Uptake and Storage of Transition Metals

There are three possible dietary levels for any essential element: deficient, optimal, and toxic, in order of increasing concentration in the diet. If the concentration of an essential element in the diet is too low, an organism must be able to extract the element from the environment and concentrate it. If the concentration of an essential element in the diet is too high, an organism must be able to limit its intake to avoid toxic effects. Moreover, organisms must be able to switch off the uptake process rapidly if dietary levels rise suddenly, and they must be able to store essential elements for future use.

Three distinct steps are involved in transition metal uptake. First, the metal must be “mobilized” from the environment and brought into contact with a cell in a form that can be absorbed. Second, the metal must be transported across the cell membrane into the cell. Third, the element must be transported to its point of utilization within a cell or to other cells within the organism. In our discussion, we focus on the uptake, transport, and storage of iron, which illustrates the most important points. Because iron deficiency (anemia) is the most widespread nutritional deficiency known in humans, the uptake of iron is especially well understood.

The solubility of metal ions such as Fe³⁺, which form highly insoluble hydroxides, depends on the pH and the presence of complexing agents. In an oxygen-containing atmosphere, iron exists as Fe(III) because of the positive reduction potential of Fe³⁺ (Fe³⁺ + e⁻ → Fe²⁺; E° = +0.77 V). Because ferric hydroxide [Fe(OH)₃] is highly insoluble (K_sp ≈ 1 × 10⁻³⁹), the equilibrium concentration of Fe³⁺(aq) at pH 7.0 is very low, about 10⁻¹⁸ M. You would have to drink 2 × 10¹³ L of iron-saturated water per day (roughly 5 mi³) to consume the recommended daily intake of Fe for humans, which is about 1 mg/day. Animals such as humans can overcome this problem by consuming concentrated sources of iron, such as red meat, but microorganisms cannot.

Consequently, most microorganisms synthesize and secrete organic molecules called siderophores to increase the total concentration of available iron in the surrounding medium. Siderophores are generally cyclic compounds that use bidentate ligands, such as the hydroxamate and catecholate groups shown here, to bind Fe³⁺ in an octahedral arrangement. Typical siderophores are ferrichrome, a cyclic peptide produced by fungi, and enterobactin, a cyclic ester produced by bacteria (Figure 1.1). The formation constants for the Fe³⁺ complexes of ferrichrome and enterobactin are about 10³² and 10⁴⁰, respectively, which are high enough to allow them to dissolve almost any Fe(III) compound.

In contrast, multicellular organisms can increase the concentration of iron in their diet by lowering the pH in the gastrointestinal tract. At pH 1.0 (the approximate pH of the stomach), most Fe(III) salts dissolve to form Fe³⁺(aq), which is absorbed by specific proteins in the intestinal wall. A protein called transferrin forms a complex with iron(III), allowing it to be transported to other cells. Proteins that bind tightly to Fe(III) can also be used as antibacterial agents because iron is absolutely essential for bacterial growth. For example, milk, tears, and egg white all contain proteins similar to transferrin, and their high affinity for Fe³⁺ allows them to sequester iron, thereby preventing bacteria from growing in these nutrient-rich media.

Iron is released from transferrin by reduction to Fe²⁺, and then it is either used immediately (e.g., for the synthesis of hemoglobin) or stored in a very large protein called ferritin for future use (Figure 1.2

). Ferritin uses oxygen to oxidize Fe²⁺ to Fe³⁺, which at neutral pH precipitates in the central cavity of the protein as a polymeric mixture of Fe(OH)₃ and FePO₄. Because a fully loaded ferritin molecule can contain as many as 4500 Fe atoms, which corresponds to about 25% Fe by mass, ferritin is an effective way to store iron in a highly concentrated form. When iron is needed by a cell, the Fe³⁺ is reduced to the much more soluble Fe²⁺ by a reductant such as ascorbic acid (vitamin C). The structure of ferritin contains channels at the junctions of the subunits, which provide pathways for iron to enter and leave the interior of a molecule.

: Ferritin, an Iron Storage Protein. A schematic drawing of the structure of iron-loaded ferritin, showing the almost spherical protein shell inside which the iron hydroxide/phosphate core is formed.