Parasites FeS Up: Iron-Sulfur Cluster Biogenesis in Eukaryotic Pathogens

Iron-sulfur (FeS) clusters are among the most ancient andversatile protein cofactors. They are used by a large and diversegroup of proteins, serving both structural and catalytic roles. Theyfunction in central metabolic processes such as electron transfer,redox chemistry, enzyme catalysis, and sensing environmental orintracellular conditions to regulate gene expression [1,2]. Ferrousiron and sulfur were readily available in the reducing atmospherein which life first evolved, but when oxygen levels rose with theadvent of photosynthetic algae, these building blocks becamescarce. Furthermore, the reactive oxygen species generated asbyproducts of aerobic respiration are highly damaging to FeSclusters, and free iron and sulfide released by FeS clusters are, inturn, toxic to cells. For these reasons, complex mechanismsevolved to coordinate and regulate the biogenesis of these simplecofactors, and these pathways are compartmentalized in theendosymbiotic organelles of eukaryotic cells.All FeS cluster biogenesis pathways follow the same basicprinciples (reviewed in [2]). The first step is the liberation of sulfurby a cysteine desulfurase, which forms a persulfide intermediate ona conserved cysteine residue. Iron is donated by iron-bindingproteins, such as frataxin. The cluster is then assembled on scaffoldproteins with the help of electron donors, which are needed for thereduction of sulfur to sulfide. The fully formed cluster istransferred to apoproteins via chaperones that facilitate the correctsubstrate specificity and proper assembly of the cluster to form themature holoprotein.FeS cluster biogenesis pathways are extremely well conserved,and are invariably essential for viability. Among eukaryoticpathogens, all endosymbiotic organelles studied to date appearto contain FeS cluster biogenesis machinery, and, in some cases,this seems to be the sole reason for retention of the organelle.Typically, the ISC (Iron-Sulfur Cluster formation) pathway residesin the mitochondrion, the CIA (Cytosolic Iron-sulfur proteinAssembly) pathway functions in the cytosol and nucleus, andplastid-containing organisms have an additional pathway, the SUF(SUlFur mobilization) system (Figure 1). In this article, we willcompare the subcellular organization of FeS cluster biogenesispathways in the diverse organelles of eukaryotic pathogens.