ATP synthase subunit c (Mycobacterium tuberculosis) (AtpE)

The Mycobacterium tuberculosis F-ATP synthase c-subunit, encoded by the atpE gene, is a critical component of the F0 domain of the F1F0-ATP synthase complex. This subunit forms a membrane-embedded oligomeric ring, known as the c-ring, which acts as a rotary motor driven by the proton motive force across the bacterial inner membrane. As protons move through the interface between the c-ring and subunit a, the resulting rotation is coupled to the F1 domain to catalyze the synthesis of ATP from ADP and inorganic phosphate. This energy production is essential for the survival of M. tuberculosis in both its actively replicating and dormant, non-replicating states. In the context of disease, this target is the primary site of action for bedaquiline, a diarylquinoline antibiotic used to treat multidrug-resistant tuberculosis. Bedaquiline binds specifically to the c-subunit, physically stalling the rotation of the c-ring and thereby halting ATP production. This leads to a rapid depletion of cellular energy and subsequent bacterial death. While highly effective, mutations in the atpE gene can lead to drug resistance, and concerns regarding off-target effects on human mitochondrial ATP synthase have been noted, potentially contributing to clinical safety issues such as QT prolongation.

Other names

AtpEATP synthase C chainF-ATP synthase c-subunitc-ringF0 subunit cF-type H+-transporting ATPase subunit c

Inhibition of ATP synthesis by binding to the c-ring rotor, which prevents proton translocation and enzyme rotation, leading to ATP depletion and bacterial death.