Figure 1 Structures of the major classes of Fe-S clusters. The larger clusters are found in nitrogenase: [8Fe-7S] and [8Fe-7S] are oxidized and

This diversity directs us to examine and understand cluster reactivities that transcend their long-established capability to serve in fast single-electron transfer. A direct role in catalysis requires that substrate molecules bind at one (or more) Fe subsites and are then activated and chemically transformed in processes that may involve bond polarization and transfer of electrons, protons, atoms, and radicals. Regulatory functions require that the cluster is sensitive to some changing aspect of the environment, such as (trace) levels of O2, superoxide, NO, and Fe (or perhaps other metals)—the point being that these agents may alter the structure and properties of the cluster and hence translate into a change in stability or conformation of the protein and consequential modulation of DNA or RNA binding. We are also reminded that these clusters are tiny “nano-chunks” of mineral-like inorganic material; questions are therefore raised about how they are assembled and transferred from one protein to another [12] and how they are degraded (disassembled). Iron-sulfur clusters are thermodynamically unstable with respect to oxide formation and tend to be O2-sensitive even in higher oxidation levels; consequently, their very existence under oxidizing conditions lies in critical balance. Figure 2 illustrates how (at least in principle) clusters may exist in many different oxidation levels covering a wide potential range; in practice, however, access to these levels is restricted by the protein environment. Through these changes in oxidation level, the chemical properties of clusters become linked to the local electrochemical potential: for example, as we will discuss below, certain reactivities of [3Fe-4S] clusters, such as