Towards a Systems Level Understanding of the Oxygen Response of Escherichia coli

Bettenbrock, Katja; Bai, Hao; Ederer, Michael; Green, J.; Hellingwerf, K.J.; Holcombe, Mike; Kunz, Simon; Rolfe,; Sanguinetti, Guido; Sawodny, Oliver; Sharma, Poonam; Steinsiek, Sonja; Poole, Robert K.

doi:10.1016/b978-0-12-800143-1.00002-6

Cited by 53 publications

(47 citation statements)

References 111 publications

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“…However, from the perspective of practical applications to develop cellular factories for biofuel and biochemical production, the effect of oxygen limitation on redox regulation with carbon catabolite regulation is critically important. Considerable effort has been expended in this regard in the Systems Understanding of Microbial Oxygen Metabolism (SUMO) project [21–27]. …”

Section: Introductionmentioning

confidence: 99%

“…At limited oxygen concentrations, the transcription factors Fnr and ArcA/B play essential roles in metabolic regulation in E. coli [21]. The direct oxygen sensor Fnr regulates the expression of metabolic pathway genes under anaerobic conditions [31], whereas ArcA/B regulates these genes under both micro-aerobic and anaerobic conditions [32, 33].…”

Section: Introductionmentioning

confidence: 99%

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Modeling and simulation of the redox regulation of the metabolism in Escherichia coli at different oxygen concentrations

Matsuoka

Kurata

2017

Biotechnol Biofuels

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BackgroundMicrobial production of biofuels and biochemicals from renewable feedstocks has received considerable recent attention from environmental protection and energy production perspectives. Many biofuels and biochemicals are produced by fermentation under oxygen-limited conditions following initiation of aerobic cultivation to enhance the cell growth rate. Thus, it is of significant interest to investigate the effect of dissolved oxygen concentration on redox regulation in Escherichia coli, a particularly popular cellular factory due to its high growth rate and well-characterized physiology. For this, the systems biology approach such as modeling is powerful for the analysis of the metabolism and for the design of microbial cellular factories.ResultsHere, we developed a kinetic model that describes the dynamics of fermentation by taking into account transcription factors such as ArcA/B and Fnr, respiratory chain reactions and fermentative pathways, and catabolite regulation. The hallmark of the kinetic model is its ability to predict the dynamics of metabolism at different dissolved oxygen levels and facilitate the rational design of cultivation methods. The kinetic model was verified based on the experimental data for a wild-type E. coli strain. The model reasonably predicted the metabolic characteristics and molecular mechanisms of fnr and arcA gene-knockout mutants. Moreover, an aerobic–microaerobic dual-phase cultivation method for lactate production in a pfl-knockout mutant exhibited promising yield and productivity.ConclusionsIt is quite important to understand metabolic regulation mechanisms from both scientific and engineering points of view. In particular, redox regulation in response to oxygen limitation is critically important in the practical production of biofuel and biochemical compounds. The developed model can thus be used as a platform for designing microbial factories to produce a variety of biofuels and biochemicals.Electronic supplementary materialThe online version of this article (doi:10.1186/s13068-017-0867-0) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modeling and simulation of the redox regulation of the metabolism in Escherichia coli at different oxygen concentrations

Matsuoka

Kurata

2017

Biotechnol Biofuels

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“…Under aerobic conditions, E. coli uses a branched electron transport chain composed of two NADH-quinone oxidoreductases and three quinol oxidases that efficiently couple electron exchange to ATP production by the F 1 F 0 ATPase (37,47). Manipulation of the rate of cellular respiration directly by gene knockout resulted in significant perturbations in bactericidal killing, suggesting a specific role for respiration in antibiotic lethality.…”

Section: Bacteriostatic Alterations To the Metabolome Correspond To Rmentioning

confidence: 99%

Antibiotic efficacy is linked to bacterial cellular respiration

Lobritz

Belenky

Porter

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

619

548

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Bacteriostatic and bactericidal antibiotic treatments result in two fundamentally different phenotypic outcomes-the inhibition of bacterial growth or, alternatively, cell death. Most antibiotics inhibit processes that are major consumers of cellular energy output, suggesting that antibiotic treatment may have important downstream consequences on bacterial metabolism. We hypothesized that the specific metabolic effects of bacteriostatic and bactericidal antibiotics contribute to their overall efficacy. We leveraged the opposing phenotypes of bacteriostatic and bactericidal drugs in combination to investigate their activity. Growth inhibition from bacteriostatic antibiotics was associated with suppressed cellular respiration whereas cell death from most bactericidal antibiotics was associated with accelerated respiration. In combination, suppression of cellular respiration by the bacteriostatic antibiotic was the dominant effect, blocking bactericidal killing. Global metabolic profiling of bacteriostatic antibiotic treatment revealed that accumulation of metabolites involved in specific drug target activity was linked to the buildup of energy metabolites that feed the electron transport chain. Inhibition of cellular respiration by knockout of the cytochrome oxidases was sufficient to attenuate bactericidal lethality whereas acceleration of basal respiration by genetically uncoupling ATP synthesis from electron transport resulted in potentiation of the killing effect of bactericidal antibiotics. This work identifies a link between antibiotic-induced cellular respiration and bactericidal lethality and demonstrates that bactericidal activity can be arrested by attenuated respiration and potentiated by accelerated respiration. Our data collectively show that antibiotics perturb the metabolic state of bacteria and that the metabolic state of bacteria impacts antibiotic efficacy.

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“…In Escherichia coli, seven global regulators (ArcA, Crp, Fis, Fnr, Ihf, Lrp, and NarL) directly modulate the expression of about one-half of all genes (1). This facultative aerobe is able to adapt its metabolism to different oxygen availability conditions through the concerted actions of a network of regulators, including the global regulators ArcAB and Fnr (2)(3)(4). These regulators affect many metabolic pathways, allowing the cells to reach an adequate redox balance under any given conditions.…”

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confidence: 99%

The CreC Regulator of Escherichia coli, a New Target for Metabolic Manipulations

Godoy

Nikel

Gomez

et al. 2016

Appl Environ Microbiol

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The CreBC (carbon source-responsive) two-component regulation system of Escherichia coli affects a number of functions, including intermediary carbon catabolism. The impacts of different creC mutations (a ⌬creC mutant and a mutant carrying the constitutive creC510 allele) on bacterial physiology were analyzed in glucose cultures under three oxygen availability conditions. Differences in the amounts of extracellular metabolites produced were observed in the null mutant compared to the wild-type strain and the mutant carrying creC510 and shown to be affected by oxygen availability. The ⌬creC strain secreted more formate, succinate, and acetate but less lactate under low aeration. These metabolic changes were associated with differences in AckA and LdhA activities, both of which were affected by CreC. Measurement of the NAD(P)H/NAD(P) ؉ ratios showed that the creC510 strain had a more reduced intracellular redox state, while the opposite was observed for the ⌬creC mutant, particularly under intermediate oxygen availability conditions, indicating that CreC affects redox balance. The null mutant formed more succinate than the wild-type strain under both low aeration and no aeration. Overexpression of the genes encoding phosphoenolpyruvate carboxylase from E. coli and a NADH-forming formate dehydrogenase from Candida boidinii in the ⌬creC mutant further increased the yield of succinate on glucose. Interestingly, the elimination of ackA and adhE did not significantly improve the production of succinate. The diverse metabolic effects of this regulator on the central biochemical network of E. coli make it a good candidate for metabolic-engineering manipulations to enhance the formation of bioproducts, such as succinate.T he survival of an organism depends, at least in part, on its ability to sense and respond to changes in the environment. In bacteria, global regulators control the transcription of genes in response to specific external stimuli and metabolic signals, finely tuning different aspects of their physiology to overcome environmental challenges. In Escherichia coli, seven global regulators (ArcA, Crp, Fis, Fnr, Ihf, Lrp, and NarL) directly modulate the expression of about one-half of all genes (1). This facultative aerobe is able to adapt its metabolism to different oxygen availability conditions through the concerted actions of a network of regulators, including the global regulators ArcAB and Fnr (2-4). These regulators affect many metabolic pathways, allowing the cells to reach an adequate redox balance under any given conditions. There is a very close association between carbon and electron flows, and even small differences in oxygen availability have been observed to elicit profound effects on the distribution of carbon fluxes (5).CreBC (for carbon source responsive) is a global sensing and regulation system affecting genes involved in a variety of functions, including enzymes of intermediary catabolism (6). Previous studies have shown that the creABCD operon is activated (i) during growth in minimal mediu...

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Towards a Systems Level Understanding of the Oxygen Response of Escherichia coli

Cited by 53 publications

References 111 publications

Modeling and simulation of the redox regulation of the metabolism in Escherichia coli at different oxygen concentrations

Modeling and simulation of the redox regulation of the metabolism in Escherichia coli at different oxygen concentrations

Antibiotic efficacy is linked to bacterial cellular respiration

The CreC Regulator of Escherichia coli, a New Target for Metabolic Manipulations

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