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Structural and Functional Analysis of the Loading Acyltransferase from Avermectin Modular Polyketide Synthase
Wang, Fen1; Wang, Yanjie1; Ji, Junjie1; Zhou, Zhan1; Yu, Jingkai1; Zhu, Hua2; Su, Zhiguo1; Zhang, Lixin2; Zheng, Jianting1
2015-04-01
Source PublicationACS Chemical Biology
ISSN1554-8929
Volume10Issue:4Pages:1017-1025
AbstractThe loading acyltransferase (AT) domains of modular polyketide synthases (PKSs) control the choice of starter units incorporated into polyketides and are therefore attractive targets for the engineering of modular PKSs. Here, we report the structural and biochemical characterizations of the loading AT from avermectin modular PKS, which accepts more than 40 carboxylic acids as alternative starter units for the biosynthesis of a series of congeners. This first structural analysis of loading ATs from modular PKSs revealed the molecular basis for the relaxed substrate specificity. Residues important for substrate binding and discrimination were predicted by modeling a substrate into the active site. A mutant with altered specificity toward a panel of synthetic substrate mimics was generated by site-directed mutagenesis of the active site residues. The hydrolysis of the N-acetylcysteamine thioesters of racemic 2-methylbutyric acid confirmed the stereospecificity of the avermectin loading AT for an S configuration at the C-2 position of the substrate. Together, these results set the stage for region-specific modification of polyketides through active site engineering of loading AT domains of modular PKSs.
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
DOI10.1021/cb500873k
Indexed BySCI
Language英语
WOS KeywordFATTY-ACID SYNTHASE ; SUBSTRATE-SPECIFICITY ; CRYSTAL-STRUCTURE ; PROTEIN INTERACTIONS ; ACTIVE-SITE ; BIOSYNTHESIS ; DOMAIN ; KETOREDUCTASES ; TRANSACYLASE ; BORRELIDIN
WOS Research AreaBiochemistry & Molecular Biology
WOS SubjectBiochemistry & Molecular Biology
WOS IDWOS:000353315100014
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Document Type期刊论文
Identifierhttp://ir.ipe.ac.cn/handle/122111/16735
Collection生化工程国家重点实验室
Affiliation1.Chinese Acad Sci, Inst Proc Engn, Natl Key Lab Biochem Engn, Beijing 100190, Peoples R China
2.Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, Beijing 100101, Peoples R China
Recommended Citation
GB/T 7714
Wang, Fen,Wang, Yanjie,Ji, Junjie,et al. Structural and Functional Analysis of the Loading Acyltransferase from Avermectin Modular Polyketide Synthase[J]. ACS Chemical Biology,2015,10(4):1017-1025.
APA Wang, Fen.,Wang, Yanjie.,Ji, Junjie.,Zhou, Zhan.,Yu, Jingkai.,...&Zheng, Jianting.(2015).Structural and Functional Analysis of the Loading Acyltransferase from Avermectin Modular Polyketide Synthase.ACS Chemical Biology,10(4),1017-1025.
MLA Wang, Fen,et al."Structural and Functional Analysis of the Loading Acyltransferase from Avermectin Modular Polyketide Synthase".ACS Chemical Biology 10.4(2015):1017-1025.
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