title: 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.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 502-8585, Japan. matsunagat@gifu-pu.ac.jp
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.forename: Midori
authors.initials: M
authors.lastname: Soda
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Zhao
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tajima
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D000074408:Aldo-Keto Reductases; D019943:Amino Acid Substitution; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D020134:Catalytic Domain / Q000235:genetics; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D036381:Diarylheptanoids; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D005973:Glutamine / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010636:Phenols / Q000494:pharmacology*; D059808:Polyphenols; D014633:Valine / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D036381:Diarylheptanoids; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D005973:Glutamine; C034786:bisdemethoxycurcumin; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; D014633:Valine; D003474:Curcumin