When metabolism meets topology: Reconciling metabolite and reaction networks

The search for a systems-level picture of metabolism as a web of molecular interactions provides a paradigmatic example of how the methods used to characterize a system can bias the interpretation of its functional meaning. Metabolic maps have been analyzed using novel techniques from network theory, revealing some non-trivial, functionally relevant properties. These include a small-world structure and hierarchical modularity. However, as discussed here, some of these properties might actually result from an inappropriate way of defining network interactions. Starting from the so-called bipartite organization of metabolism, where the two meaningful subsets (reactions and metabolites) are considered, most current works use only one of the subsets by means of so-called graph projections. Unfortunately, projected graphs often ignore relevant biological and chemical constraints, thus leading to statistical artifacts. Some of these drawbacks and alternative approaches need to be properly addressed.