Fig. 1: Mechanism of Fe²⁺ oxidation at cytosolic ferritin ferroxidase centers (FCs).

Starting at the top, two equivalents of Fe²⁺ bind at the vacant (apo) FC to give di-Fe²⁺ FC (right). Transfer of a single electron from each onto O₂ results in the formation of a di-Fe³⁺ peroxo intermediate (bottom) that is hydrolyzed to give a metastable di-Fe³⁺ oxo species and peroxide (left). In pathway (i) Fe³⁺ is then displaced by incoming Fe²⁺ substrate, regenerating the di-Fe²⁺ form of the FC and leading to the accumulation of a ferrihydrite-like mineral in the interior of the protein. In the absence of further Fe²⁺ substrate (pathway (ii)), the apo form of the FC is regenerated by the slower loss of Fe³⁺, into the interior of the protein, where it also contributes to the accumulation of a mineral core. Fe²⁺ ions are indicated in cyan, Fe³⁺ ions are in brown, and the DFP is in royal blue.