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Antibiotic inhibitors of mitochondrial ATP synthesis

H Lardy, P Reed, C H Lin

    Federation Proceedings
    |July 1, 1975
    PubMed

    Insights

    Fourteen antibiotics inhibit mitochondrial ATP synthase by binding to four distinct sites. Venturicidin at site III interferes with leucinostatin binding at site IV, revealing their proximity and interaction.

    Area of Science:

    • Biochemistry
    • Molecular Biology
    • Pharmacology

    Background:

    • Mitochondrial ATP synthase is crucial for cellular energy production.
    • Antibiotics targeting ATP synthase can disrupt oxidative phosphorylation.
    • Understanding inhibitor binding sites is key to developing targeted therapies.

    Purpose of the Study:

    • To identify and characterize the binding sites of various antibiotics on mitochondrial ATP synthase.
    • To elucidate the mechanism of interaction between different antibiotic binding sites.

    Main Methods:

    • Biochemical assays using purified MF1 ATPase and submitochondrial particles.
    • Stoichiometric analysis of inhibitor binding.
    • Assessment of antibiotic effects on ATP synthase activity and oxidative phosphorylation.

    Main Results:

    • Four distinct binding sites (I, II, III, IV) for antibiotics were identified on ATP synthase.
    • Aurovertin binds to site I, efrapeptin to site II.
    • Oligomycin, venturicidin, and ossamycin bind to site III; leucinostatin binds to site IV.
    • Venturicidin binding at site III inhibits leucinostatin binding at site IV, suggesting spatial proximity.

    Conclusions:

    • Mitochondrial ATP synthase possesses multiple antibiotic binding sites with distinct properties.
    • Sites III and IV are closely located, and venturicidin's interaction with site III influences leucinostatin's binding at site IV.
    • This interaction provides insights into the allosteric regulation of ATP synthase activity by inhibitors.

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