ABSTRACT Glycolysis is central to energy metabolism in most organisms and is highly regulated to enable optimal growth. In the yeast Saccharomyces cerevisiae , feedback mechanisms that control flux through glycolysis span transcriptional control to metabolite levels in the cell. Using a cellobiose consumption pathway, we decoupled glucose sensing from carbon utilization, revealing new modular layers of control that induce ATP consumption to drive rapid carbon fermentation. Alterations of the beta subunit of phosphofructokinase-1 ( PFK2 ), H~(+)-plasma membrane ATPase ( PMA1 ), and glucose sensors ( SNF3 and RGT2 ) revealed the importance of coupling extracellular glucose sensing to manage ATP levels in the cell. Controlling the upper bound of cellular ATP levels may be a general mechanism used to regulate energy levels in cells, via a regulatory network that can be uncoupled from ATP concentrations under perceived starvation conditions. IMPORTANCE Living cells are fine-tuned through evolution to thrive in their native environments. Genome alterations to create organisms for specific biotechnological applications may result in unexpected and undesired phenotypes. We used a minimal synthetic biological system in the yeast Saccharomyces cerevisiae as a platform to reveal novel connections between carbon sensing, starvation conditions, and energy homeostasis.
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