Accumulating evidence for trade‐offs involving metabolic traits has demonstrated their importance in the evolution of organisms. Metabolic models with different levels of complexity have already been considered when investigating mechanisms that explain various metabolic trade‐offs. Here we provide a systematic review of modelling approaches that have been used to study and explain trade‐offs between: (i) the kinetic properties of individual enzymes, (ii) rates of metabolic reactions, (iii) the rate and yield of metabolic pathways and networks, (iv) different metabolic objectives in single organisms and in metabolic communities, and (v) metabolic concentrations. In providing insights into the mechanisms underlying these five types of metabolic trade‐offs obtained from constraint‐based metabolic modelling, we emphasize the relationship of metabolic trade‐offs to the classical black box Y‐model that provides a conceptual explanation for resource acquisition–allocation trade‐offs. In addition, we identify several pressing concerns and offer a perspective for future research in the identification and manipulation of metabolic trade‐offs by relying on the toolbox provided by constraint‐based metabolic modelling for single organisms and microbial communities.

Trade-offs are inherent to biochemical networks governing diverse cellular functions, from gene expression to metabolism. Yet, trade-offs between fluxes of biochemical reactions in a metabolic network have not been formally studied. Here, we introduce the concept of absolute flux trade-offs and devise a constraint-based approach, termed FluTO, to identify and enumerate flux trade-offs in a given genome-scale metabolic network. By employing the metabolic networks of Escherichia coli and Saccharomyces cerevisiae, we demonstrate that the flux trade-offs are specific to carbon sources provided but that reactions involved in the cofactor and prosthetic group biosynthesis are present in trade-offs across all carbon sources supporting growth. We also show that absolute flux trade-offs depend on the biomass reaction used to model the growth of Arabidopsis thaliana under different carbon and nitrogen conditions. The identified flux trade-offs reflect the tight coupling between nitrogen, carbon, and sulphur metabolisms in leaves of C3 plants. Altogether, FluTO provides the means to explore the space of alternative metabolic routes reflecting the constraints imposed by inherent flux trade-offs in large-scale metabolic networks.

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