title: Curcumin is a lipid dependent inhibitor of the Na,K-ATPase that likely interacts at the protein-lipid interface.
abstract: Curcumin is an important nutraceutical widely used in disease treatment and prevention. We have previously suggested that curcumin interferes with K(+) binding to pig kidney Na,K-ATPase by interaction with its extracellular domains. The aim of this study was to further characterize the site of curcumin interaction with the ATPase. We have performed pair inhibitor studies and investigated the sided action of curcumin on pig kidney Na,K-ATPase reconstituted into lipid vesicles of defined composition. An addition of curcumin to either the intracellular or extracellular domains of the Na,K-ATPase produced similar inhibition. The lipid environment and temperature strongly influenced the potency of the drug. Curcumin inhibition decreased following insertion of the ATPase in sphingomyelin-cholesterol 'raft' domains and fully abolished following treatment with non-ionic detergents. The drug induced cross-linking of membrane embedded domains of the Na,K-ATPase. We conclude that curcumin interacts with Na,K-ATPase at the protein-lipid interface. Non-annulus lipids likely participate in this interaction. These results provide new information on the molecular mechanism of curcumin action and explain (at least partly) the ambiguous effectiveness of this polyphenol in the different systems.
authors.affiliation: Department of Physiology and Biophysics, Ole Worms Alle 6, Bld. 1180, University of Aarhus, DK-8000 Aarhus C, Denmark. yam@biophys.au.dk
authors.forename: Yasser A
authors.initials: YA
authors.lastname: Mahmmoud
mesh_terms: D000818:Animals; D003432:Cross-Linking Reagents / Q000737:chemistry; D003474:Curcumin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry; D007668:Kidney / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D021962:Membrane Microdomains / Q000737:chemistry; D010636:Phenols / Q000737:chemistry; D059808:Polyphenols; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013552:Swine; D013696:Temperature
chemical_list: D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D008055:Lipids; D010636:Phenols; D059808:Polyphenols; D011506:Proteins; D000254:Sodium-Potassium-Exchanging ATPase; D003474:Curcumin