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J. Biol. Chem., Vol. 279, Issue 19, 19755-19763, May 7, 2004

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Salicylihalamide A Inhibits the V₀ Sector of the V-ATPase through a Mechanism Distinct from Bafilomycin A₁^*

Xiao-Song Xie, David Padron¶, Xibin Liao¶, Jin Wang, Michael G. Roth¶, and Jef K. De Brabander¶||

From the Eugene McDermott Center for Human Growth and Development and ^¶Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390

The newly identified specific V-ATPase inhibitor, salicylihalamide A, is distinct from any previously identified V-ATPase inhibitors in that it inhibits only mammalian V-ATPases, but not those from yeast or other fungi (Boyd, M. R., Farina, C., Belfiore, P., Gagliardi, S., Kim, J. W., Hayakawa, Y., Beutler, J. A., McKee, T. C., Bowman, B. J., and Bowman, E. J. (2001) J. Pharmacol. Exp. Ther. 297, 114–120). In addition, salicylihalamide A does not compete with concanamycin or bafilomycin for binding to V-ATPase, indicating that it has a different binding site from those classic V-ATPase inhibitors (Huss, M., Ingenhorst, G., Konig, S., Gassel, M., Drose, S., Zeeck, A., Altendorf, K., and Wieczorek, H. (2002) J. Biol. Chem. 277, 40544–40548). By using purified bovine brain V-pump and its dissociated V₁ and V₀ sectors, we identified the recognition and binding site for salicylihalamide to be within the V₀ domain. Salicylihalamide does not inhibit the ATP hydrolysis activity of the dissociated V₁-ATPase but inhibits the ATPase activity of the holoenzyme by inhibiting the V₀ domain. Salicylihalamide causes a dramatic redistribution of cytosolic V₁ from soluble to membrane-associated form, a change not observed in cells treated with either bafilomycin or NH₄Cl. By synthesizing and characterizing a series of salicylihalamide derivatives, we investigated the structural determinants of salicylihalamide inhibition in terms of potency and reversibility, and used this information to suggest a possible binding mechanism.

Received for publication, December 17, 2003 , and in revised form, February 9, 2004.

^* This work was supported by Grants RO1 DK33627 (to X.-S. X.), RO1 CA90349 (to J. D. B.), and PO1 CA95471 (to M. G. R. and J. K. D. B.), from the National Institutes of Health, and grants from the Robert A. Welch Foundation (to J. D. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 214-648-7700; Fax: 214-648-7720; E-mail: Xiao-Song.Xie{at}UTSouthwestern.edu. || A fellow of the Alfred P. Sloan Foundation. To whom inquiries regarding the chemistry and synthesis of salicylihalamide should be addressed. E-mail: jdebra{at}biochem.swmed.edu.

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