Fe-S Clusters Emerging as Targets of Therapeutic Drugs

Abstract

Fe-S centers exhibit strong electronic plasticity, which is of importance for insuring fine redox tuning of protein biological properties. In accordance, Fe-S clusters are also highly sensitive to oxidation and can be very easily altered in vivo by different drugs, either directly or indirectly due to catabolic by-products, such as nitric oxide species (NOS) or reactive oxygen species (ROS). In case of metal ions, Fe-S cluster alteration might be the result of metal liganding to the coordinating sulfur atoms, as suggested for copper. Several drugs presented through this review are either capable of direct interaction with Fe-S clusters or of secondary Fe-S clusters alteration following ROS or NOS production. Reactions leading to Fe-S cluster disruption are also reported. Due to the recent interest and progress in Fe-S biology, it is very likely that an increasing number of drugs already used in clinics will emerge as molecules interfering with Fe-S centers in the near future. Targeting Fe-S centers could also become a promising strategy for drug development.

Figure 1

Most common iron-sulfur structures. (a) Most common Fe-S clusters associated with proteins contain 2, 3, or 4 iron atoms. Oxidation states of the cluster are variable and can be [2Fe-2S]⁺ or [2Fe-2S]²⁺, [3Fe-4S]⁺, [3Fe-4S]⁰, [3Fe-4S]⁻ or [3Fe-4S]²⁻, and [4Fe-4S]³⁺, [4Fe-4S]²⁺, [4Fe-4S]⁺, or [4Fe-4S]⁰. [3Fe-4S] clusters are most often considered as deriving from [4Fe-4S] clusters that have been oxidized by various cellular oxidants. Iron atoms are shown in red, sulfur atoms are shown in green, and carbon from cysteine residues are shown in dark blue. Coordination by histidine is not shown. (b) Conversion of [4Fe-4S] into [3Fe-4S] clusters is responsible for Fe²⁺ release and for enzyme inactivation. Fe²⁺ release might lead to Fenton reactions in the presence of hydrogen peroxide.

Figure 2

Schematic drawing of Fe-S cluster biosynthesis. Human/yeast proteins are indicated. Fe-S components are first synthesized in the mitochondria, and a yet unknown sulfur-containing component is exported into the cytosolic compartment. Further, Fe-S cluster biogenesis occurs, ultimately inserting clusters into recipient apoproteins.

Figure 3

Cluvenone-derivative MAD-28 destabilizes mitoNEET [2Fe-2S] cluster. (a) Picture of mitoNEET protein (grey) with a [2Fe-2S] cluster coordinated by 3 cysteines (not shown) and one histidine (His87, shown in grey). The coordinating bond is shown in orange. (b) The influence of MAD-28 (yellow) binding to mitoNEET. MAD-28 set up bonds with both Lys55 and His87 and weakens the bond between Iron and His87, thus destabilizing the cluster.