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Toxins 2019, 11(1), 29; https://doi.org/10.3390/toxins11010029

Toxin ζ Reduces the ATP and Modulates the Uridine Diphosphate-N-acetylglucosamine Pool

1
Department of Microbial Biotechnology, Centro Nacional de Biotecnología, CNB-CSIC, 3 Darwin Str., 28049 Madrid, Spain
2
Scientific Computing Service, Centro Nacional de Biotecnología, CNB-CSIC, 3 Darwin Str., 28049 Madrid, Spain
*
Authors to whom correspondence should be addressed.
Present address: Department for Basic Biomedical Sciences, Faculty of Biomedical Science and Health, Universidad Europea de Madrid, 28670 Madrid, Spain.
Received: 4 December 2018 / Revised: 21 December 2018 / Accepted: 4 January 2019 / Published: 9 January 2019
(This article belongs to the Special Issue Toxin-antitoxin (TA) systems)
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Abstract

Toxin ζ expression triggers a reversible state of dormancy, diminishes the pool of purine nucleotides, promotes (p)ppGpp synthesis, phosphorylates a fraction of the peptidoglycan precursor uridine diphosphate-N-acetylglucosamine (UNAG), leading to unreactive UNAG-P, induces persistence in a reduced subpopulation, and sensitizes cells to different antibiotics. Here, we combined computational analyses with biochemical experiments to examine the mechanism of toxin ζ action. Free ζ toxin showed low affinity for UNAG. Toxin ζ bound to UNAG hydrolyzed ATP·Mg2+, with the accumulation of ADP, Pi, and produced low levels of phosphorylated UNAG (UNAG-P). Toxin ζ, which has a large ATP binding pocket, may temporally favor ATP binding in a position that is distant from UNAG, hindering UNAG phosphorylation upon ATP hydrolysis. The residues D67, E116, R158 and R171, involved in the interaction with metal, ATP, and UNAG, were essential for the toxic and ATPase activities of toxin ζ; whereas the E100 and T128 residues were partially dispensable. The results indicate that ζ bound to UNAG reduces the ATP concentration, which indirectly induces a reversible dormant state, and modulates the pool of UNAG. View Full-Text
Keywords: Toxin-antitoxin system; cell wall inhibition; bacterial persistence; nucleotide hydrolysis; uridine diphosphate-N-acetylglucosamine Toxin-antitoxin system; cell wall inhibition; bacterial persistence; nucleotide hydrolysis; uridine diphosphate-N-acetylglucosamine
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Moreno-del Álamo, M.; Tabone, M.; Muñoz-Martínez, J.; Valverde, J.R.; Alonso, J.C. Toxin ζ Reduces the ATP and Modulates the Uridine Diphosphate-N-acetylglucosamine Pool. Toxins 2019, 11, 29.

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