Fig 7. Schematic representation of RitR regulation in S. pneumoniae.

Hydrogen peroxide (H₂O₂) is primarily produced from S. pneumoniae metabolism via pyruvate oxidase (SpxB). When present, iron must be kept out of the cell, or alternatively, stored such that it cannot react to yield Fenton chemistry, thereby causing cellular damage. RitR regulates this process by oxidation though Cys128 in high H₂O₂ produced in aerobic environments such as the nasopharynx, which allows its open conformation and release of the DNA-binding domain (DBD) for the Regulatory Domain (RD) to interact with the Piu promoter, repressing iron uptake. Simultaneously, RitR is postulated to remediate iron toxicity through activation of DNA repair and iron sequestration [25]. Conversely, when H₂O₂ concentrations are low, RitR stays in its inactive form, where the interaction of the RD with the DBD prevents its binding to the Piu regulatory region, ultimately allowing for more iron to enter the cell. The potential oxidation states of RitR (SO^-, SO^2-, SO^3-) and their regulatory consequences remain enigmatic.