Mycobacterial F-ATP synthase subunit c (atpE)

The mycobacterial F-ATP synthase subunit c is a vital component of the F0 sector of the ATP synthase complex, which is responsible for generating adenosine triphosphate (ATP) in Mycobacterium tuberculosis (Andries et al., 2005). This subunit assembles into a decameric ring structure that functions as a proton-driven rotary motor, coupling the flow of protons across the bacterial membrane to the synthesis of ATP (Preiss et al., 2015). As an essential enzyme for both aerobic respiration and the maintenance of membrane potential in dormant states, it serves as a validated therapeutic target for treating multi-drug-resistant tuberculosis (Koul et al., 2007). The diarylquinoline antibiotic bedaquiline exerts its bactericidal effect by binding to specific residues within the c-ring, effectively jamming the rotor and halting ATP production (Andries et al., 2005). This mechanism is highly selective for mycobacteria over human mitochondrial ATP synthase due to structural differences in the binding pocket, minimizing off-target effects in patients (Haagsma et al., 2009).

Other names

ATP synthase subunit cF-type H+-transporting ATPase subunit cSubunit c of F1F0-ATP synthaseatpEMycobacterial F-ATP synthase c-ring

Bedaquiline binds to the c-ring of the F0 rotor of mycobacterial ATP synthase, specifically interacting with residues such as Glu61 and Tyr64, which physically blocks the rotation of the enzyme and inhibits the proton pump mechanism, leading to the depletion of cellular ATP levels and subsequent bacterial death (Andries et al., 2005; Preiss et al., 2015).