Cytochrome bc1 complex (Ubiquinol-cytochrome c reductase) (Complex III)

The cytochrome bc1 complex, also known as Complex III, is a multi-subunit enzyme located in the inner mitochondrial membrane of Plasmodium falciparum that is essential for the parasite's survival [1.1.2, 1.5.2]. It functions as a central component of the mitochondrial electron transport chain, catalyzing the transfer of electrons from ubiquinol to cytochrome c while simultaneously pumping protons to maintain the mitochondrial membrane potential [1.1.1, 1.2.3]. In the asexual blood stages of the malaria parasite, the primary role of this complex is the regeneration of ubiquinone, which serves as an indispensable electron acceptor for dihydroorotate dehydrogenase (DHODH) in the de novo pyrimidine biosynthesis pathway [1.2.5, 1.5.3]. Because Plasmodium falciparum lacks the ability to salvage pyrimidines from the host, any disruption of the bc1 complex leads to metabolic failure and parasite death [1.1.2, 1.2.2]. This complex is the primary target of the clinically used antimalarial drug atovaquone, which binds to the ubiquinol-oxidation (Qo) site of the cytochrome b subunit [1.3.1, 1.3.2]. However, the therapeutic utility of atovaquone is frequently compromised by the rapid emergence of resistance-conferring point mutations, such as the Y268S mutation in the cytochrome b protein [1.1.1, 1.3.3]. Current drug development efforts are focused on identifying next-generation inhibitors that target the ubiquinone-reduction (Qi) site or utilize novel chemical scaffolds like endochin-like quinolones (ELQs) to overcome existing resistance mechanisms [1.1.2, 1.2.3]. The structural divergence between the plasmodial and human versions of the complex provides a critical window for selective toxicity, making it a highly attractive target for antimalarial intervention [1.2.2, 1.5.2].

Other names

Ubiquinol-cytochrome c reductaseCytochrome b-c1 complexUbiquinol:cytochrome c oxidoreductaseCoenzyme Q-cytochrome c reductasebc1 complex

Inhibition of the ubiquinol oxidation (Qo) or ubiquinone reduction (Qi) sites within the cytochrome b subunit, leading to the collapse of the mitochondrial membrane potential and the cessation of de novo pyrimidine biosynthesis.