Post-transfer editing by a eukaryotic leucyl-tRNA synthetase resistant to the broad-spectrum drug AN2690

	Post-transfer editing by a eukaryotic leucyl-tRNA synthetase resistant to the broad-spectrum drug AN2690
	Zhou, XL; Tan, M; Wang, M; Chen, X; Wang, ED
刊名	BIOCHEMICAL JOURNAL
	2010
卷号	430 期号:1 页码:325-333
关键词	connective peptide 1 domain (CP1 domain) editing eukarya-specific insertion 1 (ESI) Giardia lamblia leucyl-tRNA synthetase
通讯作者	Wang, ED (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, 320 Yue Yang Rd, Shanghai 200031, Peoples R China.,edwang@sibs.ac.cn
英文摘要	Some aaRSs (aminoacyl-tRNA synthetases) develop editing mechanisms to correct mis-charged tRNA. The CP1 (connective peptide 1) domain of LeuRS (leucyl-tRNA synthetase) contains the editing active site, which is the proven target for the broad-spectrum drug AN2690 (5-fluoro-1,3-dihydro-l-hydroxy-2,1-benzoxaborole). The ESI (eukarya-specific insertion 1) in the CP1 domain of G/LeuRS (Giardia lamblia LeuRS) has been identified. Similar substitution with the ESI from HsLeuRS (Homo sapiens LeuRS) impeded the leucine activation, aminoacylation and post-transfer editing of the enzyme, but had no effect on the editing specificity toward non-specific amino acids. The(341) in G/LeuRS served as a specificity discriminator, as found in other LeuRS systems, although its substitution with an alanine residue did not destroy Leu-tRNA(Leu) synthesis in vitro and in vivo. The Arg(338) was crucial for tRNA(Leu) charging and the Asp(440) was crucial for leucine activation and aminoacylation. The post-transfer editing required the CTD (C-terminal domain), Arg(338) and Asp(440) of G/LeuRS. Interestingly, G/LeuRS was completely resistant to the AN2690, which is an inhibitor of various LeuRSs. The universally conserved aspartate residue in the LeuRS CP1 domains was responsible for the resistance of G/LeuRS and another recently reported AN2690-resistant AaLeuRS (Aquifex aeolicus LeuRS). Our results indicate the functional divergence of some absolutely conserved sites, improve the understanding of the editing function of eukaryotic/archaeal LeuRSs and shed light on the development of a G/LeuRS-specific inhibitor for the treatment of giardiasis.
学科主题	Biochemistry & Molecular Biology
类目[WOS]	Biochemistry & Molecular Biology
关键词[WOS]	STRUCTURAL BASIS ; GIARDIA-LAMBLIA ; CRYSTAL-STRUCTURES ; CELL VIABILITY ; CP1 DOMAIN ; L-VALINE ; DISCRIMINATION ; TRNA(LEU) ; COMPLEX ; THREONINE
收录类别	SCI
语种	英语
WOS记录号	WOS:000281490200016
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/1110]
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	Zhou, XL,Tan, M,Wang, M,et al. Post-transfer editing by a eukaryotic leucyl-tRNA synthetase resistant to the broad-spectrum drug AN2690[J]. BIOCHEMICAL JOURNAL,2010,430(1):325-333.
APA	Zhou, XL,Tan, M,Wang, M,Chen, X,&Wang, ED.(2010).Post-transfer editing by a eukaryotic leucyl-tRNA synthetase resistant to the broad-spectrum drug AN2690.BIOCHEMICAL JOURNAL,430(1),325-333.
MLA	Zhou, XL,et al."Post-transfer editing by a eukaryotic leucyl-tRNA synthetase resistant to the broad-spectrum drug AN2690".BIOCHEMICAL JOURNAL 430.1(2010):325-333.