Meclofenamic acid selectively inhibits FTO demethylation of m(6)A over ALKBH5

doi:10.1093/nar/gku1276

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	Meclofenamic acid selectively inhibits FTO demethylation of m(6)A over ALKBH5
	Huang, Yue 1; Yan, Jingli 2; Li, Qi 1; Li, Jiafei 1; Gong, Shouzhe 1; Zhou, Hu1 ; Gan, Jianhua 3; Jiang, Hualiang4 ; Jia, Gui-Fang 2; Luo, Cheng4
刊名	NUCLEIC ACIDS RESEARCH
	2015-01
卷号	43 期号:1 页码:373-384
ISSN号	0305-1048
DOI	10.1093/nar/gku1276
文献子类	Article
英文摘要	Two human demethylases, the fat mass and obesity-associated (FTO) enzyme and ALKBH5, oxidatively demethylate abundant N-6-methyladenosine (m(6)A) residues in mRNA. Achieving a method for selective inhibition of FTO over ALKBH5 remains a challenge, however. Here, we have identified meclofenamic acid (MA) as a highly selective inhibitor of FTO. MA is a non-steroidal, anti-inflammatory drug that mechanistic studies indicate competes with FTO binding for the m(6)A-containing nucleic acid. The structure of FTO/MA has revealed much about the inhibitory function of FTO. Our newfound understanding, revealed herein, of the part of the nucleotide recognition lid (NRL) in FTO, for example, has helped elucidate the principles behind the selectivity of FTO over ALKBH5. Treatment of HeLa cells with the ethyl ester form of MA (MA2) has led to elevated levels of m(6)A modification in mRNA. Our collective results highlight the development of functional probes of the FTO enzyme that will (i) enable future biological studies and (ii) pave the way for the rational design of potent and specific inhibitors of FTO for use in medicine.
资助项目	National Natural Science Foundation of China[91313303] ; National Natural Science Foundation of China[21372237] ; National Natural Science Foundation of China[21372022] ; National Natural Science Foundation of China[21210003] ; National Basic Research Program[2015CB910603] ; Hi-Tech Research and Development Program of China[2012AA020302]
WOS关键词	PROMOTE PROTEIN STABILITY ; OBESITY-ASSOCIATED FTO ; OXIDATIVE DEMETHYLATION ; CRYSTAL-STRUCTURES ; RNA DEMETHYLASE ; ALKYLATION DAMAGE ; ESCHERICHIA-COLI ; MESSENGER-RNA ; HISTONE DEMETHYLASES ; MAXIMUM-LIKELIHOOD
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	OXFORD UNIV PRESS
WOS记录号	WOS:000350207100037
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276752]
专题	药物发现与设计中心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药理学第三研究室
通讯作者	Yang, Cai-Guang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 2.Peking Univ, Synthet & Funct Biomol Ctr, Key Lab Bioorgan Chem & Mol Engn, Beijing Natl Lab Mol Sci,Minist Educ,Coll Chem &, Beijing 100871, Peoples R China; 3.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Huang, Yue,Yan, Jingli,Li, Qi,et al. Meclofenamic acid selectively inhibits FTO demethylation of m(6)A over ALKBH5[J]. NUCLEIC ACIDS RESEARCH,2015,43(1):373-384.
APA	Huang, Yue.,Yan, Jingli.,Li, Qi.,Li, Jiafei.,Gong, Shouzhe.,...&Yang, Cai-Guang.(2015).Meclofenamic acid selectively inhibits FTO demethylation of m(6)A over ALKBH5.NUCLEIC ACIDS RESEARCH,43(1),373-384.
MLA	Huang, Yue,et al."Meclofenamic acid selectively inhibits FTO demethylation of m(6)A over ALKBH5".NUCLEIC ACIDS RESEARCH 43.1(2015):373-384.