Functional Characterization of the jadI Gene As a Cyclase Forming Angucyclinones

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Abstract

A gene designated jadI from the jadomycin B producer Streptomyces venezuelae has homology to the tetracenomycin pathway tcmI gene and encodes a putative cyclase for angucyclinone biosynthesis. Expression in Streptomyces lividans of a jadomycin (jad) gene cassette composed of the minimal polyketide synthase (PKS, jadABC), a cyclase (jadD), a ketoreductase (jadE), and jadI leads to production of several yellow compounds in liquid culture. Rabelomycin (1), a known angucyclinone, results from dehydration and oxidation of a new product, UWM6, isolated from the culture extracts. Characterization of UWM6 by UV, MS, and NMR analyses revealed a new angucyclinone structure, 4-hydroxy-12bH-12-deoxyrabelomycin. Production of these angucyclinones occurs only when jadI is present in the cassette, suggesting an essential cyclase phenotype for this gene. Engineered replacement of jadI in the jad cassette with the tcmI cyclase gene, and similar replacement of tcmI in a functional tcm PKS cassette with jadI, leads to the same set of aromatic decapolyketides produced by either cassette in the absence of jadI. From these results we conclude that both cyclases are nonfunctional out of their normal context.

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