Tài liệu Báo cáo khoa học: A novel dicyclodextrinyl diselenide compound with glutathione peroxidase

A novel dicyclodextrinyl diselenide compound with

glutathione peroxidase activity

Shao-Wu Lv1

, Xiao-Guang Wang1

, Ying Mu1

, Tian-Zhu Zang1

, Yue-Tong Ji1

, Jun-Qiu Liu2

,

Jia-Cong Shen2 and Gui-Min Luo1

1 Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun, China

2 Key Laboratory for Supramolecular Structure and Materials of the Ministry of Education, Jilin University, Changchun, China

Glutathione peroxidase (GPX; EC 1.11.1.9) is a well￾known selenoenzyme that catalyzes the reduction

of harmful hydroperoxides by glutathione (GSH)

(Scheme 1) and protects lipid membranes and other

cellular components against oxidative damage [1–4]. It

is related to many diseases and is regarded as one of

the most important antioxidant enzymes in living

organisms. GPX enzyme activity is sometimes

increased in disease, possibly as a compensatory mech￾anism to try to counteract the oxidative stress associ￾ated with the pathology, although it is also decreased

in other diseases [5–8]. Therefore, modulation of GPX

may be involved in many pathological conditions.

Because natural GPX has some shortcomings, such as

instability, antigenicity and poor availability, much

attention has been paid to its artificial imitation [9,10].

In synthetic approaches, an initial attempt is made

to synthesize organoselenium compounds in which the

interaction of Se–N in GPX catalysis is imitated by

inducing N or O in close proximity to selenium. One

way in which this is achieved is by binding the selen￾ium atom directly to a heteroatom such as nitrogen.

2-Phenyl-l,2-benzisoselenazol-3(2H)-one (Ebselen), the

first biologically active organoselenium compound,

represents an excellent example of a GPX mimic [9].

Another way to imitate the SeÆÆÆN interaction in GPX is

if the selenium is not bound directly to the heteroatom

(N or O), but is located in close proximity to it, this

Keywords

cyclodextrins; enzyme mimics; glutathione

peroxidase; selenium; substrate binding

Correspondence

G.-M. Luo, Key Laboratory for Molecular

Enzymology and Engineering of the Ministry

of Education, Jilin University, 2519 Jiefang

Road, Changchun 130021, China

Fax: +86 431 8898 0440

Tel: +86 431 8849 8974

E-mail: [email protected]

(Received 12 February 2007, revised

27 May 2007, accepted 31 May 2007)

doi:10.1111/j.1742-4658.2007.05913.x

A 6A,6A¢-dicyclohexylamine-6B,6B¢-diselenide-bis-b-cyclodextrin (6-CySeCD)

was designed and synthesized to imitate the antioxidant enzyme glutathione

peroxidase (GPX). In this novel GPX model, b-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¢-di￾selenide-bis-cyclodextrin (6-SeCD) and 2-phenyl-1,2-benzoisoselenazol￾3(2H)-one (Ebselen) in the reduction of H2O2, tert-butyl hydroperoxide and

cumenyl hydroperoxide by glutathione, respectively. A ping-pong mechanism

was observed in steady-state kinetic studies on 6-CySeCD-catalyzed reac￾tions. The enzymatic properties showed that there are two major factors for

improving the catalytic efficiency of GPX mimics. First, the substrate-bind￾ing 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.

Abbreviations

BHT, 2,6-di-tert-butyl-4-methylphenol; b-CD, b-cyclodextrin; 6-CySeCD, 6A,6A¢-dicyclohexylamine-6B,6B¢-diselenide-bis-b-cyclodextrin;

CumOOH, cumenyl hydroperoxide; Ebselen, 2-phenyl-1,2-benzoisoselenazol-3(2H)-one; GPX, glutathione peroxidase; GSH, glutathione;

6-SeCD, 6,6¢-diselenide-bis-cyclodextrin; TBARS, thiobarbituric acid reactive substances; t-BuOOH, tert-butyl hydroperoxide.

3846 FEBS Journal 274 (2007) 3846–3854 ª 2007 The Authors Journal compilation ª 2007 FEBS