page_title: Iron–sulfur protein
section_title: 4Fe–4S clusters
hierarchical_section_title: Iron–sulfur protein / Structural motifs / 4Fe–4S clusters
caption_attribution_description: redox reactions for Fe4S4 clusters
context_page_description: Iron–sulfur proteins are proteins characterized by the presence of iron–sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states. Iron–sulfur clusters are found in a variety of metalloproteins, such as the ferredoxins, as well as NADH dehydrogenase, hydrogenases, coenzyme Q – cytochrome c reductase, succinate – coenzyme Q reductase and nitrogenase. Iron–sulfur clusters are best known for their role in the oxidation-reduction reactions of electron transport in mitochondria and chloroplasts. Both Complex I and Complex II of oxidative phosphorylation have multiple Fe–S clusters. They have many other functions including catalysis as illustrated by aconitase, generation of radicals as illustrated by SAM-dependent enzymes, and as sulfur donors in the biosynthesis of lipoic acid and biotin. Additionally, some Fe–S proteins regulate gene expression. Fe–S proteins are vulnerable to attack by biogenic nitric oxide, forming dinitrosyl iron complexes. In most Fe–S proteins, the terminal ligands on Fe are thiolate, but exceptions exist.
context_section_description: A common motif features a four iron ions and four sulfide ions placed at the vertices of a cubane-type cluster.  The Fe centers are typically further coordinated by cysteinyl ligands. The [Fe₄S₄] electron-transfer proteins ([Fe₄S₄] ferredoxins) may be further subdivided into low-potential (bacterial-type) and high-potential (HiPIP) ferredoxins. Low- and high-potential ferredoxins are related by the following redox scheme:
  In HiPIP, the cluster shuttles between [2Fe³⁺, 2Fe²⁺] (Fe₄S₄²⁺) and [3Fe³⁺, Fe²⁺] (Fe₄S₄³⁺). The potentials for this redox couple range from 0.4 to 0.1 V. In the bacterial ferredoxins, the pair of oxidation states are [Fe³⁺, 3Fe²⁺] (Fe₄S₄⁺) and [2Fe³⁺, 2Fe²⁺] (Fe₄S₄²⁺).  The potentials for this redox couple range from −0.3 to −0.7 V. The two families of 4Fe–4S clusters share the Fe₄S₄²⁺ oxidation state.  The difference in the redox couples is attributed to the degree of hydrogen bonding, which strongly modifies the basicity of the cysteinyl thiolate ligands. A further redox couple, which is still more reducing than the bacterial ferredoxins is implicated in the nitrogenase.
  Some 4Fe–4S clusters bind substrates and are thus classified as enzyme cofactors. In aconitase, the Fe–S cluster binds aconitate at the one Fe centre that lacks a thiolate ligand.  The cluster does not undergo redox, but serves as a Lewis acid catalyst to convert citrate to isocitrate.  In radical SAM enzymes, the cluster binds and reduces S-adenosylmethionine to generate a radical, which is involved in many biosyntheses.
caption: 4Fe-4S clusters serve as electron-relays in proteins.
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