title: Inhibition of human aldose reductase-like protein (AKR1B10) by α- and γ-mangostins, major components of pericarps of mangosteen.
abstract: A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, was recently identified as both diagnostic marker and therapeutic target in the treatment of several types of cancer. In this study, we have examined AKR1B10 inhibition by five xanthone derivatives, components of pericarps of mangosteen, of which α- and γ-mangostins show potential anti-cancer properties. Among the five xanthones, γ-mangostin was found to be the most potent competitive inhibitor (inhibition constant, 5.6 nM), but its 7-methoxy derivative, α-mangostin, was the second potent inhibitor (inhibition constant, 80 nM). Molecular docking of the two mangostins in AKR1B10 and site-directed mutagenesis of the putative binding residues revealed that Phe123, Trp220, Val301 and Gln303 are important for the tight binding of γ-mangostin, and suggested that the 7-methoxy group of α-mangostin impairs the inhibitory potency by altering the orientation of the inhibitor molecule in the substrate-binding site of the enzyme.
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501–1196, Japan. msoda@dpc.agu.ac.jp
authors.forename: Midori
authors.initials: M
authors.lastname: Soda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Zhao
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.forename: Munekazu
authors.initials: M
authors.lastname: Iinuma
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamura
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000074408:Aldo-Keto Reductases; D000970:Antineoplastic Agents / Q000494:pharmacology*; D005638:Fruit; D029762:Garcinia mangostana; D006801:Humans; D062105:Molecular Docking Simulation; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D044004:Xanthones; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; C021053:mangostin