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Abstract Neisseria gonorrhea (Ngo) is a major concern for global public health due to its severe implications for reproductive health. Understanding its metabolic phenotype is crucial for comprehending its pathogenicity. Despite Ngo’s ability to encode tricarboxylic acid (TCA) cycle proteins, GltA and AcnB, their activities are notably restricted. To investigate this phenomenon, we used the iNgo_557 metabolic model and incorporated a constraint on total cellular protein content. Our results indicate that low cellular protein content severely limits GltA and AcnB activity, leading to a shift toward acetate overflow for Adenosine triphosphate (ATP) production, which is more efficient in terms of protein usage. Surprisingly, increasing cellular protein content alleviates this restriction on GltA and AcnB and delays the onset of acetate overflow, highlighting protein allocation as a critical determinant in understanding Ngo’s metabolic phenotype. These findings underscore the significance of Ngo’s metabolic adaptation in light of optimal protein allocation, providing a blueprint to understand Ngo’s metabolic landscape.
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This content will become publicly available on January 28, 2026
A thermodynamic bottleneck in the TCA cycle contributes to acetate overflow in Staphylococcus aureus
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.
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- Award ID(s):
- 1943310
- PAR ID:
- 10595640
- Editor(s):
- Ellermeier, Craig D
- Publisher / Repository:
- American Society for Microbiology
- Date Published:
- Journal Name:
- mSphere
- Volume:
- 10
- Issue:
- 1
- ISSN:
- 2379-5042
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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