Interaction of inhibitors of the vacuolar H(+)-ATPase with the transmembrane Vo-sector

Biochemistry
T PáliD Marsh

Abstract

The macrolide antibiotic concanamycin A and a designed derivative of 5-(2-indolyl)-2,4-pentadienamide (INDOL0) are potent inhibitors of vacuolar H(+)-ATPases, with IC(50) values in the low and medium nanomolar range, respectively. Interaction of these V-ATPase inhibitors with spin-labeled subunit c in the transmembrane V(o)-sector of the ATPase was studied by using the transport-active 16-kDa proteolipid analogue of subunit c from the hepatopancreas of Nephrops norvegicus. Analogous experiments were also performed with vacuolar membranes from Saccharomyces cerevisiae. Membranous preparations of the Nephrops 16-kDa proteolipid were spin-labeled either on the unique cysteine C54, with a nitroxyl maleimide, or on the functionally essential glutamate E140, with a nitroxyl analogue of dicyclohexylcarbodiimide (DCCD). These residues were previously demonstrated to be accessible to lipid. Interaction of the inhibitors with these lipid-exposed residues was studied by using both conventional and saturation transfer EPR spectroscopy. Immobilization of the spin-labeled residues by the inhibitors was observed on both the nanosecond and microsecond time scales. The perturbation by INDOL0 was mostly greater than that by concanamycin A. Quali...Continue Reading

References

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Citations

Nov 20, 2012·European Biophysics Journal : EBJ·Csilla FerenczTibor Páli
Aug 21, 2008·Pediatric Surgery International·Toshiya MorimuraAkira Satomi
Oct 5, 2010·The Journal of Biological Chemistry·Svenja BockelmannMarkus Huss
Dec 12, 2007·Journal of Peptide Science : an Official Publication of the European Peptide Society·Renske W HesselinkManuel Prieto
Sep 26, 2006·Biochimica Et Biophysica Acta·F FernandesM A Hemminga
Jan 20, 2009·The Journal of Experimental Biology·Markus Huss, Helmut Wieczorek
Jan 31, 2006·The Journal of Laboratory and Clinical Medicine·Lucinda M HilliardWayne D Comper
Sep 18, 2009·Cancer Treatment Reviews·Mario Pérez-SayánsAbel García-García

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