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Millard2016 - E. coli central carbon and energy metabolism

ABSTRACT: Millard2016 - E. coli central carbon and energy metabolism This model is described in the article: Metabolic regulation is sufficient for global and robust coordination of glucose uptake, catabolism, energy production and growth in Escherichia coli Pierre Millard , Kieran Smallbone, Pedro Mendes PLoS ONE Abstract: The metabolism of microorganisms is regulated through two main mechanisms: changes of enzyme capacities as a consequence of gene expression modulation (“hierarchical control”) and changes of enzyme activities through metabolite-enzyme interactions. An increasing body of evidence indicates that hierarchical control is insufficient to explain metabolic behaviors, but the system-wide impact of metabolic regulation remains largely uncharacterized. To clarify its role, we developed and validated a detailed kinetic model of Escherichia coli central metabolism that links growth to environment. Metabolic control analyses confirm that the control is widely distributed across the network and highlight strong interconnections between all the pathways. Exploration of the model solution space reveals that several robust properties emerge from metabolic regulation, from the molecular level (e.g. homeostasis of total metabolite pool) to the overall cellular physiology (e.g. coordination of carbon uptake, catabolism, energy and redox production, and growth), while allowing a large degree of flexibility at most individual metabolic steps. These properties have important physiological implications for E. coli and significantly expand the self-regulating capacities of its metabolism. This model is hosted on BioModels Database and identified by: MODEL1505110000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

SUBMITTER: Pierre Millard

PROVIDER: MODEL1505110000 | BioModels | 2017-02-21

REPOSITORIES: BioModels

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Project description:Obesity is becoming increasingly widespread in developed countries, and is often associated with heart diseases and diabetes. Elevated levels of plasma free fatty acids are a biochemical hallmark of obesity. Unlike plants and bacteria, mammals cannot utilize fatty acids to generate glucose because of the lack of glyoxylate shunt enzymes. Instead, fatty acids are used for energy storage, and their utilization is regulated at multiple levels ranging from hormonal to metabolic ensuring that glucose is preferentially oxidized before fatty acids. Here we designed a synthetic gene-metabolic circuit to alter the intracellular signaling and metabolic pathways that control fatty acid metabolism. By introducing the Escherichia coli glyoxylate shunt enzymes, isocitrate lyase (AceA) and malate synthase (AceB), into the mitochondria of human hepatocytes, we demonstrated that fatty acid utilization is preferentially increased while glucose uptake is significantly reduced. This bacterial pathway diverts signal metabolites (citrate, acetyl-CoA, and malonyl-CoA) that inhibits fatty acid uptake and provides an additional channel for fatty acid utilization. Remarkably, the hepatocytes readily adapted to the synthetic circuit by a series of global transcriptional and post-translational changes in metabolic and signal transduction pathways that further advanced our design objective. This systems approach illustrates the logic of the synergistic interaction between metabolism and signal transduction. The ready acceptance of this non-native pathway by hepatocytes suggests the plasticity of liver metabolism and opens a possibility for the synthetic approach in regulating human metabolism. Experiment Overall Design: Wild type (WT) human hepatocyte HepG2 and HepG2 cells stably transfected with pBudaceAB (designated ACE), a vector containing isocitrate lyase and malate synthase from E. coli, were analyzed after 24hour exposure to palmitate. Cells were seeded at 70% confluency in 10cm plates with DMEM growth media augmented with 300uM palmitate. After 24hours, total RNA was harvested and hybrized to Affymetrix HG_U133A 2.0 GeneChips. Data was processed using GCOS 1.2 software. Experiment Overall Design: 2 WT biological replicates and 2 ACE biological replicates were analyzed. Experiment Overall Design:

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Millard2016 - E. coli central carbon and energy metabolism

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