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Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis

The dynamic interaction of the N- and C-terminal domains of mycobacterial F-ATP synthase subunit ε is proposed to contribute to efficient coupling of H(+)-translocation and ATP synthesis. Here, we investigate crosstalk between both subunit ε domains by introducing chromosomal atpC missense mutations...

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Autores principales: Saw, Wuan-Geok, Wu, Mu-Lu, Ragunathan, Priya, Biuković, Goran, Lau, Aik-Meng, Shin, Joon, Harikishore, Amaravadhi, Cheung, Chen-Yi, Hards, Kiel, Sarathy, Jickky Palmae, Bates, Roderick W., Cook, Gregory M., Dick, Thomas, Grüber, Gerhard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856130/
https://www.ncbi.nlm.nih.gov/pubmed/31727946
http://dx.doi.org/10.1038/s41598-019-53107-3
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author Saw, Wuan-Geok
Wu, Mu-Lu
Ragunathan, Priya
Biuković, Goran
Lau, Aik-Meng
Shin, Joon
Harikishore, Amaravadhi
Cheung, Chen-Yi
Hards, Kiel
Sarathy, Jickky Palmae
Bates, Roderick W.
Cook, Gregory M.
Dick, Thomas
Grüber, Gerhard
author_facet Saw, Wuan-Geok
Wu, Mu-Lu
Ragunathan, Priya
Biuković, Goran
Lau, Aik-Meng
Shin, Joon
Harikishore, Amaravadhi
Cheung, Chen-Yi
Hards, Kiel
Sarathy, Jickky Palmae
Bates, Roderick W.
Cook, Gregory M.
Dick, Thomas
Grüber, Gerhard
author_sort Saw, Wuan-Geok
collection PubMed
description The dynamic interaction of the N- and C-terminal domains of mycobacterial F-ATP synthase subunit ε is proposed to contribute to efficient coupling of H(+)-translocation and ATP synthesis. Here, we investigate crosstalk between both subunit ε domains by introducing chromosomal atpC missense mutations in the C-terminal helix 2 of ε predicted to disrupt inter domain and subunit ε-α crosstalk and therefore coupling. The ε mutant εR105A,R111A,R113A,R115A (ε(4A)) showed decreased intracellular ATP, slower growth rates and lower molar growth yields on non-fermentable carbon sources. Cellular respiration and metabolism were all accelerated in the mutant strain indicative of dysregulated oxidative phosphorylation. The ε(4A) mutant exhibited an altered colony morphology and was hypersusceptible to cell wall-acting antimicrobials suggesting defective cell wall biosynthesis. In silico screening identified a novel mycobacterial F-ATP synthase inhibitor disrupting ε’s coupling activity demonstrating the potential to advance this regulation as a new area for mycobacterial F-ATP synthase inhibitor development.
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spelling pubmed-68561302019-11-19 Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis Saw, Wuan-Geok Wu, Mu-Lu Ragunathan, Priya Biuković, Goran Lau, Aik-Meng Shin, Joon Harikishore, Amaravadhi Cheung, Chen-Yi Hards, Kiel Sarathy, Jickky Palmae Bates, Roderick W. Cook, Gregory M. Dick, Thomas Grüber, Gerhard Sci Rep Article The dynamic interaction of the N- and C-terminal domains of mycobacterial F-ATP synthase subunit ε is proposed to contribute to efficient coupling of H(+)-translocation and ATP synthesis. Here, we investigate crosstalk between both subunit ε domains by introducing chromosomal atpC missense mutations in the C-terminal helix 2 of ε predicted to disrupt inter domain and subunit ε-α crosstalk and therefore coupling. The ε mutant εR105A,R111A,R113A,R115A (ε(4A)) showed decreased intracellular ATP, slower growth rates and lower molar growth yields on non-fermentable carbon sources. Cellular respiration and metabolism were all accelerated in the mutant strain indicative of dysregulated oxidative phosphorylation. The ε(4A) mutant exhibited an altered colony morphology and was hypersusceptible to cell wall-acting antimicrobials suggesting defective cell wall biosynthesis. In silico screening identified a novel mycobacterial F-ATP synthase inhibitor disrupting ε’s coupling activity demonstrating the potential to advance this regulation as a new area for mycobacterial F-ATP synthase inhibitor development. Nature Publishing Group UK 2019-11-14 /pmc/articles/PMC6856130/ /pubmed/31727946 http://dx.doi.org/10.1038/s41598-019-53107-3 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Saw, Wuan-Geok
Wu, Mu-Lu
Ragunathan, Priya
Biuković, Goran
Lau, Aik-Meng
Shin, Joon
Harikishore, Amaravadhi
Cheung, Chen-Yi
Hards, Kiel
Sarathy, Jickky Palmae
Bates, Roderick W.
Cook, Gregory M.
Dick, Thomas
Grüber, Gerhard
Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis
title Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis
title_full Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis
title_fullStr Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis
title_full_unstemmed Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis
title_short Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis
title_sort disrupting coupling within mycobacterial f-atp synthases subunit ε causes dysregulated energy production and cell wall biosynthesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856130/
https://www.ncbi.nlm.nih.gov/pubmed/31727946
http://dx.doi.org/10.1038/s41598-019-53107-3
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