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A Flux Balance of Glucose Metabolism Clarifies the Requirements of the Warburg Effect.

ABSTRACT: The Warburg effect, or aerobic glycolysis, is marked by the increased metabolism of glucose to lactate in the presence of oxygen. Despite its widespread prevalence in physiology and cancer biology, the causes and consequences remain incompletely understood. Here, we show that a simple balance of interacting fluxes in glycolysis creates constraints that impose the necessary conditions for glycolytic flux to generate lactate as opposed to entering into the mitochondria. These conditions are determined by cellular redox and energy demands. By analyzing the constraints and sampling the feasible region of the model, we further study how cell proliferation rate and mitochondria-associated NADH oxidizing and ATP producing fluxes are interlinked. Together this analysis illustrates the simplicity of the origins of the Warburg effect by identifying the flux distributions that are necessary for its instantiation.

SUBMITTER: Dai Z

PROVIDER: S-EPMC5018130 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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A Flux Balance of Glucose Metabolism Clarifies the Requirements of the Warburg Effect.

Dai Ziwei Z Shestov Alexander A AA Lai Luhua L Locasale Jason W JW

Biophysical journal 20160901 5

The Warburg effect, or aerobic glycolysis, is marked by the increased metabolism of glucose to lactate in the presence of oxygen. Despite its widespread prevalence in physiology and cancer biology, the causes and consequences remain incompletely understood. Here, we show that a simple balance of interacting fluxes in glycolysis creates constraints that impose the necessary conditions for glycolytic flux to generate lactate as opposed to entering into the mitochondria. These conditions are determ ...[more]

PMID: 27602736

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Project description:BackgroundPhotosynthetic organisms convert atmospheric carbon dioxide into numerous metabolites along the pathways to make new biomass. Aquatic photosynthetic organisms, which fix almost half of global inorganic carbon, have great potential: as a carbon dioxide fixation method, for the economical production of chemicals, or as a source for lipids and starch which can then be converted to biofuels. To harness this potential through metabolic engineering and to maximize production, a more thorough understanding of photosynthetic metabolism must first be achieved. A model algal species, C. reinhardtii, was chosen and the metabolic network reconstructed. Intracellular fluxes were then calculated using flux balance analysis (FBA).ResultsThe metabolic network of primary metabolism for a green alga, C. reinhardtii, was reconstructed using genomic and biochemical information. The reconstructed network accounts for the intracellular localization of enzymes to three compartments and includes 484 metabolic reactions and 458 intracellular metabolites. Based on BLAST searches, one newly annotated enzyme (fructose-1,6-bisphosphatase) was added to the Chlamydomonas reinhardtii database. FBA was used to predict metabolic fluxes under three growth conditions, autotrophic, heterotrophic and mixotrophic growth. Biomass yields ranged from 28.9 g per mole C for autotrophic growth to 15 g per mole C for heterotrophic growth.ConclusionThe flux balance analysis model of central and intermediary metabolism in C. reinhardtii is the first such model for algae and the first model to include three metabolically active compartments. In addition to providing estimates of intracellular fluxes, metabolic reconstruction and modelling efforts also provide a comprehensive method for annotation of genome databases. As a result of our reconstruction, one new enzyme was annotated in the database and several others were found to be missing; implying new pathways or non-conserved enzymes. The use of FBA to estimate intracellular fluxes also provides flux values that can be used as a starting point for rational engineering of C. reinhardtii. From these initial estimates, it is clear that aerobic heterotrophic growth on acetate has a low yield on carbon, while mixotrophically and autotrophically grown cells are significantly more carbon efficient.

Dataset Information

A Flux Balance of Glucose Metabolism Clarifies the Requirements of the Warburg Effect.

Publications

A Flux Balance of Glucose Metabolism Clarifies the Requirements of the Warburg Effect.

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