Introduction and Perspectives

Classically, metabolism was investigated by studying molecular characteristics of enzymes and their regulators in isolation. This reductionistic approach successfully established mechanistic relationships with the immediate interacting neighbors and allowed reconstruction of network structures. Severely underdeveloped was the ability to make precise predictions about the integrated operation of pathways and networks that emerged from the typically nonlinear and complex interactions of proteins and metabolites. The burden of metabolic engineering is a consequence of this fact-one cannot yet predict with any certainty precisely what needs to be engineered to produce more complex phenotypes. What was and still is missing are concepts, methods, and algorithms to integrate data and information into a quantitatively coherent whole, as well as theoretical concepts to reliably predict the consequence of environmental stimuli or genetic interventions. This introduction and perspective to Domain 3, Metabolism and Metabolic Fluxes, starts with a brief overview of the panoply of global measurement technologies that herald the dawning of systems biology and whose impact on metabolic research is apparent throughout the Domain 3. In the middle section, applications to Escherichia coli are used to illustrate general concepts and successes of computational methods that approach metabolism as a network of interacting elements, and thus have potential to fill the gap in quantitative data and information integration. The final section highlights prospective focus areas for future metabolic research, including functional genomics, eludication of evolutionary principles, and the integration of metabolism with regulatory networks.