Chemical Diversification Based on Substrate Promiscuity of a Standalone Adenylation Domain in a Reconstituted NRPS System

doi:10.1021/acschembio.8b00938

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	Chemical Diversification Based on Substrate Promiscuity of a Standalone Adenylation Domain in a Reconstituted NRPS System
	Wang, Lijuan 2; Zhu, Mengyi ; He, Jing
刊名	ACS CHEMICAL BIOLOGY
	2019
卷号	14 期号:2 页码:256
ISSN号	1554-8929
DOI	10.1021/acschembio.8b00938
英文摘要	A 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.
内容类型	期刊论文
源URL	[http://ir.scsio.ac.cn/handle/344004/17908]
专题	南海海洋研究所_中科院海洋生物资源可持续利用重点实验室
作者单位	1.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 2.Huazhong Agr Univ, Coll Life Sci & Technol, State Key Lab Agr Microbiol, Wuhan 430070, Hubei, Peoples R China
推荐引用方式 GB/T 7714	Wang, Lijuan,Zhu, Mengyi,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	Wang, Lijuan,Zhu, Mengyi,&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	Wang, Lijuan,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.