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Open Access Research article

Archazolid and apicularen: Novel specific V-ATPase inhibitors

Markus Huss1*, Florenz Sasse2, Brigitte Kunze2, Rolf Jansen2, Heinrich Steinmetz2, Gudrun Ingenhorst3, Axel Zeeck3 and Helmut Wieczorek1

Author affiliations

1 Universität Osnabrück, Fachbereich Biologie/Chemie, Abteilung Tierphysiologie, 49069 Osnabrück, Germany

2 Gesellschaft für Biotechnologische Forschung, Bereich Naturstoffe, 38124 Braunschweig, Germany

3 Universität Göttingen, Fakultät für Chemie, Institut für Organische und Biomolekulare Chemie, 37077 Göttingen, Germany

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Citation and License

BMC Biochemistry 2005, 6:13  doi:10.1186/1471-2091-6-13

Published: 4 August 2005

Abstract

Background

V-ATPases constitute a ubiquitous family of heteromultimeric, proton translocating proteins. According to their localization in a multitude of eukaryotic membranes, they energize many different transport processes. Since their malfunction is correlated with various diseases in humans, the elucidation of the properties of this enzyme for the development of selective inhibitors and drugs is one of the challenges in V-ATPase research.

Results

Archazolid A and B, two recently discovered cytotoxic macrolactones produced by the myxobacterium Archangium gephyra, and apicularen A and B, two novel benzolactone enamides produced by different species of the myxobacterium Chondromyces, exerted a similar inhibitory efficacy on a wide range of mammalian cell lines as the well established plecomacrolidic type V-ATPase inhibitors concanamycin and bafilomycin. Like the plecomacrolides both new macrolides also prevented the lysosomal acidification in cells and inhibited the V-ATPase purified from the midgut of the tobacco hornworm, Manduca sexta, with IC50 values of 20–60 nM. However, they did not influence the activity of mitochondrial F-ATPase or that of the Na+/K+-ATPase. To define the binding sites of these new inhibitors we used a semi-synthetic radioactively labelled derivative of concanamycin which exclusively binds to the membrane Vo subunit c. Whereas archazolid A prevented, like the plecomacrolides concanamycin A, bafilomycin A1 and B1, labelling of subunit c by the radioactive I-concanolide A, the benzolactone enamide apicularen A did not compete with the plecomacrolide derivative.

Conclusion

The myxobacterial antibiotics archazolid and apicularen are highly efficient and specific novel inhibitors of V-ATPases. While archazolid at least partly shares a common binding site with the plecomacrolides bafilomycin and concanamycin, apicularen adheres to an independent binding site.