Genome-scale metabolic models (GEMs) enable the mathematical simulation of the metabolism of archaea, bacteria, and eukaryotic organisms. GEMs quantitatively define a relationship between genotype and phenotype by contextualizing different types of Big Data (e.g., genomics, metabolomics, and transcriptomics). In this review, we analyze the available Big Data useful for metabolic modeling and compile the available GEM reconstruction tools that integrate Big Data. We also discuss recent applications in industry and research that include predicting phenotypes, elucidating metabolic pathways, producing industry-relevant chemicals, identifying drug targets, and generating knowledge to better understand host-associated diseases. In addition to the up-to-date review of GEMs currently available, we assessed a plethora of tools for developing new GEMs that include macromolecular expression and dynamic resolution. Finally, we provide a perspective in emerging areas, such as annotation, data managing, and machine learning, in which GEMs will play a key role in the further utilization of Big Data.

Production of biofuels and bioenergy precursors by phototrophic microorganisms, such as microalgae and cyanobacteria, is a promising alternative to conventional fuels obtained from non-renewable resources. Several species of microalgae have been investigated as potential candidates for the production of biofuels, for the most part due to their exceptional metabolic capability to accumulate large quantities of lipids. Constraint-based modeling, a systems biology approach that accurately predicts the metabolic phenotype of phototrophs, has been deployed to identify suitable culture conditions as well as to explore genetic enhancement strategies for bioproduction. Core metabolic models were employed to gain insight into the central carbon metabolism in photosynthetic microorganisms. More recently, comprehensive genome-scale models, including organelle-specific information at high resolution, have been developed to gain new insight into the metabolism of phototrophic cell factories. Here, we review the current state of the art of constraint-based modeling and computational method development and discuss how advanced models led to increased prediction accuracy and thus improved lipid production in microalgae.

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Cells can sense changes in their extracellular environment and subsequently adapt their biomass composition. Nutrient abundance defines the capability of the cell to produce biomass components. Under nutrient-limited conditions, resource allocation dramatically shifts to carbon-rich molecules. Here, we used dynamic biomass composition data to predict changes in growth and reaction flux distributions using the available genome-scale metabolic models of five eukaryotic organisms (three heterotrophs and two phototrophs). We identified temporal profiles of metabolic fluxes that indicate long-term trends in pathway and organelle function in response to nitrogen depletion. Surprisingly, our calculations of model sensitivity and biosynthetic cost showed that free energy of biomass metabolites is the main driver of biosynthetic cost and not molecular weight, thus explaining the high costs of arginine and histidine. We demonstrated how metabolic models can accurately predict the complexity of interwoven mechanisms in response to stress over the course of growth.