iron-sulfur cluster

**Structure:** Fe-S clusters contain iron atoms coordinated by inorganic (acid-labile) sulfide and usually anchored to proteins via cysteine thiolate ligands (the Rieske center uses 2 cysteines and 2 histidines). Common forms are [2Fe-2S], [3Fe-4S], and [4Fe-4S]. They are non-heme iron centers.

**Function:** - One-electron transfer. Iron cycles between Fe2+ and Fe3+. A cluster carries only one electron at a time, even though it contains several iron atoms. - Electron transport chain: - Complex I (NADH dehydrogenase): FMN, then a series of Fe-S clusters, then CoQ (ubiquinone). - Complex II (succinate dehydrogenase): FAD, then Fe-S clusters, then CoQ. Complex II is also a TCA cycle enzyme. - Complex III (cytochrome bc1): contains the Rieske Fe-S protein (2Fe-2S). - Complex IV does not use Fe-S clusters. It uses heme a/a3 and copper centers (CuA, CuB). - Other roles: - Aconitase (TCA cycle) has a [4Fe-4S] cluster that directly participates in the citrate-to-isocitrate isomerization. - Ferredoxins, in photosynthesis and in steroidogenesis (adrenodoxin, used by mitochondrial P450 enzymes). - Radical SAM enzymes (e.g., lipoic acid synthase, biotin synthase). - DNA repair and replication enzymes (DNA polymerases, helicases, glycosylases). - Regulation of iron homeostasis: cytosolic aconitase (IRP1) binds an Fe-S cluster when iron is replete, and loses it when iron is low. IRP1 then binds iron-responsive elements (IREs) on mRNA.

**Biogenesis:** Assembly occurs mainly in mitochondria through the ISC (iron-sulfur cluster) machinery. Cysteine desulfurase (NFS1) supplies sulfur. Frataxin is involved in iron delivery or regulation of cluster assembly. Clusters are then inserted into apoproteins, and a separate system exports components for cytosolic Fe-S proteins.

**Clinical correlations:** - Friedreich ataxia: autosomal recessive GAA trinucleotide repeat expansion in the FXN gene (chromosome 9) causes frataxin deficiency. Mitochondrial iron accumulates, Fe-S cluster–containing enzymes are impaired, and oxidative stress rises. Findings are spinocerebellar degeneration (ataxia, loss of position and vibration sense, areflexia), hypertrophic cardiomyopathy (the usual cause of death), diabetes mellitus, scoliosis, and pes cavus. - Sideroblastic anemia: some forms involve impaired Fe-S cluster or heme synthesis (e.g., ABCB7 mutations cause X-linked sideroblastic anemia with ataxia). - ETC inhibitors: - Rotenone inhibits Complex I at the Fe-S to CoQ step. - Malonate is a competitive inhibitor of succinate dehydrogenase (Complex II). - Antimycin A inhibits Complex III. - Cyanide, CO, azide, and H2S inhibit Complex IV. - Oxidative stress: Fe-S clusters (especially [4Fe-4S] in aconitase) are sensitive to superoxide and peroxynitrite, so aconitase activity is a marker of oxidative damage. - Mitochondrial disease: Complex I and II deficiencies can cause lactic acidosis, Leigh syndrome, and myopathy.

**High-yield pearls:** - Fe-S clusters are non-heme iron. Cytochromes contain heme iron. - One electron per cluster, in contrast to FMN/FAD/CoQ, which can carry 2 electrons. - Complexes I, II, and III contain Fe-S clusters. Complex IV does not. - Complex II is the only ETC complex that does not pump protons. - Fe-S clusters are required for aconitase function in the TCA cycle.