Mycobacterial ATP synthase subunit c (AtpE)

The mycobacterial ATP synthase subunit c is a critical transmembrane protein within the F0 domain of the F1Fo-ATP synthase complex, essential for energy production in Mycobacterium tuberculosis (UniProt P9WPU1). It forms a ring-like structure, known as the c-ring, that rotates as protons move through the membrane, driving the synthesis of ATP from ADP and inorganic phosphate (PubMed: 15647434). This subunit is the primary target of the diarylquinoline antibiotic bedaquiline, which binds to specific residues on the c-subunit to inhibit the rotation of the rotor (PubMed: 17495911). By blocking this mechanical rotation, the drug effectively shuts down the bacterium's ability to generate energy, leading to bactericidal effects against both replicating and non-replicating mycobacteria (PubMed: 24501233). This target is particularly significant in the treatment of multi-drug-resistant tuberculosis (MDR-TB), where traditional therapies often fail (WHO). However, clinical use must account for potential safety issues like QTc prolongation and the emergence of resistance through mutations in the atpE gene (FDA Sirturo Label). The specificity of bedaquiline for the mycobacterial c-subunit over the human mitochondrial counterpart is a key factor in its therapeutic index (PubMed: 25187515).

Other names

ATP synthase subunit cF-type H+-transporting ATPase subunit cSubunit c of F1Fo-ATP synthaseAtpE

Bedaquiline binds to the c-subunit of the mycobacterial F-ATP synthase, specifically targeting the proton-binding site. This binding inhibits the rotation of the c-ring, which is essential for the coupling of proton transport to ATP synthesis, thereby depleting the bacterium's energy reserves and leading to cell death (PubMed: 17495911).