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Title: Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis
Authors: 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 Wayland
Cook, Gregory M.
Dick, Thomas
Grüber, Gerhard
Keywords: Science::Biological sciences::Biochemistry
Science::Biological sciences::Molecular biology
Issue Date: 2019
Source: Saw, W.-G., Wu, M.-L., Ragunathan, P., Biuković, G., Lau, A.-M., Shin, J., . . . Grüber, G. (2019). Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis. Scientific Reports, 9, 16759-. doi:10.1038/s41598-019-53107-3
Journal: Scientific Reports
Abstract: 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 (ε4A) 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 ε4A 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.
ISSN: 2045-2322
DOI: 10.1038/s41598-019-53107-3
Rights: © 2019 The Author(s) (Nature Publishing Group). 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
Fulltext Permission: open
Fulltext Availability: With Fulltext
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