Iron acquisition and transcriptional regulation.

Iron is an essential element for all eukaryotes. The facile ability of iron to gain and lose electrons permits its participation in a wide variety of oxidation-reduction reactions. Further, the ability of iron as a component of heme to bind oxygen makes it indispensable as an oxygen carrier and sensor, particularly in vertebrates where the size of the organism provides a barrier to simple oxygen diffusion requiring specialized oxygen transport. Iron is found as a prosthetic group on proteins in various forms: elemental iron, oxoiron or oxoiron-zinc, heme, and iron-sulfur clusters. While the diversity of iron-containing proteins and the reactions they participate in highlights the usefulness of iron in biochemical reactions, iron is problematic for two reasons. First, the same facile property of electron gain and loss that permits iron to participate in oxidation-reduction reactions permits iron to donate electrons to oxygen or hydrogen peroxide, generating toxic oxygen radicals, superoxide anion and hydroxyl radical. The existence of these oxygen radicals has led to the evolution of enzyme systems capable of either preventing or removing oxygen radicals once formed. Loss of these enzymes, such as superoxide dismutase, leads to increased cellular damage and compromised growth. Because iron can be toxic, all iron acquisition systems are highly regulated in order to restrict the concentration of iron within biological fluids, extending from the cytosol of yeast to the plasma of vertebrates. Furthermore, regulation of iron acquisition is one of the most critical steps in maintaining iron homeostasis because eukaryotes do not have regulated mechanisms of iron egress. The second reason that iron is problematic is that bioavailable iron is scarce. Iron is the fourth most abundant element on earth but is not uniformly distributed. Iron is scarce both because there are vast geographical areas, such as the oceans, which are iron-poor and because iron, when abundant, is found in a biologically inaccessible form. Iron’s proclivity to react with oxygen has resulted in the predominant form of iron being the insoluble ferric hydroxide. Great investment of cellular resources is required to make iron bioavailable. Even with such effort, the external concentration of iron is often limiting, leading to cellular responses that “triage” iron to biochemical pathways that most require it. We have come to understand that not only is the acquisition and storage of iron highly regulated, but the processes that divert iron among intracellular biochemical pathways are also * Corresponding author. † Texas A&M University. ‡ University of Utah. Craig D. Kaplan obtained a B.S. in Biology and Latin Language and Literature from the University of Michigan, Ann Arbor, Michigan, in 1995, and a Ph.D. in Genetics from Harvard University in 2003 under the supervision of Dr. Fred Winston at Harvard Medical School. His Ph.D. dissertation focused on the regulation of chromatin structure and transcription by the RNA Polymerase II elongation factor Spt6. Much of this manuscript was written while he was a postdoctoral fellow with Dr. Roger Kornberg at the Stanford University School of Medicine, investigating the mechanisms of RNA Polymerase II elongation control, both innate and factor-mediated. He has recently joined the faculty in the Department of Biochemistry and Biophysics, at Texas A&M University, as an assistant professor. Chem. Rev. 2009, 109, 4536–4552 4536