期刊
ACS SYNTHETIC BIOLOGY
卷 4, 期 5, 页码 559-565出版社
AMER CHEMICAL SOC
DOI: 10.1021/sb5003136
关键词
antimycin biosynthesis; nonribosomal peptide/polyketide hybrid; heterologous expression; 3-formamidosalicylate; multicomponent oxygenase; formyltransferase
资金
- Pew Scholars Program
- University of California Cancer Research Coordinating Committee funds
- New Lecturer Startup Fund - University of Leeds
Antimycins are a family of natural products generated from a hybrid nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) assembly line. Although they possess an array of useful biological activities, their structural complexity makes chemical synthesis challenging, and their biosynthesis has thus far been dependent on slow-growing source organisms. Here, we reconstituted the biosynthesis of antimycins in Escherichia coli, a versatile host that is robust and easy to manipulate genetically. Along with Streptomyces genetic studies, the heterologous expression of different combinations of ant genes enabled us to systematically confirm the functions of the modification enzymes, AntHIJKL and AntO, in the biosynthesis of the 3-formamidosalicylate pharmacophore of antimycins. Our E. coli-based antimycin production system can not only be used to engineer the increased production of these bioactive compounds, but it also paves the way for the facile generation of novel and diverse antimycin analogues through combinatorial biosynthesis.
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