An enzyme activation network provides evidence for extensive regulatory crosstalk between metabolic pathways

Enzyme activation by cellular metabolites plays a pivotal role in regulating metabolic processes. Nevertheless, our comprehension of such activation events on a global network scale remains incomplete. In this study, we conducted a comprehensive investigation into the optimization of cell-intrinsic activation interactions within Saccharomyces cerevisiae. To achieve this, we integrated a genome-scale metabolic model with enzyme kinetic data sourced from the BRENDA database. Our objective was to map the distribution of enzyme activators throughout the cellular network. Our findings indicate that virtually all biochemical pathways encompass enzyme activators, frequently originating from disparate pathways, thus revealing extensive regulatory crosstalk between metabolic pathways. Indeed, activators have short pathway lengths, indicating they are activated quickly upon nutrient shifts, and in most instances, these activators target key enzymatic reactions to facilitate downstream metabolic processes. Interestingly, non-essential enzymes exhibit a significantly higher degree of activation compared to their essential counterparts. This observation suggests that cells employ enzyme activators to finely regulate secondary metabolic pathways that are only required under specific conditions. Conversely, the activator metabolites themselves are more likely to be essential components, and their activation levels surpass those of non-essential activators. In summary, our study unveils the widespread importance of enzymatic activators, and suggests that feed-forward activation of conditional metabolic pathways through essential metabolites mediates metabolic plasticity.