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A thermodynamic bottleneck in the TCA cycle contributes to acetate overflow in Staphylococcus aureusEllermeier, Craig D (Ed.)ABSTRACT During aerobic growth,S. aureusrelies on acetate overflow metabolism, a process where glucose is incompletely oxidized to acetate, for its bioenergetic needs. Acetate is not immediately captured as a carbon source and is excreted as waste by cells. The underlying factors governing acetate overflow inS. aureushave not been identified. Here, we show that acetate overflow is favored due to a thermodynamic bottleneck in the TCA cycle specifically involving the oxidation of succinate to fumarate by succinate dehydrogenase. This bottleneck reduces flux through the TCA cycle, making it more efficient forS. aureusto generate ATP via acetate overflow metabolism. Additionally, the protein allocation cost of maintaining ATP flux through the restricted TCA cycle is greater than that of acetate overflow metabolism. Finally, we show that the TCA cycle bottleneck providesS. aureusthe flexibility to redirect carbon toward maintaining redox balance through lactate overflow when oxygen becomes limiting, albeit at the expense of ATP production through acetate overflow. Overall, our findings suggest that overflow metabolism offersS. aureusdistinct bioenergetic advantages over a thermodynamically constrained TCA cycle, potentially supporting its commensal–pathogenic lifestyle.more » « lessFree, publicly-accessible full text available January 28, 2026
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Kozisek, Faith; Cenovic, Jonathon; Armendariz, Savannah; Muthukrishnan, Subbaratnam; Park, Yoonseong; Thomas, Vinai C; Chaudhari, Sujata S (, Insect Biochemistry and Molecular Biology)
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