From Genome to Function: Metabolism-Wide Models of Lifecycle Stages of Parasites

Metabolism is a complex network of biochemical reactions that cells use to obtain free energy transduced from nutrients and synthesize new cellular components. Understanding the wiring of metabolism can aid in metabolic engineering to boost certain metabolic functions, or, alternatively, inspire interventions to block undesired metabolism, for example, of parasites. The challenge is that interventions to metabolic networks should be studied in the context of the entire, extensive cellular metabolic networks. Incoming and outgoing fluxes may be readily measured but how fluxes are distributed within the metabolic network often remains a black box. Systems biology offers a toolset to shine light inside this black box: constraint-based metabolic models can predict intracellular flux distributions. But how to construct such a model? In this chapter, we will guide you through the steps to make a constraint-based model out of the genome sequence and demonstrate that it may be easier than it sounds. We provide a walkthrough of model construction, curation and validation-with a specific focus on protistan parasites and their lifecycle stages. While genomes can help to infer the entirety of metabolic potential encoded in the organism's genome (a so-called genome-scale metabolic model), cells do not necessarily express all metabolic enzymes simultaneously. This is particularly relevant for parasites as the different lifecycle stages rely on different sets of metabolic enzymes and host-imposed constraints. We discuss approaches to restrict the genome-wide network to become lifecycle stage specific and how you can test and use the resulting models.