Isoquinoline-1,3,4-trione Derivatives Inactivate Caspase-3 by Generation of Reactive Oxygen Species
文献类型：期刊论文
| 作者 | Du, JQ; Wu, J; Zhang, HJ; Zhang, YH; Qiu, BY; Wu, F; Chen, YH; Li, JY; Nan, FJ; Ding, JP |
| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
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| 出版日期 | 2008 |
| 卷号 | 283期号:44页码:30205-30215 |
| 通讯作者 | Nan, FJ (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, Chinese Natl Ctr Drug Screening, 189 Guo Shou Jing Rd,Zhangjiang Hi Tech Pk, Shanghai 201203, Peoples R China.,fjnan@mail.shcnc.ac.cn |
| 英文摘要 | Caspase-3 is an attractive therapeutic target for treatment of diseases involving disregulated apoptosis. We report here the mechanism of caspase-3 inactivation by isoquinoline-1,3,4-trione derivatives. Kinetic analysis indicates the compounds can irreversibly inactivate caspase-3 in a 1,4-dithiothreitol (DTT)- and oxygen-dependent manner, implying that a redox cycle might take place in the inactivation process. Reactive oxygen species detection experiments using a chemical indicator, together with electron spin resonance measurement, suggest that ROS can be generated by reaction of isoquinoline-1,3,4-trione derivatives with DTT. Oxygen-free radical scavenger catalase and superoxide dismutase eliciting the inactivation of caspase-3 by the inhibitors confirm that ROS mediates the inactivation process. Crystal structures of caspase-3 in complexes with isoquinoline-1,3,4-trione derivatives show that the catalytic cysteine is oxidized to sulfonic acid (-SO3H) and isoquinoline-1,3,4-trione derivatives are bound at the dimer interface of caspase-3. Further mutagenesis study shows that the binding of the inhibitors with caspase-3 appears to be nonspecific. Isoquinoline-1,3,4-trione derivative-catalyzed caspase-3 inactivation could also be observed when DTT is substituted with dihydrolipoic acid, which exists widely in cells and might play an important role in the in vivo inactivation process in which the inhibitors inactivate caspase-3 in cells and then prevent the cells from apoptosis. These results provide valuable information for further development of small molecular inhibitors against caspase-3 or other oxidation-sensitive proteins. |
| 学科主题 | Biochemistry & Molecular Biology |
| 类目[WOS] | Biochemistry & Molecular Biology |
| 关键词[WOS] | SELECTIVE NONPEPTIDE INHIBITORS ; HYDROGEN-PEROXIDE ; INDUCED APOPTOSIS ; LIPOIC ACID ; POTENT ; CELLS ; SPECIFICITY ; DISCOVERY ; OXIDATION ; FEATURES |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000260366900065 |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.143/handle/331003/1480]  |
| 专题 | 上海生化细胞研究所_上海生科院生化细胞研究所 |
| 推荐引用方式 GB/T 7714 | Du, JQ,Wu, J,Zhang, HJ,et al. Isoquinoline-1,3,4-trione Derivatives Inactivate Caspase-3 by Generation of Reactive Oxygen Species[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2008,283(44):30205-30215. |
| APA | Du, JQ.,Wu, J.,Zhang, HJ.,Zhang, YH.,Qiu, BY.,...&Li, J.(2008).Isoquinoline-1,3,4-trione Derivatives Inactivate Caspase-3 by Generation of Reactive Oxygen Species.JOURNAL OF BIOLOGICAL CHEMISTRY,283(44),30205-30215. |
| MLA | Du, JQ,et al."Isoquinoline-1,3,4-trione Derivatives Inactivate Caspase-3 by Generation of Reactive Oxygen Species".JOURNAL OF BIOLOGICAL CHEMISTRY 283.44(2008):30205-30215. |
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