Reactive oxygen species-sensitive iron-sulfur cluster-containing proteins (ROS-sensitive Fe-S proteins)

Reactive oxygen species (ROS)-sensitive iron-sulfur (Fe-S) cluster-containing proteins are a group of essential mitochondrial enzymes and electron carriers in Plasmodium parasites that are highly susceptible to oxidative damage (Laleve et al., 2016). These proteins, including aconitase (PfACO), succinate dehydrogenase (Complex II), and the Rieske iron-sulfur protein (Complex III), utilize Fe-S clusters as cofactors for catalysis and electron transfer (Gisselberg et al., 2013). In the presence of ROS, such as superoxide or hydroxyl radicals, the labile iron atoms in these clusters are oxidized and released, leading to enzyme inactivation and the collapse of mitochondrial functions like the tricarboxylic acid (TCA) cycle and the electron transport chain (mETC) (Wang et al., 2015). This vulnerability is exploited by several antimalarial drugs, most notably primaquine and artemisinin derivatives, which generate mitochondrial ROS to selectively disrupt parasite metabolism (Laleve et al., 2016). Because the Plasmodium mitochondrion is critical for pyrimidine biosynthesis and energy production, the targeting of these ROS-sensitive proteins leads to parasite growth inhibition and death (Mather et al., 2007). The selective sensitivity of these clusters compared to host counterparts provides a therapeutic window for drug intervention, although safety concerns like hemolysis in G6PD-deficient patients remain a challenge for drugs like primaquine (Laleve et al., 2016).

Other names

ROS-labile iron-sulfur proteinsRedox-sensitive Fe-S cluster proteinsMitochondrial Fe-S proteinsROS-sensitive Fe-S cluster proteins

Oxidative inactivation of iron-sulfur clusters leading to mitochondrial dysfunction and metabolic collapse