Inhibition of human aldose reductase-like protein (AKR1B10) by α- and γ-mangostins, major components of pericarps of mangosteen

Midori Soda, Satoshi Endo, Toshiyuki Matsunaga, Hai Tao Zhao, Ossama El-Kabbani, Munekazu Iinuma, Keiko Yamamura, Akira Hara

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

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, 5.6nM), 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.

Original languageEnglish
Pages (from-to)2075-2080
Number of pages6
JournalBiological and Pharmaceutical Bulletin
Volume35
Issue number11
DOIs
Publication statusPublished - 11-2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

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