Iron Metabolism Overview

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24.1— Iron Metabolism:
Overview
Iron is closely involved in the metabolism of oxygen, permitting the transportation and participation of oxygen in a variety of biochemical processes. The common oxidation states are either ferrous (Fe2+) or ferric (Fe3+); higher oxidation levels occur as short­lived intermediates in certain redox processes. Iron has an affinity for electronegative atoms such as oxygen, nitrogen, and sulfur, which provide the electrons that form the bonds with iron. These can be of very high affinity when favorably oriented on macromolecules. In forming complexes, no bonding electrons are derived from iron. There is an added complexity to the structure of iron: the nonbonding electrons in the outer shell of the metal (the incompletely filled 3d orbitals) can exist in two states. Where bonding interactions with iron are weak, the outer nonbonding electrons will avoid pairing and distribute throughout the 3d orbitals. Where bonding electrons interact strongly with iron, however, there will be pairing of the outer nonbonding electrons, favoring lower­energy 3d orbitals. These two different distributions for each oxidation state of iron can be determined by electron spin resonance measurements. Dispersion of 3d electrons to all orbitals leads to the high­spin state, whereas restriction of 3d electrons to lower energy orbitals, because of electron pairing, leads to a low­spin state. Some iron–protein complexes reveal changes in spin state without changes in oxidation during chemical events (e.g., binding and release of oxygen by hemoglobin).
At neutral and alkaline pH ranges, the redox potential for iron in aqueous solutions favors the Fe3+ state; at acid pH values, the equilibrium favors the Fe2+ state. In the Fe3+ state iron slowly forms large polynuclear complexes with hydroxide ion, water, and other anions that may be present. These complexes can become so large as to exceed their solubility products, leading to their aggregation and precipitation with pathological consequences.
Iron can bind to and influence the structure and function of various macromolecules, with deleterious results to the organism. To protect against such reactions, several iron­binding proteins function specifically to store and transport iron. These proteins have both a very high affinity for the metal and, in the normal physiological state, also have incompletely filled iron­binding sites. The interaction of iron with its ligands has been well characterized in some proteins (e.g., hemoglobin and myoglobin), whereas for others (e.g., transferrin) it is presently in the process of being defined. The major area of ignorance in the biochemistry of iron lies in the in vivo transfer processes of iron from one macromolecule to another. Several proposed mechanisms may explain the process of iron transfer. Two are supported by excellent model studies but have varying degrees of relevance to the physiological state. The proposed processes are the following. First, the redox change of iron has been an attractive mechanism because it is supported by selective in vitro studies and because in some cases macromolecules have a very selective affinity for Fe3+, binding Fe2+ poorly. Thus reduction of iron would permit ferrous ions to dissociate, and reoxidation would allow the iron to redistribute to appropriate macromolecules. Redox mechanisms have only been defined in a very few settings, some of which will be described below. An alternative hypothesis involves chelation of ferric ions by specific small molecules with high affinities for iron; this mechanism has been supported also by selective in vitro studies. The chelation mechanism suffers from the lack of a demonstrably specific in vivo chelator. Because the redox potential strongly favors ferric ion at almost all tissue sites and because Fe3+ binds so strongly to liganding groups, the probability is that there are cooperating mechanisms regulating the intermolecular transfer of iron.