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.

Metabolomics profiles of patients with Wilson disease reveal a distinct metabolic signature

“…With a stronger binding affinity, it has been shown in vitro that copper can preferentially displace iron in the ISC assembly (Brancaccio et al, 2017). It is also established that ISCs are highly vulnerable to ROS damage (Vernis et al, 2017). Moreover, previous studies in E. coli revealed copper overload inactivated ISC enzymes such as isopropyl malate dehydratase, fumarase A, and 6-phospho-gluconate dehydratase (Macomber and Imlay, 2009).…”

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

“…Iron is required in the mitochondria for synthesis of heme and Fe-S clusters, both of which are essential cofactors in energy production through transfer of electrons between mitochondrial respiratory complexes (7). Shifts in redox state of Fe-S clusters also act as a surveillance mechanism to detect DNA damage (8,9). Outside of its role in the mitochondria, iron acts as an essential cofactor for the activity of many enzymes.…”

“…Because Fe-S proteins act as a source of iron, there is a complex system that ensures Fe-S clusters are assembled correctly, trafficked to specific apoproteins, and remain protected during these processes. Drugs that interfere with Fe-S metabolism and destabilize the cluster can be effective at inhibiting the growth of cancers (8). Such an example is β-phenethyl isothiocyanate, an inhibitor of leukemia cell growth, in part by producing ROS which degrade the Fe-S center of NADH dehydrogenase 3 from respiratory complex I and subsequently suppresses mitochondrial respiration (8).…”

“…Drugs that interfere with Fe-S metabolism and destabilize the cluster can be effective at inhibiting the growth of cancers (8). Such an example is β-phenethyl isothiocyanate, an inhibitor of leukemia cell growth, in part by producing ROS which degrade the Fe-S center of NADH dehydrogenase 3 from respiratory complex I and subsequently suppresses mitochondrial respiration (8). Cyclooxygenase-2 (COX-2) is a heme-containing enzyme that is usually undetected in healthy tissues, but its expression is induced during inflammation and is highly expressed in some cancers and accordingly, COX-2 selective inhibitors have elucidated its role in cell growth and survival, angiogenesis, cell invasion and inflammation (127).…”

Implication of Dietary Iron-Chelating Bioactive Compounds in Molecular Mechanisms of Oxidative Stress-Induced Cell Ageing

“…Both O 2 •− and H 2 O 2 , which represent the one- and two-electron reduction products of oxygen, respectively, are moderately reactive and can only directly interact with a limited number of cellular molecules, mainly iron–sulfur (4F–4S) cluster-containing proteins, leading to the liberation of labile iron and the modulation of the activity of the corresponding proteins [ 26 ]. On the contrary, HO • s and RO • s that are generated after interaction of H 2 O 2 or ROOH with Fe 2+ exhibit an extremely high reactivity.…”