ATP synthase subunit c (Mycobacterial) (atpE)

The mycobacterial ATP synthase c-ring, primarily composed of the c-subunit (encoded by the atpE gene), is a critical component of the F0 sector of the F1F0-ATP synthase enzyme complex [9, 10]. This complex is responsible for synthesizing adenosine triphosphate (ATP), the primary energy currency of the cell, by utilizing the proton motive force across the bacterial membrane [1, 6]. The c-ring acts as a rotary motor that translocates protons; as protons move through the interface between the a-subunit and the c-ring, the ring rotates, driving the central stalk to catalyze ATP production in the F1 domain [10, 14, 20]. In Mycobacterium tuberculosis, this process is essential for survival in both replicating and non-replicating states [1, 6]. This target is clinically validated by the diarylquinoline drug bedaquiline, which binds specifically to the c-subunit to stall the rotation of the c-ring, leading to lethal ATP depletion [3, 12, 14]. While highly effective against multidrug-resistant tuberculosis, drugs targeting this molecule must be monitored for safety concerns such as QTc prolongation and the development of resistance through atpE mutations [8, 12, 14]. The high selectivity of bedaquiline for mycobacterial over human mitochondrial ATP synthase is a key factor in its therapeutic index [1, 12].

Other names

ATP synthase F0 subunit catpEc-ringF-type H+-transporting ATPase subunit cLipid-binding proteinATP synthase F(0) sector subunit c

Inhibition of the F1F0-ATP synthase by binding to the c-subunit of the F0 rotor, which stalls the rotation of the c-ring and prevents the mechanical coupling of proton translocation to ATP synthesis, leading to cellular ATP depletion and bactericidal activity.