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Two parallel pathways implement robust propionate catabolism and detoxification in mycobacteria

Katja Tummler, Michael Zimmermann, Olga T. Schubert, Ruedi Aebersold, Clemens Kühn, View ORCID ProfileUwe Sauer, View ORCID ProfileEdda Klipp
doi: https://doi.org/10.1101/258947
Katja Tummler
1Theoretical Biophysics, Humboldt-Universität zu Berlin, Invalidenstraße 42, 10115 Berlin, Germany
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Michael Zimmermann
2Department of Biology, Institute for Molecular Systems Biology, ETH Zürich, Auguste-Piccard-Hof 1, 8093 Zürich, Switzerland
3Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06510, USA
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Olga T. Schubert
2Department of Biology, Institute for Molecular Systems Biology, ETH Zürich, Auguste-Piccard-Hof 1, 8093 Zürich, Switzerland
4UCLA Human Genetics, Los Angeles, CA 90095, USA
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Ruedi Aebersold
2Department of Biology, Institute for Molecular Systems Biology, ETH Zürich, Auguste-Piccard-Hof 1, 8093 Zürich, Switzerland
5Faculty of Science, University of Zürich, 8006 Zürich, Switzerland
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Clemens Kühn
1Theoretical Biophysics, Humboldt-Universität zu Berlin, Invalidenstraße 42, 10115 Berlin, Germany
6Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353 Berlin, Germany.
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Uwe Sauer
2Department of Biology, Institute for Molecular Systems Biology, ETH Zürich, Auguste-Piccard-Hof 1, 8093 Zürich, Switzerland
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Edda Klipp
1Theoretical Biophysics, Humboldt-Universität zu Berlin, Invalidenstraße 42, 10115 Berlin, Germany
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  • For correspondence: edda.klipp@rz.hu-berlin.de
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Abstract

Tuberculosis remains a major global health threat with over 1.5 million deaths each year. Mycobacterium tuberculosis’ success story is related to a flexible metabolism, allowing growth despite restrictive conditions within the human host.

Host lipids stores are a major carbon source in vivo. Their catabolism yields propionyl-CoA, which is processed by two parallel pathways, the methylmalonyl CoA pathway and the methylcitrate pathway. Both pathways are considered potential drug targets. The methylcitrate pathway is upregulated in the pathological context. However, intermediates of this pathway can be cytotoxic and Mtb’s preference for its usage remains unclear.

We combine thermodynamic kinetic modeling, quantitative proteomics and time-resolved metabolomics to characterize the interplay between the two pathways and to show their functionalities in an efficient and fast propionate catabolism.

We find that the methylcitrate pathway acts as a transcriptionally regulated, high capacity catabolic pathway due to its favorable thermodynamics and metabolic control distribution. In contrast, the methylmalonyl pathway is constitutively fulfilling biosynthetic tasks and can quickly detoxify propionate pulses, but is thermodynamically restricted to lower capacity.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted February 02, 2018.
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Two parallel pathways implement robust propionate catabolism and detoxification in mycobacteria
Katja Tummler, Michael Zimmermann, Olga T. Schubert, Ruedi Aebersold, Clemens Kühn, Uwe Sauer, Edda Klipp
bioRxiv 258947; doi: https://doi.org/10.1101/258947
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Two parallel pathways implement robust propionate catabolism and detoxification in mycobacteria
Katja Tummler, Michael Zimmermann, Olga T. Schubert, Ruedi Aebersold, Clemens Kühn, Uwe Sauer, Edda Klipp
bioRxiv 258947; doi: https://doi.org/10.1101/258947

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