Feedback regulation of iron-sulfur cluster biosynthesis

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Abstract
Iron-sulfur clusters ([Fe-S] clusters) represent one of nature's simplest, functionally versatile, and perhaps most ancient prosthetic groups (1). Among the familiar types of [Fe-S] clusters are [2Fe-2S] and [4Fe-4S] clusters, which usually are attached to their protein partners by four cysteine thiol ligands (Fig. 1). Proteins that contain one or more [Fe-S] clusters are commonly called [Fe-S] proteins, and they represent a large class of structurally and functionally diverse proteins that participate in many metabolic processes. For example, [Fe-S] proteins are essential players in the life-sustaining processes of respiration, nitrogen fixation, and photosynthesis with [Fe-S] clusters participating as agents of electron transfer, substrate activation, catalysis, and environmental sensing. Given the structural simplicity of [Fe-S] clusters and the participation of [Fe-S] proteins in so many metabolic processes it may be surprising that the pathway for biological formation of [Fe-S] clusters is only now beginning to emerge. Pioneering work in the laboratory of Berg and Holm (2) established that the chemical synthesis of structural analogs to many biological [Fe-S] clusters is achieved when Fe3+/2+ and S2− are combined under controlled conditions and in the presence of the appropriate thiolate donors. Along these same lines, Malkin and Rabinowitz (3) showed that purified [Fe-S] proteins, for which the cluster has been removed, are often reconstituted with the correct [Fe-S] cluster species by simple treatment with Fe2+ and S2− under reducing conditions. Such in vitro “spontaneous” assembly, however, cannot represent the complete mechanism of biological [Fe-S] cluster formation because free Fe2+ and S2− are metabolic poisons. Rather, it is now known that a group of highly conserved proteins are responsible for directing the controlled assembly of [Fe-S] clusters and the maturation of [Fe-S] proteins (4). Figure 1 Structure of a [2Fe-2S] cluster ( Upper ) and [4Fe-4S] cluster ( Lower ). Cysteinyl β-carbons are shown …