Potent and selective inhibition of the tumor marker AKR1B10 by bisdemethoxycurcumin: probing the active site of the enzyme with molecular modeling and site-directed mutagenesis.

Abstract	A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, shares high sequence identity with aldose reductase (AR), and was recently identified as a therapeutic target in the treatment of several types of cancer. We have compared the inhibitory effects of plant components on recombinant AKR1B10 and AR. AKR1B10 was inhibited by curcuminoids, magnolol, honokiol and resveratrol, with IC(50) values of 0.06-5 microM, which were lower than their values for AR. Among them, bisdemethoxycurcumin was the most potent competitive inhibitor (K(i)=22 nM) with the highest selectivity (85-fold versus AR), and acted as an effective inhibitor in cellular level. In contrast, demethoxycurcumin and curcumin showed >3-fold less potency and selectivity. Molecular docking studies of the curcuminoids in the AKR1B10-NADP(+) complex and site-directed mutagenesis of the putative binding residues suggest that Gln114, Val301 and Gln303 are important for determining the inhibitory potency and selectivity of the curcuminoids.
Authors	Toshiyuki Matsunaga, Satoshi Endo, Midori Soda, Hai-Tao Zhao, Ossama El-Kabbani, Kazuo Tajima, Akira Hara
Journal	Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 389 Issue 1 Pg. 128-32 (Nov 06 2009) ISSN: 1090-2104 [Electronic] United States
PMID	19706287 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Biomarkers, Tumor Diarylheptanoids Enzyme Inhibitors Flavonoids Phenols Polyphenols Glutamine bisdemethoxycurcumin AKR1B10 protein, human Aldo-Keto Reductases Aldehyde Reductase Valine Curcumin
Topics	Aldehyde Reductase (antagonists & inhibitors, chemistry, genetics) Aldo-Keto Reductases Amino Acid Substitution Biomarkers, Tumor (antagonists & inhibitors, chemistry, genetics) Catalytic Domain (genetics) Curcumin (analogs & derivatives, pharmacology) Diarylheptanoids Enzyme Inhibitors (pharmacology) Flavonoids (pharmacology) Glutamine (genetics, metabolism) HeLa Cells Humans Models, Molecular Mutagenesis, Site-Directed Phenols (pharmacology) Polyphenols Valine (genetics, metabolism)

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