Mycobacterial F-ATP synthase epsilon subunit (AtpC)

The Mycobacterial F-ATP synthase epsilon subunit, encoded by the atpC gene, is an essential component of the F1 sector of the ATP synthase complex in Mycobacterium tuberculosis (PubMed: 25112862). It plays a unique regulatory role in mycobacteria due to its C-terminal domain, which acts as an intrinsic inhibitor to prevent the wasteful hydrolysis of ATP when the proton motive force is low (PubMed: 31434795). This regulatory mechanism is crucial for the pathogen's survival during periods of dormancy or low oxygen, making it a distinct target from the human mitochondrial ATP synthase, which lacks this specific C-terminal extension (UniProt: P9WPU3). While the F-ATP synthase complex is the target of the FDA-approved drug Bedaquiline, Bedaquiline specifically binds to the c-subunit (AtpE); however, the epsilon subunit is being actively investigated as a novel site for drug development to overcome Bedaquiline resistance (PubMed: 33483465). Targeting the epsilon subunit aims to disrupt the energy coupling of the bacteria, leading to rapid depletion of ATP and bacterial death (PubMed: 25112862). Research is ongoing to identify small molecules and peptides that can specifically bind to the epsilon subunit and disrupt the energy metabolism of the mycobacteria (PubMed: 31434795).

Other names

ATP synthase subunit epsilonF-type ATPase epsilon chainAtpCMycobacterium tuberculosis ATP synthase epsilon subunitATP synthase F1 sector epsilon subunit

Inhibition of the F-ATP synthase rotary catalysis by targeting the epsilon subunit's regulatory C-terminal domain, thereby preventing ATP synthesis and potentially promoting uncontrolled ATP hydrolysis leading to bacterial energy depletion.