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Modulating the Substrate Specificity of LTA4H Aminopeptidase by Using Chemical Compounds and Small-Molecule-Guided Mutagenesis
Jiang, Xiaolu1; Zhou, Lu1; Wu, Yiran1,2; Wei, Dengguo1,2; Sun, Chunyi1; Jia, Jia1; Liu, Ying1; Lai, Luhua1,2
2010-05-17
Source PublicationCHEMBIOCHEM
ISSN1439-4227
Volume11Issue:8Pages:1120-1128
AbstractLeukotriene A(4) hydrolase (LTA4H) is a bifunctional zinc-containing enzyme with an epoxide hydrolase activity and an aminopeptidase activity of unclear function. The two activities occupy different, but overlapping sites. In this study we have focused on the non-overlapping regions of these sites and have found that a series of previously reported compounds-diphenyl ether, 4-phenoxyphenol, and their derivatives-can change the substrate specificity of LTA4H aminopeptidase, from arginyl peptide to alanyl peptide. The possible substrate specificity alteration mechanism was studied with the aid of molecular modeling and site-directed mutagenesis. Furthermore, several mutants that show different substrate specificity, such as F314E and V367W, were successfully designed by using the proposed small-molecule binding site as a model. F314E behaves as a highly selective aminopeptidase towards arginyl peptides with a selectivity increase of 850-fold, whereas V367W prefers alanyl peptides over arginyl peptides, just as the organic modulators do.
KeywordAminopeptidase Activity Hydrolases Protein Engineering Selectivity Small Molecules
DOI10.1002/cbic.200900788
Indexed BySCI
Language英语
WOS IDWOS:000278482200014
PublisherWILEY-V C H VERLAG GMBH
Citation statistics
Cited Times:9[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.iccas.ac.cn/handle/121111/69954
Collection中国科学院化学研究所
Corresponding AuthorLai, Luhua
Affiliation1.Peking Univ, Coll Chem & Mol Engn, State Key Lab Struct Chem Unstable & Stable Speci, Beijing Natl Lab Mol Sci, Beijing 100871, Peoples R China
2.Peking Univ, Ctr Theoret Biol, Beijing 100871, Peoples R China
Recommended Citation
GB/T 7714
Jiang, Xiaolu,Zhou, Lu,Wu, Yiran,et al. Modulating the Substrate Specificity of LTA4H Aminopeptidase by Using Chemical Compounds and Small-Molecule-Guided Mutagenesis[J]. CHEMBIOCHEM,2010,11(8):1120-1128.
APA Jiang, Xiaolu.,Zhou, Lu.,Wu, Yiran.,Wei, Dengguo.,Sun, Chunyi.,...&Lai, Luhua.(2010).Modulating the Substrate Specificity of LTA4H Aminopeptidase by Using Chemical Compounds and Small-Molecule-Guided Mutagenesis.CHEMBIOCHEM,11(8),1120-1128.
MLA Jiang, Xiaolu,et al."Modulating the Substrate Specificity of LTA4H Aminopeptidase by Using Chemical Compounds and Small-Molecule-Guided Mutagenesis".CHEMBIOCHEM 11.8(2010):1120-1128.
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