Elucidation of the Mechanism for the Substrate Preference of TET Proteins
文献类型：期刊论文
| 作者 | Lu Junyan2; Hu Lulu1; Cheng Jingdong1; Wang Chen2; Xu Yanhui1; Luo Cheng2
|
| 刊名 | Chinese Journal of Cell Biology
 |
| 出版日期 | 2016 |
| 卷号 | 38期号:1页码:1-6 |
| 关键词 | QM/MM epigenetics DNA methylation ten-eleven translocation (TET) proteins QM/MM |
| ISSN号 | 1674-7666 |
| 其他题名 | 阐明TET家族蛋白质底物偏好性机制 |
| 文献子类 | Review |
| 英文摘要 | Methylation of cytosine in DNA is considered as an important epigenetic marker, which takes part in various biological processes. Ten-eleven translocation (TET) proteins are key players involving in DNA demethylation through mediating the processive oxidation of 5-methylcytosine (5mC). It can convert 5mC to 5-hydroxymethylcytosine (5hmC), then to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). According to previous reports and our biochemical experiments, although TET2 could catalyze the oxidation of 5mC, 5hmC and 5fC, the catalytic effi ciencies are different. The effi ciency for 5mC is the highest while the effi ciency for 5fC is the lowest. Biochemical experiments and crystal structures all showed TET2 could recognize and bind to its different substrates with similar binding affinities. Structure modelling and QM/MM calculations suggested different orientations of the substrates bases on the hydrogen abstraction reaction step may result in substrate preference. Further biochemical experiments such as Kinetic isotope effect (KIE) experiments and Stopped-fl ow spectroscopy experiments validated the hypothesis and indicated the difference in catalytic effi ciencies indeed resulted from the differences in hydrogen abstraction rate. Our studies for the first time demonstrate that the substrate preference of TET2 results from the intrinsic value of its substrates at their 5mC derivative groups and suggest that 5hmC is relatively stable and less prone to further oxidation by TET proteins. In addition, it will light up the road for the development of small molecule regulators against TET proteins. |
| WOS研究方向 | Biochemistry & Molecular Biology (provided by Clarivate Analytics) |
| 语种 | 中文 |
| CSCD记录号 | CSCD:5647341 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/269257]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Luo Cheng |
| 作者单位 | 1.Shanghai Medical College of Fudan University, Shanghai 200032, China. 2.Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.; |
| 推荐引用方式 GB/T 7714 | Lu Junyan,Hu Lulu,Cheng Jingdong,et al. Elucidation of the Mechanism for the Substrate Preference of TET Proteins[J]. Chinese Journal of Cell Biology,2016,38(1):1-6. |
| APA | Lu Junyan,Hu Lulu,Cheng Jingdong,Wang Chen,Xu Yanhui,&Luo Cheng.(2016).Elucidation of the Mechanism for the Substrate Preference of TET Proteins.Chinese Journal of Cell Biology,38(1),1-6. |
| MLA | Lu Junyan,et al."Elucidation of the Mechanism for the Substrate Preference of TET Proteins".Chinese Journal of Cell Biology 38.1(2016):1-6. |
入库方式： OAI收割
来源：上海药物研究所
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