A discrete intermediate for the biosynthesis of both the enediyne core and the anthraquinone moiety of enediyne natural products

The enediynes are structurally characterized by a 1,5-diyne-3-ene motif within a 9- or 10-membered enediyne core. The anthraquinone-fused enediynes (AFEs) are a subclass of 10-membered enediynes that contain an anthraquinone moiety fused to the enediyne core as exemplified by dynemicins and tiancimy...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 120; no. 9; p. e2220468120
Main Authors Bhardwaj, Minakshi, Cui, Zheng, Daniel Hankore, Erome, Moonschi, Faruk H, Saghaeiannejad Esfahani, Hoda, Kalkreuter, Edward, Gui, Chun, Yang, Dong, Phillips, Jr, George N, Thorson, Jon S, Shen, Ben, Van Lanen, Steven G
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 28.02.2023
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Summary:The enediynes are structurally characterized by a 1,5-diyne-3-ene motif within a 9- or 10-membered enediyne core. The anthraquinone-fused enediynes (AFEs) are a subclass of 10-membered enediynes that contain an anthraquinone moiety fused to the enediyne core as exemplified by dynemicins and tiancimycins. A conserved iterative type I polyketide synthase (PKSE) is known to initiate the biosynthesis of all enediyne cores, and evidence has recently been reported to suggest that the anthraquinone moiety also originates from the PKSE product. However, the identity of the PKSE product that is converted to the enediyne core or anthraquinone moiety has not been established. Here, we report the utilization of recombinant coexpressing various combinations of genes that encode a PKSE and a thioesterase (TE) from either 9- or 10-membered enediyne biosynthetic gene clusters to chemically complement Δ mutant strains of the producers of dynemicins and tiancimycins. Additionally, C-labeling experiments were performed to track the fate of the PKSE/TE product in the Δ mutants. These studies reveal that 1,3,5,7,9,11,13-pentadecaheptaene is the nascent, discrete product of the PKSE/TE that is converted to the enediyne core. Furthermore, a second molecule of 1,3,5,7,9,11,13-pentadecaheptaene is demonstrated to serve as the precursor of the anthraquinone moiety. The results establish a unified biosynthetic paradigm for AFEs, solidify an unprecedented biosynthetic logic for aromatic polyketides, and have implications for the biosynthesis of not only AFEs but all enediynes.
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Edited by Jon Clardy, Harvard Medical School, Boston, MA; received December 1, 2022; accepted January 30, 2023 by Editorial Board Member Stephen J. Benkovic
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2220468120