Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage

doi:10.1074/jbc.M115.711895

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

	Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage
	Li, Qi 2; Huang, Yue 2; Liu, Xichun 1,3; Gan, Jianhua 4; Chen, Hao 1,3; Yang, Cai-Guang2
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2016-05-20
卷号	291 期号:21 页码:11083-11093
关键词	bacteria cancer therapy chemical biology DNA repair DNA-protein interaction enzyme inhibitor enzyme structure
ISSN号	0021-9258
DOI	10.1074/jbc.M115.711895
文献子类	Article
英文摘要	The AlkB repair enzymes, including Escherichia coli AlkB and two human homologues, ALKBH2 and ALKBH3, are iron(II)- and 2-oxoglutarate-dependent dioxygenases that efficiently repair N-1-methyladenine and N-3-methylcytosine methylated DNA damages. The development of small molecule inhibitors of these enzymes has seen less success. Here we have characterized a previously discovered natural product rhein and tested its ability to inhibit AlkB repair enzymes in vitro and to sensitize cells to methyl methane sulfonate that mainly produces N-1-methyladenine and N-3-methylcytosine lesions. Our investigation of the mechanism of rhein inhibition reveals that rhein binds to AlkB repair enzymes in vitro and promotes thermal stability in vivo. In addition, we have determined a new structural complex of rhein bound to AlkB, which shows that rhein binds to a different part of the active site in AlkB than it binds to in fat mass and obesity-associated protein (FTO). With the support of these observations, we put forth the hypothesis that AlkB repair enzymes would be effective pharmacological targets for cancer treatment.
资助项目	National Natural Science Foundation of China[21372237] ; National Natural Science Foundation of China[91313303] ; National Basic Research Program[2015CB910603] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program" Grant[2014ZX09507009-01]
WOS关键词	PROMOTE PROTEIN STABILITY ; ESCHERICHIA-COLI ; ALKYLATION DAMAGE ; OXIDATIVE DEMETHYLATION ; CRYSTAL-STRUCTURES ; ADAPTIVE RESPONSE ; STRUCTURAL BASIS ; PROSTATE-CANCER ; STRANDED-DNA ; ACTIVE-SITE
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
WOS记录号	WOS:000377042100012
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276040]
专题	药理学第三研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Yang, Cai-Guang
作者单位	1.Nanjing Univ, Sch Chem & Chem Engn, State Key Lab Coordinat Chem, Nanjing 210093, Jiangsu, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Biol Chem Lab, Shanghai 201203, Peoples R China; 3.Nanjing Univ, Inst Coordinat Chem, Nanjing 210093, Jiangsu, Peoples R China; 4.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China
推荐引用方式 GB/T 7714	Li, Qi,Huang, Yue,Liu, Xichun,et al. Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2016,291(21):11083-11093.
APA	Li, Qi,Huang, Yue,Liu, Xichun,Gan, Jianhua,Chen, Hao,&Yang, Cai-Guang.(2016).Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage.JOURNAL OF BIOLOGICAL CHEMISTRY,291(21),11083-11093.
MLA	Li, Qi,et al."Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage".JOURNAL OF BIOLOGICAL CHEMISTRY 291.21(2016):11083-11093.