Mycobacterium tuberculosis partitions the Krebs cycle under iron starvation
- Department of Molecular Medicine, University of Padova, Italy
- Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, United Kingdom
- Bind Research, United Kingdom
- Chemistry Department, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, United States
Figures
Figure 1 with 1 supplement
Survival to Fe3+ starvation in M. tuberculosis (Mtb) H37Rv and Erdman strains.
Cells were exposed to 50 μM FeCl3 (HI: high iron), 0 μM FeCl3 (LI: low iron), or 0 μM FeCl3+DFO (deferoxamine [DFO]). Growth was monitored for 3 weeks by measuring OD600 (A, B), and survival was monitored for more than 4 weeks by colony-forming unit (CFU)/mL (C–F). The charts show one experiment representative of two to three independent experiments. The CFU/mL charts show average and average deviation of two technical replicates of one independent experiment. (G, H) ATP levels and growth (OD600) after 1, 2, 3, and 8 days in DFO. ATP levels were calculated as µM of ATP molecules in about 107 cells (0.1 optical density at 600 nm). The data are the average and standard deviation of three independent experiments and three technical replicates each. (I) NADH/NAD+ ratio detected after 3 days of exposure to DFO. The data are the average and standard deviation of two independent experiments and two technical replicates. The p-values were calculated against the HI condition. *=p-value<0.05.
Figure 1—figure supplement 1
Intracellular ATP content and NADH/NAD+ ratio in H37Rv and Erdman strain.
Cells were exposed to 50 μM FeCl3 (HI: high iron) or 0 μM FeCl3+DFO (deferoxamine [DFO]). Samples were collected after 3, 10, and 17 days of exposure. (A, B) The charts show ATP levels and growth (OD600). ATP levels were calculated as µM of ATP molecules in 107 cells (0.1 optical density at 600 nM). (C, D) The charts show the ratio between NADH and NAD levels. NADH and NAD+ levels were normalised on protein content of the extract. All the data are the average and standard deviation of two biological replicates, two culture aliquots from each replicate and two technical replicates on the 96-well plate. n.s.=non-significant, p-value>0.05. *=p-value<0.05. **=p-value<0.01. Black asterisk (outside the bar): DFO vs HI; red asterisk (inside the bar): day 17 vs day 10 and day 3, and day 10 vs day 3.
Figure 2 with 5 supplements
Intracellular and extracellular levels of metabolites in H37Rv.
Cells were exposed to 50 μM FeCl3 (HI: high iron), 0 μM FeCl3 (LI: low iron), or 0 μM FeCl3+DFO (deferoxamine [DFO]). The analysed metabolites are shown in black in the schematic pathways. (A) Intracellular polar metabolites levels at 8 days; the y-axis is shown on Log10 scale. Tick labels (0–5) represent the exponents of 10 (100–105); values are reported in arbitrary units. (B) Extracellular polar metabolites levels at 1, 3, and 8 days. The plots show the normalised levels of metabolites. The data represent the average and the standard deviation of four biological replicates from an independent experiment, representative of two independent experiments. The y-axis is shown on Log10 scale; values are reported in arbitrary units. (C) Viability of H37Rv from one independent experiment. Cells were grown in liquid medium in HI and DFO conditions and in the presence of 2 mM of succinate. Aliquots of cells were collected after 0, 3, and 8 days and diluted to the same final OD600; 5 μL of 10-fold serial dilutions were plated on 7H10. Growth was recorded after 19–25 days. The p-values were calculated against the HI condition and independently for the two experiments; the highest p-value was reported. n.s.f.=non-significant fold change; the observed trend change was different between independent experiments; n.s.=non-significant, p-value>0.05; n.d.=non-detected; *=p-value<0.05; **=p-value<0.01. Ac-CoA: acetyl-CoA; CIT: citrate; FUM: fumarate; α-KG: α-ketoglutarate; ISO: isocitrate; (ISO)CIT: isocitrate and citrate; MAL: malate; OAA: oxaloacetate; PYR: pyruvate; SUCC: succinate; SUCC-CoA: succinyl-CoA.
Figure 2—figure supplement 1
Intracellular and extracellular levels of metabolites in the Erdman strain.
Cells were exposed to 50 μM FeCl3 (HI: high iron), 0 μM FeCl3 (LI: low iron), or 0 μM FeCl3+DFO (deferoxamine [DFO]). The analysed metabolites are shown in black in the schematic pathways. (A) Intracellular polar metabolites levels at 8 days. The y-axis is shown on Log10 scale. Tick labels (0–5) represent the exponents of 10 (100–105); values are reported in arbitrary units. The slight decrease in succinate levels (0.66 FC) was not observed in the other four independent experiments in which no changes were observed in LI and DFO conditions compared to HI condition. (B) Extracellular polar metabolites levels at 1, 3, and 8 days. The plots show the normalised levels of metabolites. The y-axis is shown on Log10 scale; values are reported in arbitrary units. The data represent the average and the standard deviation of four biological replicates from an independent experiment, representative of four independent experiments for the HI and DFO conditions, and two independent experiments for the LI condition. The y-axis is on Log10 scale, and an arbitrary unit is reported. (C) Viability of cells exposed to DFO in the presence of 2 mM of malate (DFO+M), succinate (DFO+S), pyruvate (DFO+P), or a combination of the three (DFO+M+S+P). The plot reports the viability measured as colony-forming unit (CFU)/mL in Log10 scale. The data are representative of one independent experiment (average and average deviation of two technical replicates). The p-values were calculated against the HI condition and independently for the four experiments; the highest p-value is reported. *=p-value<0.05; **=p-value<0.01. n.d.=not detected. n.s.f.=not significant fold change; the observed trend change was different between independent experiments. Ac-CoA: acetyl-CoA; CIT: citrate; FUM: fumarate; α-KG: α-ketoglutarate; ISO: isocitrate; (ISO)CIT: isocitrate and citrate; MAL: malate; OAA: oxaloacetate; PYR: pyruvate; SUCC: succinate; SUCC-CoA: succinyl-CoA.
Figure 2—figure supplement 2
Abundance and 13C labelling of extracellular metabolites.
Cells were exposed to 50 μM FeCl3 (HI: high iron), 0 μM FeCl3 (LI: low iron), or 0 μM FeCl3+DFO (deferoxamine [DFO]). Metabolites were extracted from culture filtrate at 1, 3, and 8 days in H37Rv (A, C, E, G, I) and Erdman strain (B, D, F, H, J). (A–F) 13C total labelling of fumarate (A, B), (iso)citrate (C, D), malate (E, F), and glutamate (G, H). (I, J). The plots show the normalised levels of glutamate; the y-axes is on Log10 scale. The data represent the average and the standard deviation of four biological replicates from an independent experiment, representative of two independent experiments. n.s.f.=not significant fold change; the observed trend change was different between independent experiments; a.u.=arbitrary unit.
Figure 2—figure supplement 3
Viability of M. tuberculosis (Mtb) exposed to severe Fe3+ starvation and in the presence of 2 mM or 5 mM Krebs cycle intermediates (A, H37Rv) or 200 μM 3NP (B, Erdman).
Cells were exposed to 50 μM FeCl3 (HI: high iron) or 0 μM FeCl3+DFO (deferoxamine [DFO]) in liquid medium for 8 days. Aliquots of cells were collected after 0, 1, 3, and 8 days, diluted to a final OD600 of 0.1 and 5 μL of a 10-fold serial dilution were plated on 7 H10/ADC. Growth was recorded after 19–25 days.
Figure 2—figure supplement 4
Analysis of metabolites in the H37Rv-derived ∆icl1::icl1 complemented strain.
Cells were exposed to 50 μM FeCl3 (HI: high iron), 0 μM FeCl3 (LI: low iron), or 0 μM FeCl3+DFO (deferoxamine [DFO]), and fed with 13C3-glycerol. Intracellular metabolites were determined after 8 days; extracellular metabolites were determined after 1, 3, and 8 days. The plots show the normalised levels of metabolites. The data represent average and standard deviation from one experiment and four biological replicates. For intracellular abundance plots, the y-axis is shown on Log10 scale. Tick labels (0–5) represent the exponents of 10 (100–105); values are reported in arbitrary units. For extracellular abundance plots; the y-axis is shown on Log10 scale; values are reported in arbitrary units. The column headers contain the labels of the y-axis. The p-values were calculated against HI condition. n.s.=non-significant, p-value>0.05; *=p-value<0.05; **=p-value<0.01. a.u.=arbitrary unit.
Figure 2—figure supplement 5
Analysis of metabolites in the H37Rv-derived icl1 mutant (∆icl1) compared to its complemented strain (∆icl1::icl1) in the deferoxamine (DFO) condition.
Cells were exposed to 0 μM FeCl3+DFO (DFO), and fed with 13C3-glycerol for 8 days. Intracellular metabolites were extracted after 8 days; extracellular metabolites were extracted after 1, 3, and 8 days. (A) Normalised abundance of intracellular metabolites; the y-axis is shown on Log10 scale. Tick labels (0–4) represent the exponents of 10 (100–104); values are reported in arbitrary units. (B) Total percentage of labelled and unlabelled metabolites. (C) Isotopologue distribution of metabolites. (D) Isotopologue distribution of the α-ketoglutarate pool in the low iron (LI; 0 μM FeCl3) condition. (E) Normalised abundance of extracellular metabolites; the y-axis is shown on Log10 scale; values are reported in arbitrary units. (A–C, E) Data from one experiment representative of two independent experiments and four biological replicates. (D) Data from one independent experiment and four biological replicates each. The data represent average and standard deviation of four biological replicates from an independent experiment. n.s.f.=not significant fold change; the observed trend change was different between independent experiments. a.u.=arbitrary unit.
Figure 3 with 5 supplements
Percentage of labelled (13C) and unlabelled (12C) metabolites in H37Rv.
Metabolites were extracted from cells fed with 13C3-glycerol for 8 days in 50 μM FeCl3 (HI: high iron), 0 μM FeCl3 (LI: low iron), or 0 μM FeCl3+DFO (deferoxamine [DFO]). The analysed metabolites are shown in black in the schematic pathways. For each metabolite, except fumarate, two plots are shown. The stacked column plot shows the total percentage of labelled and unlabelled molecules per each metabolite pool; the clustered column plot shows the abundance in percentage of each isotopologue. The data represent the average and the standard deviation of four biological replicates from an independent experiment, representative of two independent experiments. The p-values were calculated independently for the two experiments, and the highest p-value was reported. DFO/LI vs HI condition: *=p-value<0.05; **=p-value<0.01; n.s.=non-significant. n.d.=non-detected. M2 vs M1: #=p-value<0.05; ##=p-value<0.01. Ac-CoA: acetyl-CoA; CIT: citrate; FUM: fumarate; α-KG: α-ketoglutarate; ISO: isocitrate; (ISO)CIT: isocitrate and citrate; MAL: malate; OAA: oxaloacetate; PYR: pyruvate; SUCC: succinate; SUCC-CoA: succinyl-CoA.
Figure 3—figure supplement 1
Schematic representation of 13C-pyruvate and 13C-carbon dioxide assimilation through pyruvate dehydrogenase (PDH), Krebs cycle, and glyoxylate shunt.
Atoms of 13C are marked in green. The panels include the activity of PDH, the Krebs cycle, and the glyoxylate shunt. Labelled acetyl-CoA reacting with glyoxylate is assumed to derive from PDH activity. The labelled input metabolite (s) are indicated at the bottom of each panel: (A) pyruvate and both acetyl-CoA; (B) pyruvate and one acetyl-CoA; (C) one acetyl-CoA . To simplify, only one of the enzymes for α-ketoglutarate degradation and citrate synthesis is reported. Acn: aconitase; GlcB: malate synthase; GltA: citrate synthase; Icd: isocitrate dehydrogenase; Icl: isocitrate lyase; Kor: αketoglutarate ferredoxin-oxidoreductase; Mdh: malate dehydrogenase; Sdh: succinate dehydrogenase.
Figure 3—figure supplement 2
Schematic representation of 13C-phosphoenolpyruvate and 13C-carbon dioxide assimilation through phosphoenolpyruvate carboxykinase (PCK), Krebs cycle, and glyoxylate shunt.
Atoms of 13C are marked in green. The panels include the activity of PCK, the Krebs cycle, and the glyoxylate shunt. Labelled acetyl-CoA is assumed to derive from PDH activity. The labelled input metabolite(s) are indicated at the bottom of each panel: (A) phosphoenolpyruvate (PEP) and both acetyl-CoA; (B, C) PEP and one acetyl-CoA; (D) PEP; (E) both acetyl-CoA; (F, G) one acetyl-CoA; (H) none. The labelling profiles of metabolites downstream to PEP are identical if PCK is replaced by pyruvate carboxylase and PEP is replaced by pyruvate. To simplify, only one of the enzymes for α-ketoglutarate degradation and citrate synthesis is reported. Carbon dioxide reacting with PEP is not labelled in any panel. Acn: aconitase; GlcB: malate synthase; GltA: citrate synthase; Icd: isocitrate dehydrogenase; Icl: isocitrate lyase; Kor: αketoglutarate ferredoxin-oxidoreductase; Sdh: succinate dehydrogenase.
Figure 3—figure supplement 3
Schematic representation of 13C-phosphoenolpyruvate and 13C-carbon dioxide assimilation through phosphoenolpyruvate carboxykinase (PCK), the Krebs cycle, and the glyoxylate shunt.
Atoms of 13C are marked in green. The panels include the activity of PCK, the Krebs cycle, and the glyoxylate shunt. Labelled acetyl-CoA is assumed to derive from PDH activity. The labelled input metabolite(s) are indicated at the bottom of each panel: (A) phosphoenolpyruvate (PEP), CO2 and both acetyl-CoA; (B, C) PEP, CO2 and one acetyl-CoA; (D) PEP and CO2; (E) CO2 and both acetyl-CoA; (F, G) CO2 and one acetyl-CoA; (H) CO2.The labelling profiles of metabolites downstream to PEP are identical if PCK is replaced by pyruvate carboxylase and PEP is replaced by pyruvate. To simplify, only one of the enzymes for α-ketoglutarate degradation and citrate synthesis is reported. Carbon dioxide reacting with PEP is labelled in each panel. Acn: aconitase; GlcB: malate synthase; GltA: citrate synthase; Icd: isocitrate dehydrogenase; Icl: isocitrate lyase; Kor: αketoglutarate ferredoxin-oxidoreductase; Sdh: succinate dehydrogenase.
Figure 3—figure supplement 4
Schematic representation of 13C-phosphoenolpyruvate and 13C-carbon dioxide assimilation through phosphoenolpyruvate carboxykinase (PCK) and Krebs cycle.
The panels include the activity of PCK and the Krebs cycle. Labelled acetyl-CoA is assumed to derive from PDH activity. The labelled input metabolite(s) are indicated at the bottom of each panel: (A) phosphoenolpyruvate (PEP) and acetyl-CoA; (B) PEP: (C) acetyl-CoA; (D) none; (E) PEP, CO2 and acetyl-CoA; (F) PEP and CO2; (G) CO2 and acetyl-CoA; (H) CO2. The labelling profiles of metabolites downstream to PEP are identical if PCK is replaced by pyruvate carboxylase and PEP is replaced by pyruvate. To simplify, only one of the enzymes for α-ketoglutarate degradation and citrate synthesis is reported. The bottom of each panel indicates which input metabolite is labelled. Acn: aconitase; GltA: citrate synthase; Icd: isocitrate dehydrogenase; Kor: α-ketoglutarate oxidoreductase; Sdh: succinate dehydrogenase.
Figure 3—figure supplement 5
Schematic representation of 13C-phosphoenolpyruvate, 13C-pyruvate, and 13C-carbon dioxide assimilation through phosphoenolpyruvate carboxykinase (PCK) and Krebs cycle.
The panels include the activity of PCK and the Krebs cycle. Labelled acetyl-CoA is assumed to derive from pyruvate dehydrogenase (PDH) activity. The panels A–D include the anaplerotic reaction of PCK and the reduction of oxaloacetate to malate by MDH. The labelling profiles of metabolites downstream to phosphoenolpyruvate (PEP) are identical if PCK is replaced by pyruvate carboxylase and PEP is replaced by pyruvate. The panels E–H include the anaplerotic reaction of malic enzyme (MEZ) from pyruvate to malate. The bottom of each panel indicates which input metabolite is labelled.
Figure 4 with 1 supplement
Percentage of labelled (13C) and unlabelled (12C) metabolites in the Erdman strain.
Metabolites were extracted from cells fed with 13C3-glycerol for 8 days in 50 μM FeCl3 (HI: high iron), 0 μM FeCl3 (LI: low iron), or 0 μM FeCl3+DFO (DFO). The analysed metabolites are shown in black in the schematic pathways. For each metabolite, two plots are shown. The stacked column plots show the total percentage of labelled and unlabelled molecules per each metabolite pool; the clustered column plots show the abundance in percentage of each isotopologue. The data represent the average and the standard deviation of four biological replicates from an independent experiment, representative of four independent experiments (only two for LI condition). The p-values were calculated independently between experiments and the highest value is reported. DFO/LI vs HI: **=p-value<0.01; n.s.=non-significant; n.s.f.=non-significant fold change; the observed trend change was different between independent experiments. n.d.=non-detected. M2 vs M1: ##=p-value<0.01. Ac-CoA: acetyl-CoA; CIT: citrate; FUM: fumarate; α-KG: α-ketoglutarate; ISO: isocitrate; (ISO)CIT: isocitrate and citrate; MAL: malate; OAA: oxaloacetate; PYR: pyruvate; SUCC: succinate; SUCC-CoA: succinyl-CoA.
Figure 4—figure supplement 1
Analysis of intracellular glycine in the H37Rv, Erdman, and H37Rv-derived icl1 mutant in high iron (HI) and deferoxamine (DFO) condition.
Cells were exposed to 50 μM FeCl3 (HI), 0 μM FeCl3+DFO (DFO), and fed with 13C3-glycerol for 8 days. (A, C) Normalised levels of glycine in H37Rv and Erdman strains; the y-axis is shown on Log10 scale. Tick labels (0–5) represent the exponents of 10 (100–105); values are reported in arbitrary units. (B, D) Isotopologue distribution expressed in percentage in H37Rv and Erdman strains. Plots show average and standard deviation from one experiment and four biological replicates. (E) The table shows the qualitative analysis of the glycine isotopologues produced by the scenarios illustrated in Figure 3—figure supplements 1–5. (F) Normalised levels of glycine in an icl1 mutant and complemented strains; the y-axis is shown on Log10 scale; values are reported in arbitrary units. (G) Isotopologue distribution expressed in percentage in an icl1 mutant and complemented strains. The data are representative of two to four independent experiments. The p-values were calculated against HI condition. a.u.: arbitrary unit (see paragraph in Materials and methods). n.s.f=non-significant fold change; the observed trend change was different between independent experiments. **=p-value<0.01.
Figure 5 with 2 supplements
Analysis of iron-independent metabolic routes.
Cells were exposed to 50 μM FeCl3 (high iron [HI]) or 0 μM FeCl3+DFO (deferoxamine [DFO]). (A) Enzymatic activity of phosphoenolpyruvate carboxykinase (PCK), reaction from phosphoenolpyruvate to oxaloacetate. (B) Enzymatic activity of isocitrate lyase (ICL); the plots show the activity in (mM of NADH×min–1)/mg of total protein detected in cell-free extracts after 3 days of exposure to DFO or HI condition. Data show average and standard deviation from two (H37Rv) or three (Erdman strain) independent experiments and two technical replicates each (A) or from one independent experiment and three technical replicates (B). (C, D) Isotopologue distribution of intracellular malate (C) and isocitrate (D) in Erdman-derived ∆pckA::pckA and ∆pckA strains after 8 days of exposure to DFO or HI conditions and fed with 13C3-glycerol. The plots show the abundance in percentage of each isotopologue. The histograms represent average and standard deviation from four biological replicates from one experiment, representative of three independent experiments. (E, F) Enzymatic activity of pyruvate carboxylase (PCA), reaction from pyruvate to oxaloacetate; the plots show the activity in (mM of NADH×min–1)/mg of total protein detected in cell-free extracts after 3 days of exposure to DFO or HI condition. Data show average and standard deviation from three independent experiments and two technical replicates each. (G, H) Erdman strain cells were exposed to HI or DFO condition for 8 days with or without 200 μM of inhibitor 3-nitropropionate (3NP) and fed with 13C3-glycerol. (G) The plots show the normalised levels of metabolites; the y-axis is shown on Log10 scale. Tick labels (0–5) represent the exponents of 10 (100–105); values are reported in arbitrary units. (H) The plots show the isotopologue distribution in percent abundance. The data represent the average and the standard deviation of four biological replicates from an independent experiment, representative of two independent experiments. The p-values were calculated independently between experiments, and the highest value is reported. The p-values were calculated as follows. DFO vs HI for A, B, E, F; HI+3 NP vs HI and DFO+3 NP vs DFO for H; mutant vs complemented for C, D. n.s.f.=non-significant fold change; the observed trend change was different between independent experiments. **=p-value<0.01.
Figure 5—figure supplement 1
Isocitrate lyase (ICL), phosphoenolpyruvate carboxykinase (PCK), pyruvate carboxylase (PCA), and malic enzyme (MEZ) activities in H37Rv and Erdman strains.
The plots report the decrease of absorbance at 340 nm due to the use of NAD(P)H or NADH from two or three technical replicates. The data are representative of one (ICL, MEZ) or two (PCK, PCA) independent experiments. The activity was performed in protein extracts from cells exposed to 50 μM FeCl3 (HI: high iron) and 0 μM FeCl3+DFO (DFO) for 3 days. The plots report the raw values not normalised on protein content.
Figure 5—figure supplement 2
Analysis of γ-aminobutyric acid (GABA) shunt metabolites in H37RV and Erdman strains.
Cells were exposed to 50 μM FeCl3 (HI: high iron), 0 μM FeCl3 (LI: low iron), or 0 μM FeCl3+DFO (DFO) and fed with 13C3-glycerol for 8 days. (A) Schematic representation of the GABA shunt and the Krebs cycle. (B–D) H37Rv; (E–G) Erdman strain; (B, E) glutamate; (C, F) GABA; and (D, G) succinate. Plots with one colour-filled histogram represent the normalised levels of metabolites; the y-axis is shown on Log10 scale. Tick labels (0–5) represent the exponents of 10 (100–105); values are reported in arbitrary units; plots with two colour-stacked histograms represent the total abundance in percentage of labelled and unlabelled metabolite pools; plots with clustered histograms represent the abundance in percentage of each isotopologue. H37Rv data are from one experiment representative of two independent experiments and four biological replicates each; Erdman-derived strain data are from one experiment representative of four independent experiments (only two of them for the LI condition) and four biological replicates each. The histograms show average and standard deviation of four biological replicates from an independent experiment. The p-values were calculated against the HI condition; the highest p-value from the two independent experiments is shown. The differences between M+1 and M+2 isotopologues in the Erdman strain (E, F) are not significant between the three experiments, and the trend varied between independent experiments. a.u.: arbitrary unit (see paragraph in Materials and methods). n.s.f.=non-significant fold change; the observed trend change was different between independent experiments. DFO vs HI or LI vs HI: *=p-value<0.05; **=p-value<0.01; ‘n.s.f.’ above the individual M+1 and M+2 bars of succinate and GABA.
Figure 6
Remodelling of central carbon metabolism (CCM) under iron starvation in M. tuberculosis (Mtb).
The picture depicts a schematic representation of the CCM pathways active in Mtb exposed to Fe3+ deprivation in the presence of D-glucose and glycerol as carbon sources and asparagine as sole nitrogen source. The thickening arrows indicate the increased levels of the metabolite; thicker arrows indicate a preferred route. Bold and larger font indicates accumulated metabolites. Under iron starvation, the pool of iron-dependent enzymes (denoted by Fe in parentheses in the figure) contains a reduced number of fully active molecules, which then slows the carbon flux through the Krebs cycle. The reduction in the transcript levels of iron-independent enzymes of the CCM pathways is likely a consequence of this. The disparity in efficiency between iron-dependent and iron-independent enzyme pools gives rise to the accumulation of (iso)citrate, pyruvate, and α-ketoglutarate. Mtb responds to these accumulations by expelling these metabolites from the cell and splitting the carbon flux from PEP/pyruvate (via phosphoenolpyruvate carboxykinase [PCK], pyruvate carboxylase [PCA], and pyruvate dehydrogenase [PDH] activities) into both oxidative and reductive branches of the Krebs cycle. Both fluxes terminate in malate synthesis, which is then secreted. To maintain malate synthesis by succinate oxidation, Mtb limits its secretion. Malate secretion relieves the slowdown of carbon flux through the oxidative branch of Krebs cycle. PCK and PCA anaplerotic reactions control pyruvate levels and recycle carbon dioxide stoichiometric to the α-ketoglutarate accumulation. GDH: glutamate dehydrogenase; GADB: glutamate decarboxylase; GABT: 4-aminobutyrate aminotransferase; GABD: succinate-semialdehyde dehydrogenase. For the other enzyme acronyms, see main text.
Additional files
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MDAR checklist
- https://cdn.elifesciences.org/articles/107596/elife-107596-mdarchecklist1-v1.pdf
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Source data 1
Publicly available transcriptomic datasets referenced in this study.
- https://cdn.elifesciences.org/articles/107596/elife-107596-data1-v1.xlsx
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Mycobacterium tuberculosis partitions the Krebs cycle under iron starvation
eLife 14:RP107596.
https://doi.org/10.7554/eLife.107596.3
