One-Pot Combinatorial Biosynthesis of Glycosylated Anthracyclines by Cocultivation of Streptomyces Strains Producing Aglycones and Nucleotide Deoxysugars

• Published in: ACS combinatorial science Vol. 19; no. 4; pp. 262 - 270
• Main Authors: Kim, Eunji, Song, Myoung Chong, Kim, Myoun Su, Beom, Ji Yoon, Jung, Jin A, Cho, Hang Soo, Yoon, Yeo Joon
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.04.2017
• Subjects: Anthracyclines - metabolism; Combinatorial Chemistry Techniques; Deoxy Sugars - biosynthesis; Glycosides - biosynthesis; Glycosylation; Glycosyltransferases - metabolism; Mutation; Naphthacenes - metabolism; Nucleotides - metabolism; Polyketides - metabolism; Streptomyces - genetics; Streptomyces - metabolism; cocultivation; Streptomyces; glycosylation; anthracycline; deoxysugar
• ISSN: 2156-8952; 2156-8944
• DOI: 10.1021/acscombsci.6b00194

Anthracyclines, such as doxorubicin, are effective anticancer drugs composed of a tetracyclic polyketide aglycone and one or more deoxysugar moieties, which play a critical role in their biological activity. A facile one-pot combinatorial biosynthetic system was developed for the generation of a range of glycosylated derivatives of anthracyclines. Cocultivation of Streptomyces venezuelae mutants producing two anthracycline aglycones with eight different nucleotide deoxysugar-producing S. venezuelae mutants that coexpress a substrate-flexible glycosyltransferase led to the generation of 16 aklavinone or ε-rhodomycinone glycosides containing diverse deoxysugar moieties, seven of which are new. This demonstrates the potential of the one-pot combinatorial biosynthetic system based on cocultivation as a facile biological tool capable of combining diverse aglycones and deoxysugars to generate structurally diverse polyketides carrying engineered sugars for drug discovery and development.