Dataset Information

Phenotypic bistability in Escherichia coli's central carbon metabolism.

ABSTRACT: Fluctuations in intracellular molecule abundance can lead to distinct, coexisting phenotypes in isogenic populations. Although metabolism continuously adapts to unpredictable environmental changes, and although bistability was found in certain substrate-uptake pathways, central carbon metabolism is thought to operate deterministically. Here, we combine experiment and theory to demonstrate that a clonal Escherichia coli population splits into two stochastically generated phenotypic subpopulations after glucose-gluconeogenic substrate shifts. Most cells refrain from growth, entering a dormant persister state that manifests as a lag phase in the population growth curve. The subpopulation-generating mechanism resides at the metabolic core, overarches the metabolic and transcriptional networks, and only allows the growth of cells initially achieving sufficiently high gluconeogenic flux. Thus, central metabolism does not ensure the gluconeogenic growth of individual cells, but uses a population-level adaptation resulting in responsive diversification upon nutrient changes.

SUBMITTER: Kotte O

PROVIDER: S-EPMC4299493 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phenotypic bistability in Escherichia coli's central carbon metabolism.

Kotte Oliver O Volkmer Benjamin B Radzikowski Jakub L JL Heinemann Matthias M

Molecular systems biology 20140701

Fluctuations in intracellular molecule abundance can lead to distinct, coexisting phenotypes in isogenic populations. Although metabolism continuously adapts to unpredictable environmental changes, and although bistability was found in certain substrate-uptake pathways, central carbon metabolism is thought to operate deterministically. Here, we combine experiment and theory to demonstrate that a clonal Escherichia coli population splits into two stochastically generated phenotypic subpopulations ...[more]

PMID: 24987115

Similar Datasets

Project description:BackgroundThe cellular responses of bacteria to superoxide stress can be used to model adaptation to severe environmental changes. Superoxide stress promotes the excessive production of reactive oxygen species (ROS) that have detrimental effects on cell metabolic and other physiological activities. To antagonize such effects, the cell needs to regulate a range of metabolic reactions in a coordinated way, so that coherent metabolic responses are generated by the cellular metabolic reaction network as a whole. In the present study, we have used a quantitative metabolic flux analysis approach, together with measurement of gene expression and activity of key enzymes, to investigate changes in central carbon metabolism that occur in Escherichia coli in response to paraquat-induced superoxide stress. The cellular regulatory mechanisms involved in the observed global flux changes are discussed.ResultsFlux analysis based on nuclear magnetic resonance (NMR) and mass spectroscopy (MS) measurements and computation provided quantitative results on the metabolic fluxes redistribution of the E. coli central carbon network under paraquat-induced oxidative stress. The metabolic fluxes of the glycolytic pathway were redirected to the pentose phosphate pathway (PP pathway). The production of acetate increased significantly, the fluxes associated with the TCA cycle decreased, and the fluxes in the glyoxylate shunt increased in response to oxidative stress. These global flux changes resulted in an increased ratio of NADPH:NADH and in the accumulation of α-ketoglutarate.ConclusionsMetabolic flux analysis provided a quantitative and global picture of responses of the E. coli central carbon metabolic network to oxidative stress. Systematic adjustments of cellular physiological state clearly occurred in response to changes in metabolic fluxes induced by oxidative stress. Quantitative flux analysis therefore could reveal the physiological state of the cell at the systems level and is a useful complement to molecular systems approaches, such as proteomics and transcription analyses.

Project description:BackgroundSystems biology calls for studying system-level properties of genes and proteins rather than their individual chemical/biological properties, regarding the bio-molecules as system components. By characterizing how critical the components are to the system and classifying them accordingly, we can study the underlying complex mechanisms, facilitating researches in drug target selection, metabolic engineering, complex disease, etc. Up to date, most studies aiming at this goal are confined to the topology-based or flux-analysis approaches. However, proteins have tertiary structures and specific functions, especially in metabolic systems. Thus topological properties such as connectivity, path length, etc., are not good surrogates for protein properties. Also, the manner of individual sensitivity analysis in most flux-analysis approaches cannot reveal the simultaneous impacts on collateral components as well as the overall impact on the system, thus lacking in system-level perspective.ResultsIn the present work, we developed a method to directly assess protein system-level properties based on system dynamics and in silico knockouts, regarding to the conceptual term "criticality". Applying the method to E. coli central carbon metabolic system, we found that multiple enzymes including phosphoglycerate kinase, enolase, transketolase-b, etc., had critical roles in the system in terms of both system states and dynamical stability. In contrast, another set of enzymes including glucose-6-phosphate isomerise, pyruvate kinase, phosphoglucomutase, etc., exerted very little influences when deleted. The finding is consistent with experimental characterization of metabolic essentiality and other studies on E. coli gene essentiality and functions. We also found that enzymes could affect distant metabolites or enzymes even greater than a close neighbour and asymmetry in system-level properties of enzymes catalyzing alternative pathways could give rise to local flux compensation.ConclusionsOur method creates a different angle for evaluating protein criticality to a biological system from the conventional methodologies. Moreover, the method leads to consistent results with experimental references, showing its efficiency in studying protein system-level properties. Besides working on metabolic systems, the application of the method can be extended to other kinds of bio-systems to reveal the constitutive/functional properties of system building blocks.

Dataset Information

Phenotypic bistability in Escherichia coli's central carbon metabolism.

Publications

Phenotypic bistability in Escherichia coli's central carbon metabolism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets