Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage
文献类型：期刊论文
| 作者 | Li, Qi2; Huang, Yue2; Liu, Xichun1,3; Gan, Jianhua4; Chen, Hao1,3; Yang, Cai-Guang2
|
| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
 |
| 出版日期 | 2016-05-20 |
| 卷号 | 291期号:21页码:11083-11093 |
| 关键词 | bacteria cancer therapy chemical biology DNA repair DNA-protein interaction enzyme inhibitor enzyme structure |
| ISSN号 | 0021-9258 |
| DOI | 10.1074/jbc.M115.711895 |
| 文献子类 | Article |
| 英文摘要 | The AlkB repair enzymes, including Escherichia coli AlkB and two human homologues, ALKBH2 and ALKBH3, are iron(II)- and 2-oxoglutarate-dependent dioxygenases that efficiently repair N-1-methyladenine and N-3-methylcytosine methylated DNA damages. The development of small molecule inhibitors of these enzymes has seen less success. Here we have characterized a previously discovered natural product rhein and tested its ability to inhibit AlkB repair enzymes in vitro and to sensitize cells to methyl methane sulfonate that mainly produces N-1-methyladenine and N-3-methylcytosine lesions. Our investigation of the mechanism of rhein inhibition reveals that rhein binds to AlkB repair enzymes in vitro and promotes thermal stability in vivo. In addition, we have determined a new structural complex of rhein bound to AlkB, which shows that rhein binds to a different part of the active site in AlkB than it binds to in fat mass and obesity-associated protein (FTO). With the support of these observations, we put forth the hypothesis that AlkB repair enzymes would be effective pharmacological targets for cancer treatment. |
| WOS关键词 | PROMOTE PROTEIN STABILITY ; ESCHERICHIA-COLI ; ALKYLATION DAMAGE ; OXIDATIVE DEMETHYLATION ; CRYSTAL-STRUCTURES ; ADAPTIVE RESPONSE ; STRUCTURAL BASIS ; PROSTATE-CANCER ; STRANDED-DNA ; ACTIVE-SITE |
| 资助项目 | National Natural Science Foundation of China[21372237] ; National Natural Science Foundation of China[91313303] ; National Basic Research Program[2015CB910603] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program" Grant[2014ZX09507009-01] |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000377042100012 |
| 出版者 | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276040]  |
| 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 | Yang, Cai-Guang |
| 作者单位 | 1.Nanjing Univ, Sch Chem & Chem Engn, State Key Lab Coordinat Chem, Nanjing 210093, Jiangsu, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Biol Chem Lab, Shanghai 201203, Peoples R China; 3.Nanjing Univ, Inst Coordinat Chem, Nanjing 210093, Jiangsu, Peoples R China; 4.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Qi,Huang, Yue,Liu, Xichun,et al. Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2016,291(21):11083-11093. |
| APA | Li, Qi,Huang, Yue,Liu, Xichun,Gan, Jianhua,Chen, Hao,&Yang, Cai-Guang.(2016).Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage.JOURNAL OF BIOLOGICAL CHEMISTRY,291(21),11083-11093. |
| MLA | Li, Qi,et al."Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage".JOURNAL OF BIOLOGICAL CHEMISTRY 291.21(2016):11083-11093. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。