Spontaneous Reaction Silencing in Metabolic Optimization

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Abstract
Metabolic reactions of single-cell organisms are routinely observed to become dispensable or even incapable of carrying activity under certain circumstances. Yet, the mechanisms as well as the range of conditions and phenotypes associated with this behavior remain very poorly understood. Here we predict computationally and analytically that any organism evolving to maximize growth rate, ATP production, or any other linear function of metabolic fluxes tends to significantly reduce the number of active metabolic reactions compared to typical nonoptimal states. The reduced number appears to be constant across the microbial species studied and just slightly larger than the minimum number required for the organism to grow at all. We show that this massive spontaneous reaction silencing is triggered by the irreversibility of a large fraction of the metabolic reactions and propagates through the network as a cascade of inactivity. Our results help explain existing experimental data on intracellular flux measurements and the usage of latent pathways, shedding new light on microbial evolution, robustness, and versatility for the execution of specific biochemical tasks. In particular, the identification of optimal reaction activity provides rigorous ground for an intriguing knockout-based method recently proposed for the synthetic recovery of metabolic function. Cellular growth and other integrated metabolic functions are manifestations of the coordinated interconversion of a large number of chemical compounds. But what is the relation between such whole-cell behaviors and the activity pattern of the individual biochemical reactions? In this study, we have used flux balance-based methods and reconstructed networks of Helicobacter pylori, Staphylococcus aureus, Escherichia coli, and Saccharomyces cerevisiae to show that a cell seeking to optimize a metabolic objective, such as growth, has a tendency to spontaneously inactivate a significant number of its metabolic reactions, while all such reactions are recruited for use in typical suboptimal states. The mechanisms governing this behavior not only provide insights into why numerous genes can often be disabled without affecting optimal growth but also lay a foundation for the recently proposed synthetic rescue of metabolic function in which the performance of suboptimally operating cells can be enhanced by disabling specific metabolic reactions. Our findings also offer explanation for another experimentally observed behavior, in which some inactive reactions are temporarily activated following a genetic or environmental perturbation. The latter is of utmost importance given that nonoptimal and transient metabolic behaviors are arguably common in natural environments.
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