A practical guide to genome-scale metabolic models and their analysis.

Genome-scale metabolic reconstructions and their analysis with constraint-based modeling techniques have gained enormous momentum. It is a natural next step after sequencing of a genome, as a technique that links top-down systems biology analyses at genome scale with bottom-up systems biology modeling scrutiny. This chapter aims at (systems) biologists that have an interest in, but no extensive knowledge of, applying genome-scale metabolic reconstruction and modeling to their organism. Rather than being comprehensive--excellent and extensive reviews exist on every aspect of this field--we give a rather personal account on our experience with the process of reconstruction and modeling. First, we place genome-scale metabolic models in the spectrum of modeling approaches, and rather extensively discuss, for nonexperts, the central concept in constraint-based modeling: the solution space that is bounded through constraints on fluxes. We subsequently provide an overview of the different steps involved in metabolic reconstruction and modeling, pointing to aspects that we found difficult, important, not well enough addressed in the current reviews, or any combination thereof. In this way, we hope that this chapter serves as a practical guide through the field.