Crystal structures of isoorotate decarboxylases reveal a novel catalytic mechanism of 5-carboxyl-uracil decarboxylation and shed light on the search for DNA decarboxylase

	Crystal structures of isoorotate decarboxylases reveal a novel catalytic mechanism of 5-carboxyl-uracil decarboxylation and shed light on the search for DNA decarboxylase
	Xu, ST; Li, WJ; Zhu, JJ; Wang, R; Li, Z; Xu, GL; Ding, JP
刊名	CELL RESEARCH
	2013
卷号	23 期号:11 页码:1296-1309
关键词	catalytic mechanism crystal structure DNA demethylation DNA decarboxylation decarboxylase pyrimidine metabolism thymidine salvage pathway
通讯作者	Ding, JP (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai 200031, Peoples R China.,jpding@sibcb.ac.cn
英文摘要	DNA methylation and demethylation regulate many crucial biological processes in mammals and are linked to many diseases. Active DNA demethylation is believed to be catalyzed by TET proteins and a putative DNA decarboxylase that may share some similarities in sequence, structure and catalytic mechanism with isoorotate decarboxylase (IDCase) that catalyzes decarboxylation of 5caU to U in fungi. We report here the structures of wild-type and mutant IDCases from Cordyceps militaris and Metarhizium anisopliae in apo form or in complexes with 5caU, U, and an inhibitor 5-nitro-uracil. IDCases adopt a typical (beta/alpha)(8) barrel fold of the amidohydrolase superfamily and function as dimers. A Zn2+ is bound at the active site and coordinated by four strictly conserved residues, one Asp and three His. The substrate is recognized by several strictly conserved residues. The functional roles of the key residues at the active site are validated by mutagenesis and biochemical studies. Based on the structural and biochemical data, we present for the first time a novel catalytic mechanism of decarboxylation for IDCases, which might also apply to other members of the amidohydrolase superfamily. In addition, our biochemical data show that IDCases can catalyzes decarboxylation of 5caC to C albeit with weak activity, which is the first in vitro evidence for direct decarboxylation of 5caC to C by an enzyme. These findings are valuable in the identification of potential DNA decarboxylase in mammals.
学科主题	Cell Biology
类目[WOS]	Cell Biology
关键词[WOS]	EPSILON-SEMIALDEHYDE DECARBOXYLASE ; THYMIDINE SALVAGE PATHWAY ; THYMINE 7-HYDROXYLASE ; ENZYMATIC CONVERSION ; THYMIDYLATE SYNTHASE ; ADENOSINE-DEAMINASE ; CYTOSINE DEAMINASE ; NEUROSPORA-CRASSA ; MAMMALIAN DNA ; TET PROTEINS
收录类别	SCI
语种	英语
WOS记录号	WOS:000326683600011
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/443]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Xu, ST,Li, WJ,Zhu, JJ,et al. Crystal structures of isoorotate decarboxylases reveal a novel catalytic mechanism of 5-carboxyl-uracil decarboxylation and shed light on the search for DNA decarboxylase[J]. CELL RESEARCH,2013,23(11):1296-1309.
APA	Xu, ST.,Li, WJ.,Zhu, JJ.,Wang, R.,Li, Z.,...&Ding, JP.(2013).Crystal structures of isoorotate decarboxylases reveal a novel catalytic mechanism of 5-carboxyl-uracil decarboxylation and shed light on the search for DNA decarboxylase.CELL RESEARCH,23(11),1296-1309.
MLA	Xu, ST,et al."Crystal structures of isoorotate decarboxylases reveal a novel catalytic mechanism of 5-carboxyl-uracil decarboxylation and shed light on the search for DNA decarboxylase".CELL RESEARCH 23.11(2013):1296-1309.