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

CORC > 生态环境研究中心 > 中国科学院生态环境研究中心 > 环境化学与生态毒理学国家重点实验室

	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
	Qin, Li ; Huang, Chun-Hua ; Xu, Dan ; Xie, Lin-Na ; Shao, Jie ; Mao, Li ; Kalyanaraman, Balaraman 4; Zhu, Ben-Zhan
刊名	FREE RADICAL BIOLOGY AND MEDICINE
	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.
内容类型	期刊论文
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.Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA 2.Chinese Acad Sci, State Key Lab Environm Chem & Ecotoxicol, Res Ctr Ecoenvironm Sci, Beijing 100085, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Chinese Ctr Dis Control & Prevent, Natl Inst Environm Hlth, Beijing, Peoples R China 5.Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 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.