Protozoal mitochondrial cytochrome bc1 complex (Complex III)

The protozoal mitochondrial cytochrome bc1 complex, also known as Complex III, is a multi-subunit enzyme essential for the electron transport chain in protozoan parasites such as Plasmodium and Toxoplasma (Birth et al., 2014, Nature Communications). It catalyzes the transfer of electrons from ubiquinol to cytochrome c while simultaneously pumping protons across the inner mitochondrial membrane to generate a proton motive force (Fisher et al., 2020, Science). In many protozoa, this complex is particularly critical because it is linked to the regeneration of ubiquinone required for dihydroorotate dehydrogenase, an enzyme essential for de novo pyrimidine biosynthesis (Srivastava et al., 1997, JBC). Because parasites often lack the ability to salvage pyrimidines, inhibition of the bc1 complex leads to a lethal halt in DNA synthesis. Drugs like atovaquone target the ubiquinol-binding site (Qo) of the complex, exploiting structural differences between the parasite and host versions of the enzyme to achieve selective toxicity (Kessl et al., 2007, JBC). Resistance to these drugs frequently arises through point mutations in the cytochrome b subunit, which is encoded by the mitochondrial genome (Fisher et al., 2020, Science). This target remains a primary focus for developing new antimalarial and antiparasitic agents due to its fundamental role in parasite metabolism.

Other names

Ubiquinol-cytochrome c reductaseCytochrome bc1 complexMitochondrial complex IIIbc1 complexCytochrome b-c1 complexCoenzyme Q-cytochrome c reductase

Inhibition of ubiquinol oxidation at the Qo site or reduction at the Qi site of the cytochrome bc1 complex, leading to the collapse of the mitochondrial membrane potential and cessation of pyrimidine biosynthesis.