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From a Natural Product to Its Biosynthetic Gene Cluster: A Demonstration Using Polyketomycin from Streptomyces diastatochromogenes Tü6028
Published on: January 13, 2017
Elucidating the Biosynthetic Pathway of Lactone-Type Spirotetronate Polyketide PA-46101s with Inhibitory Activities
Li-Li Hong1,2, Yijia Cheng1, Wenyu Zhang1
1Department of Pharmacy, Ren Ji Hospital, College of Clinical Pharmacy, State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Abstract:
The spirotetronate polyketides are a class of microbial antibiotics structurally featuring a macrocycle core embedded with a cyclohexene ring spiro-linked to tetronic acid and/or a decalin ring. Of them, PA-46101s are characterized with an extra lactone moiety in the macrocycle scaffold. Despite the remarkable antibacterial activities, the biosynthetic pathway of PA-46101s has not been investigated. Herein, the PA-46101s biosynthetic gene cluster was identified from a Streptomyces species. Overexpression of a LuxR transcriptional regulator led to around a 15-fold rise of PA-46101s production. Characterization of an intermediate accumulated upon deletion of the Baeyer-Villiger monooxygenase homologous gene paE1 revealed the first lactone-formation gene from spirotetronate biosynthetic pathways. Characterization of the metabolites of glycosyltransferase gene mutants allowed us to dissect the tailoring glycosylation orders. The obtained PA-46101s analogs exhibited obvious inhibitory activities against the aquatic pathogenic bacteria Edwardsiella piscicida and Vibrio alginolyticus. This study paves the way for the structural diversification of PA-46101s through combinatorial biology.
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