Bacterial FOF1 ATP: Nanomotor for ATP Synthesis and Hydrolysis and Mechanism of Interaction with the Macrolide Antibioti
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erial FOF1 ATP: Nanomotor for ATP Synthesis and Hydrolysis and Mechanism of Interaction with the Macrolide Antibiotic Oligomycin A A. A. Vatlina, * and V. N. Danilenkoa aVavilov
Institute of General Genetics, Russian Academy of Sciences, Moscow, 117971 Russia *e-mail: [email protected] Received January 13, 2020; revised January 20, 2020; accepted January 20, 2020
Abstract—FOF1-ATP synthase is a highly conserved enzyme of eukaryotic or bacterial cells. This enzyme contains eight species of various subunits in bacteria. The F1 sector contains subunits α3, β3, γ, δ, and ε, and the FO sector contains subunits a, b2, and c(10–15). According to modern nomenclature, the rotor of FOF1-ATF synthase consists of the γ, ε, and c subunits; the stator of the enzyme molecule includes the α3, β3, δ, a, and b2 subunits. The rotation of the complex relative to the stator subunits leads to the synthesis or hydrolysis of ATP with the translocation of protons through the a subunit and c ring of the FO sector. The most famous ATP synthase inhibitor is oligomycin A. Oligomycin A inhibits proton translocation in the FOF1-ATP synthase complexes, which leads to an impaired energy metabolism in cells. Oligomycin has a cytotoxic effect against a number of pathogenic bacteria and a high antitumor activity due to the inactivation of FOF1-ATF synthase, a promising biological target for modern drugs. Since FOF1-ATP synthase is highly conserved and ATP synthesis is one of the central processes necessary for the vital functions of cells, this enzyme is a promising biotarget for new antibacterial drugs synthesized based on oligomycin A. This article describes the latest data on the functioning of ATP synthase in bacterial and eukaryotic cells, as well as recent work on the development of new antibacterial drugs based on oligomycin A and its derivatives. Keywords: FОF1 ATP synthase, ATP synthesis, biomicin, oligomycin A DOI: 10.1134/S2079086420060067
INTRODUCTION The membrane-bound FОF1-ATP synthase (ЕС 3.6.3.14) is a unique enzyme complex with a bifunctional catalytic mechanism of ATP synthesis and hydrolysis. Detailed research on the FОF1-ATP synthase structure and function remains an important challenge for modern biochemistry. Functional impairment of ATP synthase is associated with different diseases (Ahmad et al., 2013). The enzyme consists of two structurally and functionally different parts: a membrane-integrated ion-translocating FО sector and a peripheral F1 sector that contains the catalytic sites for ATP synthesis and hydrolysis (Walker, 2013). Although the structures of FOF1-ATP synthases differ in different living organisms, this enzyme is highly conservative in both bacteria and humans. At present, the function of FОF1-ATP synthase is considered in the context of a single complex with other enzymes contained in the eukaryotic mitochondria and bacterial cell walls. The FОF1-ATP synthase complex is a promising molecular target for the treatment of infections and cancer. The best known FОF1-ATP synthase inhibitor is oligomycin A.
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