A novel dicyclodextrinyl diselenide compound with glutathione peroxidase activity.
A 6A,6A'-dicyclohexylamine-6B,6B'-diselenide-bis-beta-cyclodextrin (6-CySeCD) was designed and synthesized to imitate the antioxidant enzyme glutathione peroxidase (GPX). In this novel GPX model, beta-cyclodextrin provided a hydrophobic environment for substrate binding within its cavity, and a cyclohexylamine group was incorporated into cyclodextrin in proximity to the catalytic selenium in order to increase the stability of the nucleophilic intermediate selenolate. 6-CySeCD exhibits better GPX activity than 6,6'-diselenide-bis-cyclodextrin (6-SeCD) and 2-phenyl-1,2-benzoisoselenazol-3(2H)-one (Ebselen) in the reduction of H(2)O(2), tert-butyl hydroperoxide and cumenyl hydroperoxide by glutathione, respectively. A ping-pong mechanism was observed in steady-state kinetic studies on 6-CySeCD-catalyzed reactions. The enzymatic properties showed that there are two major factors for improving the catalytic efficiency of GPX mimics. First, the substrate-binding site should match the size and shape of the substrate and second, incorporation of an imido-group increases the stability of selenolate in the catalytic cycle. More efficient antioxidant ability compared with 6-SeCD and Ebselen was also seen in the ferrous sulfate/ascorbate-induced mitochondria damage system, and this implies its prospective therapeutic application.
Lv
Shao-Wu
SW
Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun, China.
Wang
Xiao-Guang
XG
Mu
Ying
Y
Zang
Tian-Zhu
TZ
Ji
Yue-Tong
YT
Liu
Jun-Qiu
JQ
Shen
Jia-Cong
JC
Luo
Gui-Min
GM
D000818:Animals; D002384:Catalysis; D002417:Cattle; D002713:Chlorine / Q000737:chemistry*; D003505:Cyclodextrins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism*; D007700:Kinetics; D008929:Mitochondria, Heart / Q000378:metabolism; D015394:Molecular Structure; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D018384:Oxidative Stress; D012643:Selenium / Q000737:chemistry*; D047392:beta-Cyclodextrins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*
C586642:6A,6A'-dicyclohexylamine-6B,6B'-diselenide-bis-beta-cyclodextrin; D003505:Cyclodextrins; D016566:Organoselenium Compounds; D047392:beta-Cyclodextrins; D002713:Chlorine; D005979:Glutathione Peroxidase; D012643:Selenium