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Originally published In Press as doi:10.1074/jbc.M108778200 on October 9, 2001

J. Biol. Chem., Vol. 276, Issue 50, 46905-46911, December 14, 2001
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Curcumin, a Molecule That Inhibits the Ca2+-ATPase of Sarcoplasmic Reticulum but Increases the Rate of Accumulation of Ca2+*

Melanie J. Logan-SmithDagger , Peter J. Lockyer§, J. Malcolm EastDagger , and Anthony G. LeeDagger

From the Dagger  Division of Biochemistry and Molecular Biology, School of Biological Sciences, University of Southampton, Southampton SO16 7PX and the § Department of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom

Curcumin, an important inhibitor of carcinogenesis, is an inhibitor of the ATPase activity of the Ca2+-ATPase of skeletal muscle sarcoplasmic reticulum (SR). Inhibition by curcumin is structurally specific, requiring the presence of a pair of -OH groups at the 4-position of the rings. Inhibition is not competitive with ATP. Unexpectedly, addition of curcumin to SR vesicles leads to an increase in the rate of accumulation of Ca2+, unlike other inhibitors of the Ca2+-ATPase that result in a reduced rate of accumulation. An increase in the rate of accumulation of Ca2+ is seen in the presence of phosphate ion, which lowers the concentration of free Ca2+ within the lumen of the SR, showing that the effect is not passive leak across the SR membrane. Rather, simulations suggest that the effect is to reduce the rate of slippage on the ATPase, a process in which a Ca2+-bound, phosphorylated intermediate releases its bound Ca2+ on the cytoplasmic rather than on the lumenal side of the membrane. The structural specificity of the effects of curcumin on ATPase activity and on Ca2+ accumulation is the same, and the apparent dissociation constants for the two effects are similar, suggesting that the two effects of curcumin could follow from binding to a single site on the ATPase.

* This work was supported by studentships from the Biotechnology and Biological Sciences Research Council (to M. J. L.-S. and P. J. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The 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: Division of Biochemistry and Molecular Biology, School of Biological Sciences, University of Southampton, Southampton, SO16 7PX, UK. Tel.: 44 023 8059 4331; Fax: 44 023 8059 4459; E-mail: agl@soton.ac.uk.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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