The transport of iron and copper across the cell membrane: different mechanisms for different metals?

Iron and copper are both essential elements and deficiencies in either lead to a wide variety of symptoms. They also appear to be linked to each other biologically. One of the most characteristic hallmarks of Cu deficiency is a hypochromic, microcytic anaemia. The mechanism involved has not been worked out, but it seems that Cu, especially and perhaps exclusively as ceruloplasmin (EC 1.16.3. 1), is necessary to maintain the flow of Fe through the hepatocyte (for a recent review, see Linder, 1991). So much work has been done on the steps involved in Fe uptake that the number of examples used to illustrate any point has been restricted. Since the mechanism is essentially the same in all tissues studied thus far, the present discussion will use the placenta as the major example. Information gained from other tissues and cell types will be discussed where appropriate, however. In contrast, since little is known about Cu transport, data from a variety of different cell types will be discussed. Fe in plasma is almost exclusively carried on transferrin (Tf). Tf is a serum glycoprotein, molecular weight about 80 000. It can carry two Fe atoms per molecule, which it binds in two extremely-high-affinity sites, one in the N-terminal domain and the other in the C-terminal domain (for a recent review, see de Jong et al. 1990). Tf is the major source of Fe for most cells, although there is evidence that some cells, especially in human and guinea-pig, can utilize the Fe carried in serum ferritin (Blight & Morgan, 1987; Lamparelli et al. 1989). Most of the plasma Cu is also protein bound. The majority is associated with ceruloplasmin, an a-globulin which has a sky-blue colour (hence the name) (Holmberg & Laurell, 1947,1948). The Cu is incorporated into the protein in the liver. There are six or seven Cu atoms per molecule (Messerschmidt & Huber, 1990), none of which are readily exchangeable. They are found as three types: I, I1 and 111; respectively, these are the ‘blue’ Cu (type I), Cu attached to histidyl imidazoles similar to the low-molecular-weight histidine-Cu complexes (type 11), and the type I11 Cu, a pair forming a diamagnetic complex (Calabrese et al. 1989). In vitro, only the blue Cu can be exchanged. This requires the presence of an oxidizing agent, such as vitamin C, and Cu with which to exchange. Removal of the other Cu atoms necessitates very harsh treatment (Herve, 1985; Winyard etal. 1989). In addition to ceruloplasmin, significant (perhaps as much as 20%), and probably biologically important amounts of Cu are found attached to a specific site on the N-terminal end of albumin (Lau & Sarkar, 1971) and to amino acids, primarily histidine (Harris & Sass-Kortsak, 1967; Neumann & Sass-Kortsak, 1967). A high-molecular-weight plasma protein, transcuprein, has been described by Linder and co-workers (Weiss et al. 1985; Wirth et al. 1985) which may also be involved in Cu uptake, especially by hepatocytes. Neither Cu nor Fe are present as the free ion.