Unique structural and mechanistic properties of mycobacterial F-ATP synthases: Implications for drug design

Publication date: Available online 16 November 2019Source: Progress in Biophysics and Molecular BiologyAuthor(s): Neelagandan Kamariah, Priya Ragunathan, Joon Shin, Wuan-Geok Saw, Chui-Fann Wong, Thomas Dick, Gerhard GrüberAbstractThe causative agent of Tuberculosis (TB) Mycobacterium tuberculosis (Mtb) encounters unfavourable environmental conditions in the lungs, including nutrient limitation, low oxygen tensions and/or low/high pH values. These harsh conditions in the host triggers Mtb to enter a dormant state in which the pathogen does not replicate and uses host-derived fatty acids instead of carbohydrates as an energy source. Independent to the energy source, the bacterium's energy currency ATP is generated by oxidative phosphorylation, in which the F1FO-ATP synthase uses the proton motive force generated by the electron transport chain. This catalyst is essential in Mtb and inhibition by the diarylquinoline class of drugs like Bedaquilline, TBAJ-587, TBAJ-876 or squaramides demonstrated that this engine is an attractive target in TB drug discovery. A special feature of the mycobacterial F-ATP synthase is its inability to establish a significant proton gradient during ATP hydrolysis, and its latent ATPase activity, to prevent energy waste and to control the membrane potential. Recently, unique epitopes of mycobacterial F1FO-ATP synthase subunits absent in their prokaryotic or mitochondrial counterparts have been identified to contribute to the regulation of the low ATP...
Source: Progress in Biophysics and Molecular Biology - Category: Molecular Biology Source Type: research