Signal perception by FNR: the role of the iron–sulfur cluster¹

The metabolic flexibility of bacteria is key to their ability to survive and thrive in a wide range of environments. Optimal switching from one metabolic pathway to another is a key requirement for this flexibility. Respiration is a good example: many bacteria utilize O₂ as the terminal electron acceptor, but can switch to a range of other acceptors, such as nitrate, when O₂ becomes limiting. Sensing environmental levels of O₂ is the key step in switching from aerobic to anaerobic respiration. In Escherichia coli, the fumarate and nitrate reduction transcriptional regulator (FNR) controls this switch. Under O₂-limiting conditions, FNR binds a [4Fe–4S]²⁺ cluster, generating a transcriptionally active dimeric form. Exposure to O₂ results in conversion of the cluster into a [2Fe–2S]²⁺ form, leading to dissociation of the protein into inactive monomers. The mechanism of cluster conversion, together with the nature of the reaction products, is of considerable current interest, and a near-complete description of the process has now emerged. The [4Fe–4S]²⁺ into [2Fe–2S]²⁺ cluster conversion proceeds via a two-step mechanism. In step 1, a one-electron oxidation of the cluster takes place, resulting in the release of a Fe²⁺ ion, the formation of an intermediate [3Fe–4S]¹⁺ cluster, together with the generation of a superoxide anion. In step 2, the intermediate [3Fe–4S]¹⁺ cluster rearranges spontaneously to form the [2Fe–2S]²⁺ cluster, releasing two sulfide ions and an Fe³⁺ ion in the process. The one-electron activation of the cluster, coupled to catalytic recycling of the superoxide anion back to oxygen via superoxide dismutase and catalase, provides a novel means of amplifying the sensitivity of [4Fe–4S]²⁺ FNR to its signal molecule.