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Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus

To gain a better insight of how Copper (Cu) ions toxify cells, metabolomic analyses were performed in S. aureus strains that lacks the described Cu ion detoxification systems (ΔcopBL ΔcopAZ; cop(-)). Exposure of the cop(-) strain to Cu(II) resulted in an increase in the concentrations of metabolites...

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Autores principales: Norambuena, Javiera, Al-Tameemi, Hassan, Bovermann, Hannah, Kim, Jisun, Beavers, William N., Skaar, Eric P., Parker, Dane, Boyd, Jeffrey M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10249872/
https://www.ncbi.nlm.nih.gov/pubmed/37235600
http://dx.doi.org/10.1371/journal.ppat.1011393
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author Norambuena, Javiera
Al-Tameemi, Hassan
Bovermann, Hannah
Kim, Jisun
Beavers, William N.
Skaar, Eric P.
Parker, Dane
Boyd, Jeffrey M.
author_facet Norambuena, Javiera
Al-Tameemi, Hassan
Bovermann, Hannah
Kim, Jisun
Beavers, William N.
Skaar, Eric P.
Parker, Dane
Boyd, Jeffrey M.
author_sort Norambuena, Javiera
collection PubMed
description To gain a better insight of how Copper (Cu) ions toxify cells, metabolomic analyses were performed in S. aureus strains that lacks the described Cu ion detoxification systems (ΔcopBL ΔcopAZ; cop(-)). Exposure of the cop(-) strain to Cu(II) resulted in an increase in the concentrations of metabolites utilized to synthesize phosphoribosyl diphosphate (PRPP). PRPP is created using the enzyme phosphoribosylpyrophosphate synthetase (Prs) which catalyzes the interconversion of ATP and ribose 5-phosphate to PRPP and AMP. Supplementing growth medium with metabolites requiring PRPP for synthesis improved growth in the presence of Cu(II). A suppressor screen revealed that a strain with a lesion in the gene coding adenine phosphoribosyltransferase (apt) was more resistant to Cu. Apt catalyzes the conversion of adenine with PRPP to AMP. The apt mutant had an increased pool of adenine suggesting that the PRPP pool was being redirected. Over-production of apt, or alternate enzymes that utilize PRPP, increased sensitivity to Cu(II). Increasing or decreasing expression of prs resulted in decreased and increased sensitivity to growth in the presence of Cu(II), respectively. We demonstrate that Prs is inhibited by Cu ions in vivo and in vitro and that treatment of cells with Cu(II) results in decreased PRPP levels. Lastly, we establish that S. aureus that lacks the ability to remove Cu ions from the cytosol is defective in colonizing the airway in a murine model of acute pneumonia, as well as the skin. The data presented are consistent with a model wherein Cu ions inhibits pentose phosphate pathway function and are used by the immune system to prevent S. aureus infections.
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spelling pubmed-102498722023-06-09 Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus Norambuena, Javiera Al-Tameemi, Hassan Bovermann, Hannah Kim, Jisun Beavers, William N. Skaar, Eric P. Parker, Dane Boyd, Jeffrey M. PLoS Pathog Research Article To gain a better insight of how Copper (Cu) ions toxify cells, metabolomic analyses were performed in S. aureus strains that lacks the described Cu ion detoxification systems (ΔcopBL ΔcopAZ; cop(-)). Exposure of the cop(-) strain to Cu(II) resulted in an increase in the concentrations of metabolites utilized to synthesize phosphoribosyl diphosphate (PRPP). PRPP is created using the enzyme phosphoribosylpyrophosphate synthetase (Prs) which catalyzes the interconversion of ATP and ribose 5-phosphate to PRPP and AMP. Supplementing growth medium with metabolites requiring PRPP for synthesis improved growth in the presence of Cu(II). A suppressor screen revealed that a strain with a lesion in the gene coding adenine phosphoribosyltransferase (apt) was more resistant to Cu. Apt catalyzes the conversion of adenine with PRPP to AMP. The apt mutant had an increased pool of adenine suggesting that the PRPP pool was being redirected. Over-production of apt, or alternate enzymes that utilize PRPP, increased sensitivity to Cu(II). Increasing or decreasing expression of prs resulted in decreased and increased sensitivity to growth in the presence of Cu(II), respectively. We demonstrate that Prs is inhibited by Cu ions in vivo and in vitro and that treatment of cells with Cu(II) results in decreased PRPP levels. Lastly, we establish that S. aureus that lacks the ability to remove Cu ions from the cytosol is defective in colonizing the airway in a murine model of acute pneumonia, as well as the skin. The data presented are consistent with a model wherein Cu ions inhibits pentose phosphate pathway function and are used by the immune system to prevent S. aureus infections. Public Library of Science 2023-05-26 /pmc/articles/PMC10249872/ /pubmed/37235600 http://dx.doi.org/10.1371/journal.ppat.1011393 Text en © 2023 Norambuena et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Norambuena, Javiera
Al-Tameemi, Hassan
Bovermann, Hannah
Kim, Jisun
Beavers, William N.
Skaar, Eric P.
Parker, Dane
Boyd, Jeffrey M.
Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus
title Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus
title_full Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus
title_fullStr Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus
title_full_unstemmed Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus
title_short Copper ions inhibit pentose phosphate pathway function in Staphylococcus aureus
title_sort copper ions inhibit pentose phosphate pathway function in staphylococcus aureus
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10249872/
https://www.ncbi.nlm.nih.gov/pubmed/37235600
http://dx.doi.org/10.1371/journal.ppat.1011393
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