Avoidance of iron toxicity through regulation of bacterial iron transport.

Under oxic conditions and at pH 7, ferric iron is insoluble, and complex formation of Fe3+ with ligands is required to supply cells with iron. Bacteria and fungi synthesize and secrete low-molecular-weight compounds, termed siderophores, that bind Fe3+. Certain human pathogens take up iron from human transferrin, lactoferrin, hemoglobin, and heme. The ferric siderophores are actively transported into bacterial cells by highly specific transport systems. In Gram-negative bacteria, the ferric siderophores and iron released from the host proteins are actively transported across the outer membrane (OM). The electrochemical potential of the cytoplasmic membrane (CM) energizes transport across the outer membrane, which requires an energy-transducing device, consisting of the proteins TonB, ExbB and ExbD, from the CM to the OM. Active transport across the CM is energized by ATP hydrolysis. Transport is regulated at the level of gene transcription. In Gram-negative bacteria, this is controlled by the Fur protein, in most gram-positive bacteria, by the DtxR protein. Fur and DtxR act as repressors when loaded with Fe2+. In the cytoplasm, iron is released from the siderophores by reduction to Fe2+, and the siderophores are either inactivated or secreted. The intracellular iron is built into heme and non-heme iron proteins, and a small proportion is incorporated into bacterioferritin, but most of the iron is present in a poorly defined state. Iron overload results in iron toxicity, mainly due to the formation of hydroxyl radicals that strongly react with all kinds of biomolecules, of which DNA damage has the most deleterious consequences.