A genetic approach to elucidating eukaryotic iron metabolism.

Studies of mutants of the yeast Saccharomyces cerevisiae have led to the identification of genes required for high affinity iron uptake. Reduction of iron (III) outside the cell is accomplished by means of reductases encoded by FRE1 and FRE2, homologues of the gp91-phox component of the oxygen reductase of human granulocytes. High affinity iron (II) transport from the exterior to the interior of the cell occurs by means of a transport system that has not been molecularly characterized. However, the transport process requires the activity of a copper-containing oxidase encoded by FET3. The amino acid sequence of this protein resembles other multi-copper oxidases, including mammalian ceruloplasmin. High affinity copper uptake mediated by the copper transport protein encoded by CTR1 is required to provide the FET3 protein with copper, and thus copper uptake is indirectly required for ferrous iron uptake. These genetic elements of yeast and their relationships may be conserved in complex eukaryotic organisms.