Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 279, Issue 19, Pages 19755-19763Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M313796200
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Funding
- NCI NIH HHS [R01 CA 90349, P01 CA095471, P01 CA 95471] Funding Source: Medline
- NIDDK NIH HHS [R01 DK 33627] Funding Source: Medline
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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 V-1 and V-0 sectors, we identified the recognition and binding site for salicylihalamide to be within the V-0 domain. Salicylihalamide does not inhibit the ATP hydrolysis activity of the dissociated V-1-ATPase but inhibits the ATPase activity of the holoenzyme by inhibiting the V-0 domain. Salicylihalamide causes a dramatic redistribution of cytosolic V-1 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.
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