human disease

components of respiratory electron transfer complexes as well as the tricarboxylic acid cycle (TCA cycle) enzymes, aconitase and succinate dehydrogenase (Figure 1a). In addition, the Fe–S clusters within DNA repair enzymes Fanconi anemia group J protein (FancJ) and Xeroderma pigmentosum group D protein (XPD) facilitate DNA damage recognition and repair [3]. Moreover, Fe–S cluster assembly and disassembly in mammalian iron regulatory protein-1 (IRP1) alters the active site conformation and accessibility and determines whether IRP1 binds its mRNA targets in response to oxidative stress and intra-cellular iron levels (reviewed in Refs. [4–6]). enzymes: aconitase and succinate dehydrogenase. Because ferrous iron bioavailability is limited in the oxidative environment of modern earth and because Fe–S proteins are required for basic intermediary metabolism, it is not surprising that nearly all organisms use highly conserved proteins and enzymes to facilitate Fe–S cluster synthesis. The basic components of this process were originally ident-ified in bacterial operons [1], and homologs of these proteins have been identified in eukaryotes, including the Saccharomyces cerevisiae (reviewed in Ref. [2]) and human genomes (reviewed in Ref. [12]). Studies in yeast, zebrafish and plants have shown that up to 20 different proteins are involved in eukaryotic Fe–S cluster biogenesis (Table 1). A cysteine desulfurase (IscS or SufS in bacteria, NFS1 or ISCS in human) is required to abstract the sulfur atom from cysteine and to donate th