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Journal of Biochemistry Advance Access published online on November 1, 2007
Journal of Biochemistry, doi:10.1093/jb/mvm194
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© 2007 The Japanese Biochemical Society

Enzymatic Characterization and Inhibitor Discovery of a new Cystathionine ({gamma}-Synthase (CGS) from Helicobacter pylori

Yunhua Kong1,#, Dalei Wu1,#, Haiyun Bai1, Cong Han1, Jing Chen1, Lili Chen1, Lihong Hu1,2, Hualiang Jiang1,2 and Xu Shen*,1,2

1Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, 2School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China

*To whom correspondence should be addressed: Prof. Xu Shen, Tel&Fax: +86-21-50806918, E-mail: xshen{at}mail.shcnc.ac.cn

Received September 9, 2007; Accepted October 1, 2007


  Abstract

Summary:

Cystathionine {gamma}-synthase (CGS) catalyzes the first step of the transsulfuration pathway that converts L-cysteine to L-homocysteine in bacteria, whereas this pathway is absent in human. In this report, we identified a new metB gene from H. pyloristrain SS1, and the recombinant H. pylori Cystathionine {gamma}-synthase (HpCGS) was successfully cloned, expressed and purified in E. coli system. Enzymatic study of HpCGS indicated that the Km and kcat/Km values against the substrate O-succinyl-L-homoserine (L-OSHS) were 3.02 mM and 98.7 M-1s-1 respectively. Moreover, four natural products ({alpha}-lapachone, 9-hydroxy-{alpha}-lapachone, Paulownin, and Yangambin, Fig. 1) were discovered to demonstrate inhibitory activities against HpCGS with IC50 values of 11 ± 3, 9 ± 1, 19 ± 2 and 27 ± 6 µM, respectively. All these four inhibitors prevent the binding of L-OSHS to HpCGS in a noncompetitive fashion. In vitro antibacterial assays further indicated that these four discovered compounds could highly inhibit the growth of H. pylori and exhibited strong inhibitory specificity against H. pylori related to E. coli.

Key Words: cystathionine {gamma}-synthase, Helicobacter pylori, inhibitor, minimum inhibition concentration, inhibitor type, transsulfuration

#These authors contributed equally.


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