TY - JOUR
T1 - Inhibition of human aldose reductase-like protein (AKR1B10) by a- and y-mangostins, major components of pericarps of mangosteen
AU - Soda, Midori
AU - Endo, Satoshi
AU - Matsunaga, Toshiyuki
AU - Zhao, Hai-Tao
AU - El-Kabbani, Ossama
AU - Iinuma, Munekazu
AU - Yamamura, Keiko
AU - Hara, Akira
PY - 2012
Y1 - 2012
N2 - 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 alpha- and gamma-mangostins show potential anti-cancer properties. Among the five xanthones, gamma-mangostin was found to be the most potent competitive inhibitor (inhibition constant, 5.6nm), but its 7-methoxy derivative, alpha-mangostin, was the second potent inhibitor (inhibition constant, 80nm). 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 gamma-mangostin, and suggested that the 7-methoxy group of alpha-mangostin impairs the inhibitory potency by altering the orientation of the inhibitor molecule in the substrate-binding site of the enzyme.
AB - 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 alpha- and gamma-mangostins show potential anti-cancer properties. Among the five xanthones, gamma-mangostin was found to be the most potent competitive inhibitor (inhibition constant, 5.6nm), but its 7-methoxy derivative, alpha-mangostin, was the second potent inhibitor (inhibition constant, 80nm). 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 gamma-mangostin, and suggested that the 7-methoxy group of alpha-mangostin impairs the inhibitory potency by altering the orientation of the inhibitor molecule in the substrate-binding site of the enzyme.
UR - http://bpb.pharm.or.jp/index.html
U2 - 10.1248/bpb.b12-00538
DO - 10.1248/bpb.b12-00538
M3 - Article
VL - 35
SP - 2075
EP - 2080
JO - Biological & Pharmaceutical Bulletin
JF - Biological & Pharmaceutical Bulletin
SN - 0918-6158
IS - 11
ER -