Cytochrome bc1 complex (Plasmodium falciparum) (bc1 complex)

The **cytochrome bc1 complex** in Plasmodium falciparum, also known as complex III of the mitochondrial respiratory chain, is a multisubunit enzyme complex responsible for electron transfer from ubiquinol to cytochrome c, coupled with proton translocation across the mitochondrial inner membrane[1][2][5][4]. The complex contains two distinct binding sites for quinone substrates: the Qo (quinol oxidation) site and the Qi (quinone reduction) site, both located within cytochrome b[1][2][3][7]. Inhibitors targeting either site block the electron transport chain, collapse mitochondrial membrane potential, and ultimately kill the malaria parasite, as the parasite relies on an active mitochondrial electron transport chain for pyrimidine biosynthesis via DHODH, an essential metabolic pathway[2][3][7]. The cytochrome bc1 complex is a validated and important target for antimalarial therapy, with multiple classes of inhibitors developed, including atovaquone (Qo site binder), 4(1H)-pyridones, and ELQs (some binding the Qi site)[1][2][3][7][11]. Resistance to atovaquone is common and linked to mutations in the Qo site, whereas alternative inhibitors targeting the Qi site offer a strategy to overcome such resistance[1][2][3]. Cardiotoxicity has been an issue with some Qi site inhibitors, highlighting the need for careful safety evaluation in drug development[1][2][6]. The enzyme is also a proposed drug target in other protozoan infections such as toxoplasmosis, but its most established clinical role is in the treatment and prophylaxis of malaria[1][2][13].

Other names

Ubiquinol-cytochrome c reductaseComplex IIIPfbc1Cytochrome b-c1 complexMitochondrial complex III

Inhibition of electron transfer in the mitochondrial respiratory chain by binding to either the ubiquinol oxidation (Qo) site or the ubiquinone reduction (Qi) site, leading to collapse of the mitochondrial membrane potential and disruption of ATP production. Resulting pyrimidine starvation due to inhibition of dihydroorotate dehydrogenase (DHODH)-dependent pyrimidine biosynthesis.