Discovery and dissection of metabolic oscillations in the microaerobic nitric oxide response network of Escherichia coli

The virulence of many pathogens depends upon their ability to cope with immune-generated nitric oxide (NO center dot). In Escherichia coli, the major NO center dot detoxification systems are Hmp, an NO center dot dioxygenase (NOD), and NorV, an NO center dot reductase (NOR). It is well established that Hmp is the dominant system under aerobic conditions, whereas NorV dominates anaerobic conditions; however, the quantitative contributions of these systems under the physiologically relevant microaerobic regime remain ill defined. Here, we investigated NO center dot detoxification in environments ranging from 0 to 50 mu M O-2, and discovered a regime in which E. coli NO center dot defenses were severely compromised, as well as conditions that exhibited oscillations in the concentration of NO center dot. Using an integrated computational and experimental approach, E. coli NO center dot detoxification was found to be extremely impaired at low O-2 due to a combination of its inhibitory effects on NorV, Hmp, and translational activities, whereas oscillations were found to result from a kinetic competition for O-2 between Hmp and respiratory cytochromes. Because at least 777 different bacterial species contain the genetic requirements of this stress response oscillator, we hypothesize that such oscillatory behavior could be a widespread phenomenon. In support of this hypothesis, Pseudomonas aeruginosa, whose respiratory and NO center dot response networks differ considerably from those of E. coli, was found to exhibit analogous oscillations in lowO(2) environments. This work provides insight into how bacterial NO center dot defenses function under the low O-2 conditions that are likely to be encountered within host environments.