The Binding Site of the V-ATPase Inhibitor Apicularen Is in the Vicinity of Those for Bafilomycin and Archazolid.

2.50
Hdl Handle:
http://hdl.handle.net/10033/251212
Title:
The Binding Site of the V-ATPase Inhibitor Apicularen Is in the Vicinity of Those for Bafilomycin and Archazolid.
Authors:
Osteresch, Christin; Bender, Tobias; Grond, Stephanie; von Zezschwitz, Paultheo; Kunze, Brigitte; Jansen, Rolf; Huss, Markus; Wieczorek, Helmut
Abstract:
The investigation of V-ATPases as potential therapeutic drug targets and hence of their specific inhibitors is a promising approach in osteoporosis and cancer treatment because the occurrence of these diseases is interrelated to the function of the V-ATPase. Apicularen belongs to the novel inhibitor family of the benzolactone enamides, which are highly potent but feature the unique characteristic of not inhibiting V-ATPases from fungal sources. In this study we specify, for the first time, the binding site of apicularen within the membrane spanning V(O) complex. By photoaffinity labeling using derivatives of apicularen and of the plecomacrolides bafilomycin and concanamycin, each coupled to (14)C-labeled 4-(3-trifluoromethyldiazirin-3-yl)benzoic acid, we verified that apicularen binds at the interface of the V(O) subunits a and c. The binding site is in the vicinity to those of the plecomacrolides and of the archazolids, a third family of V-ATPase inhibitors. Expression of subunit c homologues from Homo sapiens and Manduca sexta, both species sensitive to benzolactone enamides, in a Saccharomyces cerevisiae strain lacking the corresponding intrinsic gene did not transfer this sensitivity to yeast. Therefore, the binding site of benzolactone enamides cannot be formed exclusively by subunit c. Apparently, subunit a substantially contributes to the binding of the benzolactone enamides.
Affiliation:
From the Fachbereich Biologie/Chemie, Abteilung Tierphysiologie, Universität Osnabrück, Barbarastrasse 11, 49069 Osnabrück.
Citation:
The Binding Site of the V-ATPase Inhibitor Apicularen Is in the Vicinity of Those for Bafilomycin and Archazolid. 2012, 287 (38):31866-76 J. Biol. Chem.
Journal:
The Journal of biological chemistry
Issue Date:
14-Sep-2012
URI:
http://hdl.handle.net/10033/251212
DOI:
10.1074/jbc.M112.372169
PubMed ID:
22815478
Type:
Article
Language:
en
ISSN:
1083-351X
Appears in Collections:
Publications of RG Microbial Communication (KOM)

Full metadata record

DC FieldValue Language
dc.contributor.authorOsteresch, Christinen_GB
dc.contributor.authorBender, Tobiasen_GB
dc.contributor.authorGrond, Stephanieen_GB
dc.contributor.authorvon Zezschwitz, Paultheoen_GB
dc.contributor.authorKunze, Brigitteen_GB
dc.contributor.authorJansen, Rolfen_GB
dc.contributor.authorHuss, Markusen_GB
dc.contributor.authorWieczorek, Helmuten_GB
dc.date.accessioned2012-11-06T13:28:20Z-
dc.date.available2012-11-06T13:28:20Z-
dc.date.issued2012-09-14-
dc.identifier.citationThe Binding Site of the V-ATPase Inhibitor Apicularen Is in the Vicinity of Those for Bafilomycin and Archazolid. 2012, 287 (38):31866-76 J. Biol. Chem.en_GB
dc.identifier.issn1083-351X-
dc.identifier.pmid22815478-
dc.identifier.doi10.1074/jbc.M112.372169-
dc.identifier.urihttp://hdl.handle.net/10033/251212-
dc.description.abstractThe investigation of V-ATPases as potential therapeutic drug targets and hence of their specific inhibitors is a promising approach in osteoporosis and cancer treatment because the occurrence of these diseases is interrelated to the function of the V-ATPase. Apicularen belongs to the novel inhibitor family of the benzolactone enamides, which are highly potent but feature the unique characteristic of not inhibiting V-ATPases from fungal sources. In this study we specify, for the first time, the binding site of apicularen within the membrane spanning V(O) complex. By photoaffinity labeling using derivatives of apicularen and of the plecomacrolides bafilomycin and concanamycin, each coupled to (14)C-labeled 4-(3-trifluoromethyldiazirin-3-yl)benzoic acid, we verified that apicularen binds at the interface of the V(O) subunits a and c. The binding site is in the vicinity to those of the plecomacrolides and of the archazolids, a third family of V-ATPase inhibitors. Expression of subunit c homologues from Homo sapiens and Manduca sexta, both species sensitive to benzolactone enamides, in a Saccharomyces cerevisiae strain lacking the corresponding intrinsic gene did not transfer this sensitivity to yeast. Therefore, the binding site of benzolactone enamides cannot be formed exclusively by subunit c. Apparently, subunit a substantially contributes to the binding of the benzolactone enamides.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to The Journal of biological chemistryen_GB
dc.titleThe Binding Site of the V-ATPase Inhibitor Apicularen Is in the Vicinity of Those for Bafilomycin and Archazolid.en
dc.typeArticleen
dc.contributor.departmentFrom the Fachbereich Biologie/Chemie, Abteilung Tierphysiologie, Universität Osnabrück, Barbarastrasse 11, 49069 Osnabrück.en_GB
dc.identifier.journalThe Journal of biological chemistryen_GB

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