A novel yeast hybrid modeling framework integrating Boolean and enzyme-constrained networks enables exploration of the interplay between signaling and metabolism

Abstract

The interplay between nutrient-induced signaling and metabolism plays an important role in maintaining homeostasis and its malfunction has been implicated in many different human diseases such as obesity, type 2 diabetes, cancer, and neurological disorders. Therefore, unraveling the role of nutrients as signaling molecules and metabolites together with their interconnectivity may provide a deeper understanding of how these conditions occur. Both signaling and metabolism have been extensively studied using various systems biology approaches. However, they are mainly studied individually and in addition, current models lack both the complexity of the dynamics and the effects of the crosstalk in the signaling system. To gain a better understanding of the interconnectivity between nutrient signaling and metabolism in yeast cells, we developed a hybrid model, combining a Boolean module, describing the main pathways of glucose and nitrogen signaling, and an enzyme-constrained model accounting for the central carbon metabolism of Saccharomyces cerevisiae, using a regulatory network as a link. The resulting hybrid model was able to capture a diverse utalization of isoenzymes and to our knowledge outperforms constraint-based models in the prediction of individual enzymes for both respiratory and mixed metabolism. The model showed that during fermentation, enzyme utilization has a major contribution in governing protein allocation, while in low glucose conditions robustness and control are prioritized. In addition, the model was capable of reproducing the regulatory effects that are associated with the Crabtree effect and glucose repression, as well as regulatory effects associated with lifespan increase during caloric restriction. Overall, we show that our hybrid model provides a comprehensive framework for the study of the non-trivial effects of the interplay between signaling and metabolism, suggesting connections between the Snf1 signaling pathways and processes that have been related to chronological lifespan of yeast cells.

D-Xylose Sensing in Saccharomyces cerevisiae: Insights from D-Glucose Signaling and Native D-Xylose Utilizers

“…So called hybrid models that integrate reconstructions of both the metabolic and the signaling networks and are able to take metabolic flux and signal transduction into account have indeed been in the works for some time and are increasing in complexity [324][325][326][327]. The challenge with implementing these models is that metabolic and signaling networks have intrinsically different mechanisms of action and require distinct modeling methods [56,320].…”

Multi-scale model suggests the trade-off between protein and ATP demand as a driver of metabolic changes during yeast replicative ageing

“…The first step in the construction was to extend a hybrid model of the central carbon metabolism and nutrient signalling in budding yeast [ 37 ] by reactions and components attributed to the production and removal of ROS and RNS, as well as the signalling response to it. In particular, we built a Boolean model of the Yap1 and Sln1 pathways ( Fig 1A ) and incorporated it in the already existing Boolean model of the nutrient sensing pathways PKA, Snf1 and TOR [ 37 ]. While Msn2 and Msn4 are part of the PKA pathway, we also included the crosstalk to the Yap1 pathway.…”

“…While Msn2 and Msn4 are part of the PKA pathway, we also included the crosstalk to the Yap1 pathway. In addition, we summarised reactions that create and remove ROS/RNS ( Fig 1B ) and added them to the existing model of the central carbon metabolism [ 37 ]. The modules of signalling and metabolism are connected by a transcriptional layer, that modifies the enzyme consumption in the metabolic model depending on the binary activities of transcription factors in the Boolean model by imposing regulatory constraints.…”

Modelling of glucose repression signalling in yeast Saccharomyces cerevisiae

“…To understand this interplay, Österberg et al . ( 2021 ) recently developed a framework that integrates a Boolean model of the SNF1, TOR and PKA pathways, with an enzyme constraint flux balance model of the central carbon metabolism. Within this hybrid model, the intracellular glucose level is obtained from the metabolism module and then used as an input to the nutrient-sensing module.…”