Direct and Indirect Inhibition of <italic toggle="yes">Salmonella</italic> Peptide Deformylase by Nitric Oxide
ABSTRACT Salmonella enterica serovar Typhimurium is an intracellular pathogen that elicits nitric oxide (NO·) production by host macrophages. NO· is a potent antimicrobial mediator with diverse targets, including protein thiols and metal centers. The mobilization of zinc from metalloproteins by NO·...
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| Autores principales: | , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
American Society for Microbiology
2020
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/30091c9385584c8d849123329ef60762 |
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| Sumario: | ABSTRACT Salmonella enterica serovar Typhimurium is an intracellular pathogen that elicits nitric oxide (NO·) production by host macrophages. NO· is a potent antimicrobial mediator with diverse targets, including protein thiols and metal centers. The mobilization of zinc from metalloproteins by NO· increases the availability of free intracellular zinc, which is detrimental to bacterial cells, but the precise mechanism of zinc cytotoxicity is uncertain. Here, we show that excess zinc results in the mismetallation of the essential iron-containing enzyme peptide deformylase (PDF), thereby diminishing its activity. PDF mismetallation is observed in zinc-treated bacteria lacking the zinc exporters ZntA and ZitB and is also observed during nitrosative stress, suggesting that NO·-mediated zinc mobilization results in PDF mismetallation. However, NO· also inhibits PDF directly by S-nitrosylating the metal-binding Cys90 residue. These observations identify PDF as an essential bacterial protein that is subject to both direct and indirect inactivation by NO·, providing a novel mechanism of zinc toxicity and NO·-mediated antibacterial activity. IMPORTANCE We have previously shown that the host-derived antimicrobial mediator nitric oxide (NO·) mobilizes zinc from bacterial metalloproteins. The present study demonstrates that NO· inactivates the essential iron-containing enzyme peptide deformylase, both by promoting its mismetallation by zinc and by directly modifying its metal-binding site. We explain how free intracellular zinc is detrimental for cells and reveal a new mechanism of NO·-mediated bacterial growth inhibition that is distinct from previously known targets. |
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