Principles of flux and concentration sensing in metabolic regulation

Abstract

To efficiently regulate metabolism, cells must continuously monitor and respond to their metabolic state. Cells are generally thought to achieve this monitoring by sensing metabolite concentrations. However, many cellular responses do not correlate with metabolite concentrations but with the fluxes through metabolic pathways. The mechanisms with which cells sense these metabolic fluxes have largely remained unclear. In chapter 2 of this thesis, we report that one of the most–studied eukaryotic nutrient sensing pathways, galactose-responsive (GAL) signaling of Saccharomyces cerevisiae, is regulated by galactose flux and that this flux sensing is achieved by a simple mechanism: The enzyme that catabolizes galactose has a signaling activity that is coupled to its catalytic activity, resulting in the proportionality of signaling and flux. This flux sensing has the critical physiological role of maintaining GAL signaling when cells catabolize galactose. Additionally, the GAL pathway is regulated by the intracellular galactose concentration which is sensed by a dedicated sensor protein. This concentration sensing has the separate physiological role of activating GAL signaling when cells first encounter galactose. In chapter 3 of this thesis, we show that concentration sensing is tuned by cellular and evolutionary history, determining whether all or only some cells of a population respond to galactose. Overall, flux and concentration sensing underlie distinct regulatory behaviors in the GAL pathway and their combination could be a recurrent motif of metabolic regulation.