Biochemical characterization and inhibitor discovery of shikimate dehydrogenase from Helicobacter pylori
文献类型：期刊论文
| 作者 | Han, Cong; Wang, Lirui; Yu, Kunqian ; Chen, Lili; Hu, Lihong; Chen, Kaixian; Jiang, Hualiang; Shen, Xu
|
| 刊名 | FEBS JOURNAL
 |
| 出版日期 | 2006-10 |
| 卷号 | 273期号:20页码:4682-4692 |
| 关键词 | antibacterial agent drug target enzyme inhibition Helicobacter pylori shikimate dehydrogenase |
| ISSN号 | 1742-464X |
| DOI | 10.1111/j.1742-4658.2006.05469.x |
| 文献子类 | Article |
| 英文摘要 | Shikimate dehydrogenase (SDH) is the fourth enzyme involved in the shikimate pathway. It catalyzes the NADPH-dependent reduction of 3-dehydroshikimate to shikimate, and has been developed as a promising target for the discovery of antimicrobial agent. In this report, we identified a new aroE gene encoding SDH from Helicobacter pylori strain SS1. The recombinant H. pylori shikimate dehydrogenase (HpSDH) was cloned, expressed, and purified in Escherichia coli system. The enzymatic characterization of HpSDH demonstrates its activity with k(cat) of 7.7 s(-1) and K-m of 0.148 mM toward shikimate, k(cat) of 7.1 s(-1) and K-m of 0.182 mM toward NADP, k(cat) of 5.2 s(-1) and K-m of 2.9 mM toward NAD. The optimum pH of the enzyme activity is between 8.0 and 9.0, and the optimum temperature is around 60 degrees C. Using high throughput screening against our laboratory chemical library, five compounds, curcumin (1), 3-(2-naphthyloxy)-4-oxo-2-(trifluoromethyl)-4H-chromen-7-yl 3-chlorobenzoate (2), butyl 2-{[3-(2-naphthyloxy)-4-oxo-2-(trifluoromethyl)-4H-chromen-7-yl]oxy}propanoate (3), 2-({2-[(2-{[2-(2,3-dimethylanilino)-2-oxoethyl]sulfanyl}-1,3-benzothiazol-6-yl)amino]-2-oxoethyl}sulfanyl)-N-(2-naphthyl)acetamide (4), and maesaquinone diacetate (5) were discovered as HpSDH inhibitors with IC50 values of 15.4, 3.9, 13.4, 2.9, and 3.5 mu M, respectively. Further investigation indicates that compounds 1, 2, 3, and 5 demonstrate noncompetitive inhibition pattern, and compound 4 displays competitive inhibition pattern with respect to shikimate. Compounds 1, 4, and 5 display noncompetitive inhibition mode, and compounds 2 and 3 show competitive inhibition mode with respect to NADP. Antibacterial assays demonstrate that compounds 1, 2, and 5 can inhibit the growth of H. pylori with MIC of 16, 16, and 32 mu g.mL(-1), respectively. This current work is expected to favor better understanding the features of SDH and provide useful information for the development of novel antibiotics to treat H. pylori-associated infection. |
| WOS关键词 | AMINO-ACID BIOSYNTHESIS ; MYCOBACTERIUM-TUBERCULOSIS ; CRYSTAL-STRUCTURE ; CHORISMATE SYNTHASE ; DRUG DESIGN ; PATHWAY ; 5-DEHYDROGENASE ; DEHYDROQUINASE ; ERADICATION ; SEQUENCE |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000240918900008 |
| 出版者 | BLACKWELL PUBLISHING |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273480]  |
| 专题 | 药理学第三研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Hu, Lihong |
| 作者单位 | 1.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Han, Cong,Wang, Lirui,Yu, Kunqian,et al. Biochemical characterization and inhibitor discovery of shikimate dehydrogenase from Helicobacter pylori[J]. FEBS JOURNAL,2006,273(20):4682-4692. |
| APA | Han, Cong.,Wang, Lirui.,Yu, Kunqian.,Chen, Lili.,Hu, Lihong.,...&Shen, Xu.(2006).Biochemical characterization and inhibitor discovery of shikimate dehydrogenase from Helicobacter pylori.FEBS JOURNAL,273(20),4682-4692. |
| MLA | Han, Cong,et al."Biochemical characterization and inhibitor discovery of shikimate dehydrogenase from Helicobacter pylori".FEBS JOURNAL 273.20(2006):4682-4692. |
入库方式： OAI收割
来源：上海药物研究所
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