Abstract
One of the primary mechanisms through which a cell exerts control over its metabolic state is by modulating expression levels of its enzyme-coding genes. However, the changes at the level of enzyme expression allow only indirect control over metabolite levels, for two main reasons. First, at the level of individual reactions, metabolite levels are non-linearly dependent on enzyme abundances as per the reaction kinetics mechanisms. Secondly, specific metabolite pools are tightly interlinked with the rest of the metabolic network through their production and consumption reactions. While the role of reaction kinetics in metabolite concentration control is well studied at the level of individual reactions, the contribution of network connectivity has remained relatively unclear. Here we report a modeling framework that integrates both reaction kinetics and network connectivity constraints for describing the interplay between metabolite concentrations and mRNA levels. We used this framework to investigate correlations between the gene expression and the metabolite concentration changes in Saccharomyces cerevisiae during its metabolic cycle, as well as in response to three fundamentally different biological perturbations, namely gene knockout, nutrient shock and nutrient change. While the kinetic constraints applied at the level of individual reactions were found to be poor descriptors of the mRNA-metabolite relationship, their use in the context of the network enabled us to correlate changes in the expression of enzyme-coding genes to the alterations in metabolite levels. Our results highlight the key contribution of metabolic network connectivity in mediating cellular control over metabolite levels, and have implications towards bridging the gap between genotype and metabolic phenotype.
Highlights
Cellular metabolic networks provide basic biochemical building blocks and a thermodynamically favorable environment for growth and maintenance
The link between the expression levels of enzymes and metabolite concentrations is governed by the kinetics of individual reactions, which in turn are interlinked with each other due to the complex connectivity structure of metabolic networks
The enzyme-metabolite relationship is relatively well studied at the level of individual reactions, our understanding of the regulation of metabolite levels in complex networks has remained incomplete
Summary
Cellular metabolic networks provide basic biochemical building blocks and a thermodynamically favorable environment for growth and maintenance. Due to this crucial role of metabolism, cells have evolved various mechanisms to regulate metabolic reactions in response to genetic and environmental changes. Our knowledge of the landscape of transcriptional, translational and post-translational regulation of metabolism is expanding with the increasing availability of datasets that provide genome-wide views of the abundance and interactions between mRNAs, proteins and metabolites [1,2,3,4,5,6]. Previous studies have shown that the gene expression changes in metabolic networks are centered on metabolites that are crucial for adjusting the network state in response to specific perturbations [10,11]. Despite successful outcomes of these and other studies suggesting a strong link between transcriptional regulation and changes in metabolite levels [7,10,12,13], the relationship between the two has remained elusive
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