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Chemical Diversification Based on Substrate Promiscuity of a Standalone Adenylation Domain in a Reconstituted NRPS System
Zhu, Mengyi; Wang, Lijuan1; He, Jing
2019
Source PublicationACS CHEMICAL BIOLOGY
ISSN1554-8929
Volume14Issue:2Pages:256
AbstractA nonribosomal peptide synthetase (NRPS) assembly line (sfa) in Streptomyces thioluteus that directs the formation of the diisonitrile chalkophore SF2768 (1) has been characterized by heterologous expression and directed gene knockouts. Herein, differential metabolic analysis of the heterologous expression strain and the original host led to the isolation of an SF2768 analogue (2, a byproduct of sfa) that possesses N-isovaleryl rather than 3-isocyanobutyryl side chains. The proposed biosynthetic logic of sfa and the structural difference between 1 and 2 suggested substrate promiscuity of the adenylate-forming enzyme SfaB. Further substrate scope investigation of SfaB and a successfully reconstituted NRPS system including a four-enzyme cascade enabled incorporation of diverse carboxylic acid building blocks into peptide scaffolds, and 30 unnatural products were thus generated. This structural diversification strategy based on substrate flexibility of the adenylation domain and in vitro reconstitution can be applied to other adenylation-priming pathways, thus providing a supplementary method for diversity-oriented total synthesis. Additionally, the biocatalytic process of the putative lysine S-hydroxylase SfaE was validated through the derivatization of two key aldehyde intermediates (2a and 2b), thereby expanding the toolkit of enzymatic C-H bond activation.
DepartmentLMB
DOI10.1021/acschembio.8b00938
Citation statistics
Cited Times:5[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.scsio.ac.cn/handle/344004/17908
Collection中科院海洋生物资源可持续利用重点实验室
Affiliation1.Huazhong Agr Univ, Coll Life Sci & Technol, State Key Lab Agr Microbiol, Wuhan 430070, Hubei, Peoples R China
2.Chinese Acad Sci, South China Sea Inst Oceanol, Guangdong Key Lab Marine Mat Med, CAS Key Lab Trop Marine Bioresources & Ecol,RNAM, 164 West Xingang Rd, Guangzhou 510301, Guangdong, Peoples R China
Recommended Citation
GB/T 7714
Zhu, Mengyi,Wang, Lijuan,He, Jing. Chemical Diversification Based on Substrate Promiscuity of a Standalone Adenylation Domain in a Reconstituted NRPS System[J]. ACS CHEMICAL BIOLOGY,2019,14(2):256, 265.
APA Zhu, Mengyi,Wang, Lijuan,&He, Jing.(2019).Chemical Diversification Based on Substrate Promiscuity of a Standalone Adenylation Domain in a Reconstituted NRPS System.ACS CHEMICAL BIOLOGY,14(2),256.
MLA Zhu, Mengyi,et al."Chemical Diversification Based on Substrate Promiscuity of a Standalone Adenylation Domain in a Reconstituted NRPS System".ACS CHEMICAL BIOLOGY 14.2(2019):256.
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