The topology of FPN is not yet fully elucidated but it is considered to be a twelve transmembrane domain protein with both the N and the C terminus in an intracellular position. 3, 4 For many years, whether FPN functions as a monomeric4-6 or as an oligomeric form7 has remained controversial and conclusions have not yet been reached. Several biochemical studies performed on transfected cells expressing tag-FPN molecules or on recombinant FPN in solution have yielded conflicting results. Evidence based on type 4 hemochromatosis, an autosomal dominant iron overload disorder due to FPN mutations, suggest that FPN behaves as a dimer, the mutated FPN exerting a dominant negative effect on the FPN molecule synthesized by the normal allele, thereby impairing iron transport. 8 It is thought that haploinsufficiency alone is not sufficient to impair iron recycling by macrophages and induce tissue iron overload. This issue is still a matter of debate.

The metal transport activity of FPN has not been studied in detail but all the evidence points to a ferrous Fe (II) transport activity, although FPN can also transport other divalent metals but with a lower affinity. The export of ferrous iron is concomitant with the oxidation to the ferric Fe (III) state by proteins of the multi-copper oxidase family. Ceruloplasmin synthesized by hepatocytes and secreted in the plasma, also present as a GPI-anchored form in macrophages, or hephestin in duodenal enterocytes catalyze the oxidation of ferrous to ferric iron prior to its binding by serum transferrin (Figure 1). When the oxidase is deficient, as in aceruloplasminemia, iron is retained in the macrophages, probably because the pro-oxidant ferrous iron remains bound to FPN and induces its degradation. 9