Basic Iron-Sulfur Centers

Iron-sulfur clusters are ubiquitous protein cofactors composed of iron and inorganic sulfur. These cofactors are among the most ancient ones and may have contributed to the birth of life on Earth. Therefore, they are found even today in many enzymes central to metabolic processes like nitrogen fixation, respiration, and DNA processing and repair. Due to the toxicity associated with iron and sulfur ions, living organisms evolved dedicated machineries to synthetize and then transfer iron-sulfur clusters into client proteins. The iron-sulfur cluster (ISC) machinery is responsible for iron-sulfur cluster biogenesis in prokaryotes and in the mitochondrion of eukaryotes; the sulfur mobilization (SUF) machinery is present in prokaryotes and in the chloroplasts of plants; finally, the cytosolic iron-sulfur assembly (CIA) machinery is only present in the cytoplasm of eukaryotes. Genome analysis allowed the prediction of the proteins containing iron-sulfur clusters across a broad variety of living organisms, establishing links between the size and composition of iron-sulfur proteomes and the types of organisms that encode them. For example, the iron-sulfur proteomes of aerobes are generally smaller than those of anaerobes with similar genome size; furthermore, aerobes are enriched in [2Fe-2S] proteins compared to anaerobes, which predominantly use [4Fe-4S] proteins. This relates to the lower bioavailability of iron and the higher lability of [4Fe-4S] clusters within aerobic environments. Analogous considerations apply to humans, where the occurrence and functions of iron-sulfur proteins depend on the cellular compartment where they are localized. For example, an emerging primary role for nuclear iron-sulfur proteins is in DNA maintenance. Given their key functions in metabolism, dysfunctions of mutations in iron-sulfur proteins, or in proteins participating in iron-sulfur cluster biogenesis, are associated with serious human diseases.