Molecular mechanism for the activation of the anti-tuberculosis drug isoniazid by Mn(III): First detection and unequivocal identification of the critical N-centered isoniazidyl radical and its exact location
文献类型：期刊论文
| 作者 | Qin, Li; Huang, Chun-Hua; Xu, Dan; Xie, Lin-Na; Shao, Jie; Mao, Li; Kalyanaraman, Balaraman1; Zhu, Ben-Zhan |
| 刊名 | FREE RADICAL BIOLOGY AND MEDICINE
 |
| 出版日期 | 2019-11-01 |
| 卷号 | 143页码:232-239 |
| 关键词 | Isoniazid Mn(III)(Acetate) 3 Isoniazidyl radical Distal-nitrogen of the hydrazine group Diisonicotinyl hydrazine |
| ISSN号 | 0891-5849 |
| 英文摘要 | Isoniazid (INH), the most-widely used anti-tuberculosis drug, has been shown to be activated by Mn(III) to produce the reactive carbon-centered isonicotinic acyl radical, which was considered to be responsible for its anti-tuberculosis activity. However, it is still not clear whether the previously-proposed N-centered isoniazidyl radical intermediate can be initially produced or not; and if so, what is its exact location on the hydrazine group, distal- or proximal-nitrogen? Through complementary applications of ESR spin-trapping and HPLC/MS methods, here we show that the characteristic and transient N-centered isoniazidyl radical intermediate can be detected and identified from INH activation uniquely by Mn(III)Acetate not by Mn(III) pyrophosphate. The exact location of the radical was found to be at the distal-nitrogen of the hydrazine group by N-15-isotope-labeling techniques via using N-15-labeled INH. Diisonicotinyl hydrazine was identified as a new reaction product from INH/Mn(III). Analogous results were observed with other hydrazides. This study represents the first detection and unequivocal identification of the initial N-centered isoniazidyl radical and its exact location. These findings should provide a new perspective on the molecular mechanism of INH activation, which may have broad biomedical and toxicological significance for future research for more efficient hydrazide anti-tuberculosis drugs. |
| 源URL | [http://ir.rcees.ac.cn/handle/311016/42563]  |
| 专题 | 生态环境研究中心_环境化学与生态毒理学国家重点实验室 |
| 作者单位 | 1.Chinese Ctr Dis Control & Prevent, Natl Inst Environm Hlth, Beijing, Peoples R China 2.Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA 3.Chinese Acad Sci, State Key Lab Environm Chem & Ecotoxicol, Res Ctr Ecoenvironm Sci, Beijing 100085, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA |
| 推荐引用方式 GB/T 7714 | Qin, Li,Huang, Chun-Hua,Xu, Dan,et al. Molecular mechanism for the activation of the anti-tuberculosis drug isoniazid by Mn(III): First detection and unequivocal identification of the critical N-centered isoniazidyl radical and its exact location[J]. FREE RADICAL BIOLOGY AND MEDICINE,2019,143:232-239. |
| APA | Qin, Li.,Huang, Chun-Hua.,Xu, Dan.,Xie, Lin-Na.,Shao, Jie.,...&Zhu, Ben-Zhan.(2019).Molecular mechanism for the activation of the anti-tuberculosis drug isoniazid by Mn(III): First detection and unequivocal identification of the critical N-centered isoniazidyl radical and its exact location.FREE RADICAL BIOLOGY AND MEDICINE,143,232-239. |
| MLA | Qin, Li,et al."Molecular mechanism for the activation of the anti-tuberculosis drug isoniazid by Mn(III): First detection and unequivocal identification of the critical N-centered isoniazidyl radical and its exact location".FREE RADICAL BIOLOGY AND MEDICINE 143(2019):232-239. |
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来源：生态环境研究中心
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