Characterization of full length and truncated type I human methionine aminopeptidases expressed from Escherichia coli

doi:10.1021/bi0360859

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	Characterization of full length and truncated type I human methionine aminopeptidases expressed from Escherichia coli
	Li, Jing-Ya1 ; Chen, Ling-Ling 1; Cui, Yong-Mei 1; Luo, Qun-Li 1; Gu, Min1 ; Nan, Fa-Jun1 ; Ye, Qi-Zhuang 1,2
刊名	Biochemistry
	2004-06-22
卷号	43 期号:24 页码:7892-7898
ISSN号	00062960
DOI	10.1021/bi0360859
文献子类	Article
英文摘要	Methionine aminopeptidase (MetAP) carries out an essential posttranslational modification of nascent proteins by removing the initiator methionine and is recognized as a potential target for developing antibacterial, antifungal, and anticancer agents. We have established an Escherichia coli expression system for human type I MetAP (HsMetAP1) and characterized the full length HsMetAP1 and its N-terminal-truncated mutants HsMetAP1 (Δ1-66) and HsMetAP1 (Δ1-135) for hydrolysis of several thiopeptolide and peptide substrates and inhibition by a series of nonpeptidic inhibitors. Although the N-terminal extension with zinc finger motifs in HsMetAP1 is not required for enzyme activity, it has a significant impact on the interaction of the enzyme with substrates and inhibitors. In hydrolysis of the thiopeptolide substrates, a relaxation of stringent specificity for the terminal methionine was observed in the truncated mutants. However, this relaxation of specificity was not detectable in hydrolysis of tripeptide or tetrapeptide substrates. Several nonpeptidic inhibitors showed potent inhibition of the mutant HsMetAP1 (Δ1-66) but exhibited only weak or no inhibition of the full length enzyme. With the recombinant HsMetAP1 available, we have identified several MetAP inhibitors with submicromolar inhibitory potencies against E. coli MetAP (EcMetAP1) that do not affect HsMetAP1. These results have demonstrated the possibility of developing MetAP inhibitors as antibacterial agents with minimum human toxicity. In addition, micromolar inhibitors of HsMetAP1 identified in this study can serve as tools for investigating the functions of HsMetAP1 in physiological and pathological processes.
语种	英语
出版者	American Chemical Society
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/266992]
专题	国家新药筛选中心
通讯作者	Nan, Fa-Jun
作者单位	1.Chinese Natl. Ctr. Drug Screening, Shanghai Institute of Materia Medica, Shanghai Inst. for Biol. Sciences, Shanghai 201203, China; 2.High Throughput Screening Laboratory, Higuchi Biosciences Center, University of Kansas, Lawrence, KS 66047, United States
推荐引用方式 GB/T 7714	Li, Jing-Ya,Chen, Ling-Ling,Cui, Yong-Mei,et al. Characterization of full length and truncated type I human methionine aminopeptidases expressed from Escherichia coli[J]. Biochemistry,2004,43(24):7892-7898.
APA	Li, Jing-Ya.,Chen, Ling-Ling.,Cui, Yong-Mei.,Luo, Qun-Li.,Gu, Min.,...&Ye, Qi-Zhuang.(2004).Characterization of full length and truncated type I human methionine aminopeptidases expressed from Escherichia coli.Biochemistry,43(24),7892-7898.
MLA	Li, Jing-Ya,et al."Characterization of full length and truncated type I human methionine aminopeptidases expressed from Escherichia coli".Biochemistry 43.24(2004):7892-7898.