Iron regulatory proteins in pathobiology

The capacity of readily exchanging electrons makes iron not only essential for fundamental cell functions, but also a potential catalyst for chemical reactions involving free-radical formation and subsequent oxidative stress and cell damage. Cellular iron levels are therefore carefully regulated in order to maintain an adequate substrate while also minimizing the pool of p otentially toxic 'free iron'. Iron homoeostasis is controlled through sever al genes, an increasing number of which have been found to contain non-codi ng sequences [i.e. the iron-responsive elements (IREs)] which are recognize d at the mRNA level by two cytoplasmic iron-regulatory proteins (IRP-1 and IRP-2). The IRPs belong to the aconitase superfamily. By means of an Fe-S-c luster-dependent switch, IRP-1 can function as an mRNA-binding protein or a s an enzyme that converts citrate into isocitrate. Although structurally an d functionally similar to IRP-1, IRP-2 does not seem to assemble a cluster nor to possess aconitase activity; moreover, it has a distinct pattern of t issue expression and is modulated by means of proteasome-mediated degradati on. In response to fluctuations in the level of the 'labile iron pool', IRP s act as key regulators of cellular iron homoeostasis as a result of the tr anslational control of the expression of a number of iron metabolism-relate d genes. Conversely, various agents and conditions may affect IRP activity, thereby modulating iron and oxygen radical levels in different pathobiolog ical settings. As the number of mRNAs regulated through IRE-IRP interaction s keeps growing, the definition of IRPs as iron-regulatory proteins may in the near future become limiting as their role expands to other essential me tabolic pathways.