Interactions between iron metabolism and oxygen activation

On account of its easy access in aqueous solution to the two states ferrous (FeII) and ferric (FeIII), iron is ideally suited for the activation of molecular oxygen. It is, therefore, logical to seek links between the normal and pathological metabolism of iron and oxygen activation. The pathways of intracellular iron metabolism require changes in the oxidation state of iron both in its deposition in the storage form, ferritin, and in its mobilization from the storage form and use in the cell. Evidence is presented which shows that iron oxidation and deposition in ferritin involves activation of molecular oxygen with formation of a stable peroxo-complex as an intermediate in which the oxygen is bound between two iron atoms attached to adjacent polypeptide chains. The release of iron from ferritin is thought to involve reduction by a flavin, which is associated with the protein, and serves as a cofactor being alternately reduced by NADH or NADPH and oxidized by iron(III). The nature of the low-molecular-weight iron complex which serves to transfer storage iron to transferrin and to supply iron for intracellular use remains to be established. The consequence of excessive iron overload can be rationalized on the basis of oxidative free-radical reactions which provoke lesions typical of deregulated oxygen activation. In some cases these pathological defects can be reversed by iron chelators. Progress in the development of chelation therapy for iron overload are reviewed.