Mycobacterium tuberculosis ATP synthase F1 catalytic core (Mtb F1-ATPase)

The Mycobacterium tuberculosis ATP synthase F1 catalytic core is the hydrophilic, extrinsic component of the F1F0-ATP synthase complex, which is essential for the bacterium's energy production (Lu et al., 2014, Journal of Bacteriology). It consists of a hexameric alpha3beta3 ring that contains the catalytic sites for ATP synthesis and hydrolysis, surrounding a central gamma subunit stalk that couples the proton-motive force from the F0 sector to mechanical rotation (Wong et al., 2017, Frontiers in Pharmacology). This enzyme is a critical therapeutic target because M. tuberculosis relies heavily on oxidative phosphorylation for survival during both active growth and latent infection phases (Andries et al., 2005, Science). While the FDA-approved drug Bedaquiline primarily binds to the c-ring of the F0 sector, the F1 catalytic core is an active area of drug discovery for identifying inhibitors that can disrupt the enzyme's rotational mechanism or catalytic turnover (Preiss et al., 2015, Science Advances). Targeting the F1 sector offers a strategy to overcome resistance associated with F0 mutations and provides a pathway for developing narrow-spectrum antitubercular agents. However, a major challenge in targeting this core is ensuring selectivity to avoid inhibiting the highly conserved human mitochondrial ATP synthase, which could lead to significant host toxicity (Bai et al., 2021, Bioorganic & Medicinal Chemistry).

Other names

F1-ATPaseF1 sectoralpha3beta3gamma complexATP synthase subunit alphaATP synthase subunit beta

Inhibition of the catalytic activity of the alpha3beta3 hexamer, preventing the synthesis of ATP from ADP and inorganic phosphate, thereby depleting cellular energy levels and leading to bacterial death (Wong et al., 2017).