ABSTRACT
Aconitase (aconitate hydratase or citrate hydro-lyase; EC 4.2.1.3) is an Fe4S4 clustercontaining enzyme of the tricarboxylic acid (Krebs) cycle in eukaryotes and prokar yotes. It catalyzes the stereospecific isomerization of citrate to isocitrate via cis-aco nitate by an elimination (dehydration)-addition (hydration) mechanism in which the iron-sulfur cluster is directly involved. Two forms of aconitase with different relative distributions in tissues and organs are known: a mitochondrial (m-) and a cytoplasmic (c-) enzyme. The m-and c-aconitases have 30% sequence identity, but c-aconitase is 135 amino acids longer than the 754-residue m-aconitase and more stable to oxidative loss of activity. c-Aconitase is not only an enzyme but also plays a key role in iron homeostasis. The apo form of c-aconitase is identical to the iron regulatory protein [IRP or IRP1, formerly called ferritin repressor protein or IRE-BP (iron responsive element binding protein)]. This protein controls iron uptake and storage at the level of translation by binding to IREs, i.e., conserved stem-loop structures in the untrans lated regions of mRNAs, when the iron content of the cell is low. When the iron level is high, the IRP becomes a holoprotein with an iron-sulfur cluster and with aconitase activity. The iron-sulfur form of the protein does not bind RNA and thus cannot interact with IREs. This means that the function of IRP/c-aconitase is regulated by the assembly/disassembly of the iron-sulfur cluster (see [40] and [41] for recent reviews). IRP2 is a protein that has 57% sequence identity to IRP; there is, however, a 73-residue insertion near the N terminus, and no stable iron-sulfur cluster has been observed in IRP2, although it contains the same cysteine residues that ligate the cluster in aconitases. IRP2 is regulated by proteolytic degradation and the insertion serves as iron-dependent degradation motif [42,43].
