期刊
METABOLIC ENGINEERING
卷 29, 期 -, 页码 26-35出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymben.2015.02.006
关键词
Reactive oxygen species; Oxidative stress; Futile cycle; Hydrogen peroxide; Metabolism
资金
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R21AI105342]
- National Science Foundation Division of Materials Research through the Princeton University MRSEC [NSF-DMR 0819860]
- Princeton University
Reactive oxygen species (ROS) are toxic molecules utilized by the immune system to combat invading pathogens. Recent evidence suggests that inefficiencies in ATP production or usage can lead to increased endogenous ROS production and sensitivity to oxidative stress in bacteria. With this as inspiration, and knowledge that ATP is required for a number of DNA repair mechanisms, we hypothesized that futile cycling would be an effective way to increase sensitivity to oxidative stress. We developed a mixed integer linear optimization framework to identify experimentally-tractable futile cycles, and confirmed metabolic modeling predictions that futile cycling depresses growth rate, and increases both O-2 consumption and ROS production per biomass generated. Further, intracellular ATP was decreased and sensitivity to oxidative stress increased in all actively cycling strains compared to their catalytically inactive controls. This research establishes a fundamental connection between ATP metabolism, endogenous ROS production, and tolerance toward oxidative stress in bacteria. (C) 2015 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.
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