Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase

doi:10.1038/nature09497

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第三研究室

	Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase
	Yi, Chengqi 2,5; Jia, Guifang 2,5; Hou, Guanhua 3,4; Dai, Qing 1; Zhang, Wen 2,5; Zheng, Guanqun 2,5; Jian, Xing 2,5; Yang, Cai-Guang2,5,6 ; Cui, Qiang 3,4; He, Chuan 2,5
刊名	NATURE
	2010-11-11
卷号	468 期号:7321 页码:330-U223
ISSN号	0028-0836
DOI	10.1038/nature09497
文献子类	Article
英文摘要	Mononuclear iron-containing oxygenases conduct a diverse variety of oxidationfunctions in biology(1,2), includingthe oxidative demethylation of methylated nucleic acids and histones(3,4). Escherichia coli AlkB is the first such enzyme that was discovered to repair methylated nucleic acids(5,6), which are otherwise cytotoxic and/or mutagenic. AlkB human homologues are known to play pivotal roles in various processes(7-11). Here we present structural characterization of oxidation intermediates for these demethylases. Using a chemical cross-linking strategy(12,13), complexes of AlkB-double stranded DNA (dsDNA) containing 1,N-6-etheno adenine (epsilon A), N-3-methyl thymine (3-meT) and N-3-methyl cytosine (3-meC) are stabilized and crystallized, respectively. Exposing these crystals, grown under anaerobic conditions containing iron(II) and alpha-ketoglutarate (alpha KG), to dioxygen initiates oxidation in crystallo. Glycol (from epsilon A) and hemiaminal (from 3-meT) intermediates are captured; a zwitterionic intermediate (from 3-meC) is also proposed, based on crystallographic observations and computational analysis. The observation of these unprecedented intermediates provides direct support for the oxidative demethylation mechanism for these demethylases. This study also depicts a general mechanistic view of how a methyl group is oxidatively removed from different biological substrates.
资助项目	National Institutes of Health[GM071440] ; National Institutes of Health[GM084028] ; Advanced Photon Source at Argonne National Laboratory[00000000] ; United States Department of Energy[00000000]
WOS关键词	BASE-EXCISION-REPAIR ; ESCHERICHIA-COLI ; CRYSTAL-STRUCTURES ; ALKB PROTEINS ; ENZYME ALKB ; FTO GENE ; DEMETHYLATION ; DAMAGE ; 3-METHYLTHYMINE ; RECOGNITION
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000284051000056
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278721]
专题	药理学第三研究室
通讯作者	He, Chuan
作者单位	1.Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA; 2.Univ Chicago, Dept Chem, Chicago, IL 60637 USA; 3.Univ Wisconsin, Inst Theoret Chem, Madison, WI 53706 USA; 4.Univ Wisconsin, Dept Chem, Madison, WI 53706 USA; 5.Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA; 6.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Yi, Chengqi,Jia, Guifang,Hou, Guanhua,et al. Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase[J]. NATURE,2010,468(7321):330-U223.
APA	Yi, Chengqi.,Jia, Guifang.,Hou, Guanhua.,Dai, Qing.,Zhang, Wen.,...&He, Chuan.(2010).Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase.NATURE,468(7321),330-U223.
MLA	Yi, Chengqi,et al."Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase".NATURE 468.7321(2010):330-U223.