Molecular basis of dimer formation during the biosynthesis of benzofluorene-containing atypical angucyclines

Chunshuai Huang, Chunfang Yang, Wenjun Zhang, Liping Zhang, Bidhan Chandra De, Yiguang Zhu, Xiaodong Jiang, Chunyan Fang, Qingbo Zhang, Cheng-Shan Yuan, Hung-wen Liu () and Changsheng Zhang ()
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Chunshuai Huang: Chinese Academy of Sciences
Chunfang Yang: Chinese Academy of Sciences
Wenjun Zhang: Chinese Academy of Sciences
Liping Zhang: Chinese Academy of Sciences
Bidhan Chandra De: Chinese Academy of Sciences
Yiguang Zhu: Chinese Academy of Sciences
Xiaodong Jiang: Chinese Academy of Sciences
Chunyan Fang: Chinese Academy of Sciences
Qingbo Zhang: Chinese Academy of Sciences
Cheng-Shan Yuan: Chinese Academy of Sciences
Hung-wen Liu: University of Texas at Austin
Changsheng Zhang: Chinese Academy of Sciences

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract Lomaiviticin A and difluostatin A are benzofluorene-containing aromatic polyketides in the atypical angucycline family. Although these dimeric compounds are potent antitumor agents, how nature constructs their complex structures remains poorly understood. Herein, we report the discovery of a number of fluostatin type dimeric aromatic polyketides with varied C−C and C−N coupling patterns. We also demonstrate that these dimers are not true secondary metabolites, but are instead derived from non-enzymatic deacylation of biosynthetic acyl fluostatins. The non-enzymatic deacylation proceeds via a transient quinone methide like intermediate which facilitates the subsequent C–C/C−N coupled dimerization. Characterization of this unusual property of acyl fluostatins explains how dimerization takes place, and suggests a strategy for the assembly of C–C and C–N coupled aromatic polyketide dimers. Additionally, a deacylase FlsH was identified which may help to prevent accumulation of toxic quinone methides by catalyzing hydrolysis of the acyl group.

Date: 2018
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DOI: 10.1038/s41467-018-04487-z

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