nucleotide messenger. (p)ppGpp rewires bacterial transcription and metabolism to cope with stress, and at high concentrations inhibits the process of protein synthesis and bacterial growth to save and redirect resources until conditions improve. Single domain Small Alarmone Synthetases (SAS) are RSH family members that contain the (p)ppGpp synthesis (SYNTH) domain, but lack the hydrolysis (HD) domain, and regulatory C-terminal domains of the long RSHs such as Rel, RelA and SpoT. We have discovered that multiple SAS subfamilies can be encoded in broadly distributed bicistronic operon architectures in bacteria and bacteriophages that are reminiscent of those typically seen in toxin-antitoxin (TA) operons. We have validated five of these SASs as being toxic (toxSASs), and shown that the toxicity can be neutralised by five distinct neighbouring antitoxin genes that act at the protein level.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted March 14, 2019.
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Discovery of small alarmone synthetases and their inhibitors as toxin-antitoxin loci
Steffi Jimmy, Chayan Kumar Saha, Constantine Stavropoulos, Abel Garcia-Pino, Vasili Hauryliuk, Gemma C. Atkinson
bioRxiv 575399; doi: https://doi.org/10.1101/575399
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Discovery of small alarmone synthetases and their inhibitors as toxin-antitoxin loci
Steffi Jimmy, Chayan Kumar Saha, Constantine Stavropoulos, Abel Garcia-Pino, Vasili Hauryliuk, Gemma C. Atkinson
bioRxiv 575399; doi: https://doi.org/10.1101/575399

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