Mycobacterium tuberculosis FoF1 ATP synthase (Mtb ATP synthase)

Mycobacterium tuberculosis FoF1 ATP synthase is an essential multi-subunit enzyme complex that generates cellular ATP from ADP and inorganic phosphate by utilizing the proton motive force across the bacterial membrane [2, 3]. The enzyme consists of two main sectors: the membrane-embedded Fo part, which translocates protons, and the soluble F1 part, which contains the catalytic sites for ATP synthesis [3, 7]. It is indispensable for the viability of M. tuberculosis in both actively replicating and dormant (latent) states, as the bacterium relies on this complex to maintain energy homeostasis under various environmental conditions [2, 12]. The diarylquinoline drug bedaquiline (Sirturo) targets this enzyme by binding to the c-ring and the ε-subunit, thereby stalling the rotation of the enzyme and inhibiting ATP production [1, 6, 13]. This mechanism is highly selective for mycobacteria due to unique structural features not found in human mitochondrial ATP synthase, such as specific subunit extensions and loops [2, 11, 14]. Despite its clinical success in treating multidrug-resistant tuberculosis, therapeutic use is associated with safety concerns like QTc prolongation and the potential for resistance through mutations in the atpE gene [2, 8, 9].

Other names

F-type ATPase [2, 3]H+-transporting ATP synthase [2, 7]Mycobacterial ATP synthase [2, 4]ATP synthase enzyme of Mycobacterium tuberculosis [2]FoF1-ATPase [3, 7]

Inhibition of ATP synthesis by binding to the c-ring rotor and the ε-subunit, which prevents proton translocation and mechanical rotation of the enzyme complex, leading to cellular ATP depletion and bacterial death [1, 2, 6, 10, 13].