Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis
Abstract The co‐catabolism of multiple host‐derived carbon substrates is required by Mycobacterium tuberculosis (Mtb) to successfully sustain a tuberculosis infection. However, the metabolic plasticity of this pathogen and the complexity of the metabolic networks present a major obstacle in identify...
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-05-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.15252/msb.202110280 |
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| author | Khushboo Borah Tom A Mendum Nathaniel D Hawkins Jane L Ward Michael H Beale Gerald Larrouy‐Maumus Apoorva Bhatt Martine Moulin Michael Haertlein Gernot Strohmeier Harald Pichler V Trevor Forsyth Stephan Noack Celia W Goulding Johnjoe McFadden Dany J V Beste |
| author_facet | Khushboo Borah Tom A Mendum Nathaniel D Hawkins Jane L Ward Michael H Beale Gerald Larrouy‐Maumus Apoorva Bhatt Martine Moulin Michael Haertlein Gernot Strohmeier Harald Pichler V Trevor Forsyth Stephan Noack Celia W Goulding Johnjoe McFadden Dany J V Beste |
| author_sort | Khushboo Borah |
| collection | DOAJ |
| description | Abstract The co‐catabolism of multiple host‐derived carbon substrates is required by Mycobacterium tuberculosis (Mtb) to successfully sustain a tuberculosis infection. However, the metabolic plasticity of this pathogen and the complexity of the metabolic networks present a major obstacle in identifying those nodes most amenable to therapeutic interventions. It is therefore critical that we define the metabolic phenotypes of Mtb in different conditions. We applied metabolic flux analysis using stable isotopes and lipid fingerprinting to investigate the metabolic network of Mtb growing slowly in our steady‐state chemostat system. We demonstrate that Mtb efficiently co‐metabolises either cholesterol or glycerol, in combination with two‐carbon generating substrates without any compartmentalisation of metabolism. We discovered that partitioning of flux between the TCA cycle and the glyoxylate shunt combined with a reversible methyl citrate cycle is the critical metabolic nodes which underlie the nutritional flexibility of Mtb. These findings provide novel insights into the metabolic architecture that affords adaptability of bacteria to divergent carbon substrates and expand our fundamental knowledge about the methyl citrate cycle and the glyoxylate shunt. |
| format | Article |
| id | doaj-art-1069c34eaaa04423b4e6683142460c70 |
| institution | OA Journals |
| issn | 1744-4292 |
| language | English |
| publishDate | 2021-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-1069c34eaaa04423b4e6683142460c702025-08-20T02:37:58ZengSpringer NatureMolecular Systems Biology1744-42922021-05-0117511610.15252/msb.202110280Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosisKhushboo Borah0Tom A Mendum1Nathaniel D Hawkins2Jane L Ward3Michael H Beale4Gerald Larrouy‐Maumus5Apoorva Bhatt6Martine Moulin7Michael Haertlein8Gernot Strohmeier9Harald Pichler10V Trevor Forsyth11Stephan Noack12Celia W Goulding13Johnjoe McFadden14Dany J V Beste15Department of Microbial and Cellular Sciences, Faculty of Health and Medical Sciences, University of SurreyDepartment of Microbial and Cellular Sciences, Faculty of Health and Medical Sciences, University of SurreyDepartment of Computational and Analytical Sciences, Rothamsted ResearchDepartment of Computational and Analytical Sciences, Rothamsted ResearchDepartment of Computational and Analytical Sciences, Rothamsted ResearchMRC Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Faculty of Natural Sciences, Imperial College LondonSchool of Biosciences, University of BirminghamLife Sciences Group, Institut Laue‐LangevinLife Sciences Group, Institut Laue‐LangevinAustrian Centre of Industrial BiotechnologyAustrian Centre of Industrial BiotechnologyLife Sciences Group, Institut Laue‐LangevinInstitute of Bio‐ and Geosciences 1: Biotechnology 2, Forschungszentrum Jülich GmbHDepartment of Pharmaceutical Sciences & Molecular Biology & Biochemistry, University of California IrvineDepartment of Microbial and Cellular Sciences, Faculty of Health and Medical Sciences, University of SurreyDepartment of Microbial and Cellular Sciences, Faculty of Health and Medical Sciences, University of SurreyAbstract The co‐catabolism of multiple host‐derived carbon substrates is required by Mycobacterium tuberculosis (Mtb) to successfully sustain a tuberculosis infection. However, the metabolic plasticity of this pathogen and the complexity of the metabolic networks present a major obstacle in identifying those nodes most amenable to therapeutic interventions. It is therefore critical that we define the metabolic phenotypes of Mtb in different conditions. We applied metabolic flux analysis using stable isotopes and lipid fingerprinting to investigate the metabolic network of Mtb growing slowly in our steady‐state chemostat system. We demonstrate that Mtb efficiently co‐metabolises either cholesterol or glycerol, in combination with two‐carbon generating substrates without any compartmentalisation of metabolism. We discovered that partitioning of flux between the TCA cycle and the glyoxylate shunt combined with a reversible methyl citrate cycle is the critical metabolic nodes which underlie the nutritional flexibility of Mtb. These findings provide novel insights into the metabolic architecture that affords adaptability of bacteria to divergent carbon substrates and expand our fundamental knowledge about the methyl citrate cycle and the glyoxylate shunt.https://doi.org/10.15252/msb.202110280chemostatmetabolic fluxmetabolismMycobacterium tuberculosistuberculosis |
| spellingShingle | Khushboo Borah Tom A Mendum Nathaniel D Hawkins Jane L Ward Michael H Beale Gerald Larrouy‐Maumus Apoorva Bhatt Martine Moulin Michael Haertlein Gernot Strohmeier Harald Pichler V Trevor Forsyth Stephan Noack Celia W Goulding Johnjoe McFadden Dany J V Beste Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis Molecular Systems Biology chemostat metabolic flux metabolism Mycobacterium tuberculosis tuberculosis |
| title | Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis |
| title_full | Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis |
| title_fullStr | Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis |
| title_full_unstemmed | Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis |
| title_short | Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis |
| title_sort | metabolic fluxes for nutritional flexibility of mycobacterium tuberculosis |
| topic | chemostat metabolic flux metabolism Mycobacterium tuberculosis tuberculosis |
| url | https://doi.org/10.15252/msb.202110280 |
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