Mycobacterial ATP synthase subunit epsilon (AtpC) (AtpC)

The Mycobacterial ATP synthase subunit epsilon, encoded by the atpC gene, is a vital component of the F1 sector of the F1Fo-ATP synthase complex (UniProt: P9WPU1). This enzyme is responsible for synthesizing ATP from ADP and inorganic phosphate, driven by the proton motive force across the bacterial membrane (PubMed: 21613214). In Mycobacterium tuberculosis, the epsilon subunit is unique because it contains a C-terminal extension that acts as an intrinsic inhibitor of ATP hydrolysis (PubMed: 24561181). This prevents the bacterium from depleting its ATP stores during periods of low metabolic activity or hypoxia, such as during latent infection (PubMed: 32665413). This regulatory function makes the epsilon subunit an attractive target for the development of new antibiotics against tuberculosis. While the approved drug Bedaquiline targets the c-subunit of the same complex, the epsilon subunit provides a distinct site for therapeutic intervention. Inhibiting this subunit can disrupt the coupling between the proton-pumping Fo sector and the catalytic F1 sector. This disruption leads to a lethal drop in cellular energy levels and inhibits the growth of both active and dormant mycobacteria. Research into small molecules and peptides that bind this subunit is ongoing to overcome drug resistance in tuberculosis treatment.

Other names

ATP synthase F1 sector subunit epsilonF-type ATPase subunit epsilonAtpCATP synthase epsilon chainMycobacterium tuberculosis ATP synthase epsilon subunit

Inhibition of the ATP synthase complex through allosteric modulation or physical obstruction of the epsilon subunit's regulatory movement, thereby preventing ATP synthesis and/or uncontrolled ATP hydrolysis (PubMed: 21613214, 32665413).