Hierarchical organization of fluxes in Escherichia coli metabolic network: Using flux coupling analysis for understanding the physiological properties of metabolic genes

• Flux coupling analysis is used to study the relations among metabolic reactions.
• We constructed a hierarchical graph based on the flux coupling relations of reactions.
• A cell tends to regulate higher-level reactions of the flux coupling graph.
• Essential and evolutionarily conserved reactions are located at the top of the graph.
• The most important biological processes are enriched among higher level reactions.

Flux coupling analysis is a method for investigating the connections between reactions of metabolic networks. Here, we construct the hierarchical flux coupling graph for the reactions of the Escherichia coli metabolic network model to determine the level of each reaction in the graph. This graph is constructed based on flux coupling analysis of metabolic network: if zero flux through reaction a results in zero flux through reaction b (and not vice versa), then reaction a is located at the top of reaction b in the flux coupling graph. We show that in general, more important, older and essential reactions are located at the top of the graph. Strikingly, genes corresponding to these reactions are found to be the genes which are most regulated.