Controlling circuitry underlies the growth optimization of Saccharomyces cerevisiae.

Microbial growth emerges from coordinated synthesis of various cellular components from limited resources. In Saccharomyces cerevisiae, cyclic AMP (cAMP)-mediated signaling is shown to orchestrate cellular metabolism; however, it remains unclear quantitatively how the controlling circuit drives resource partition and subsequently shapes biomass growth. Here we combined experiment with mathematical modeling to dissect the signaling-mediated growth optimization of S. cerevisiae. We showed that, through cAMP-mediated control, the organism achieves maximal or nearly maximal steady-state growth during the utilization of multiple tested substrates as well as under perturbations impairing glucose uptake. However, the optimal cAMP concentration varies across cases, suggesting that different modes of resource allocation are adopted for varied conditions. Under settings with nutrient alterations, S. cerevisiae tunes its cAMP level to dynamically reprogram itself to realize rapid adaptation. Moreover, to achieve growth maximization, cells employ additional regulatory systems such as the GCN2-mediated amino acid control. This study establishes a systematic understanding of global resource allocation in S. cerevisiae, providing insights into quantitative yeast physiology as well as metabolic strain engineering for biotechnological applications.

Suboptimal resource allocation in changing environments constrains response and growth in bacteria.

To respond to fluctuating conditions, microbes typically need to synthesize novel proteins. As this synthesis relies on sufficient biosynthetic precursors, microbes must devise effective response strategies to manage depleting precursors. To better understand these strategies, we investigate the active response of Escherichia coli to changes in nutrient conditions, connecting transient gene expression to growth phenotypes. By synthetically modifying gene expression during changing conditions, we show how the competition by genes for the limited protein synthesis capacity constrains cellular response. Despite this constraint cells substantially express genes that are not required, trapping them in states where precursor levels are low and the genes needed to replenish the precursors are outcompeted. Contrary to common modeling assumptions, our findings highlight that cells do not optimize growth under changing environments but rather exhibit hardwired response strategies that may have evolved to promote fitness in their native environment. The constraint and the suboptimality of the cellular response uncovered provide a conceptual framework relevant for many research applications, from the prediction of evolution to the improvement of gene circuits in biotechnology.