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

Minakshi Bhardwaj, Zheng Cui, Erome Daniel Hankore, Faruk H. Moonschi, Hoda Saghaeiannejad Esfahani, Edward Kalkreuter, Chun Gui, Dong Yang, George N. Phillips, Jon S. Thorson, Ben Shen, Steven G. Van Lanena

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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 E. coli 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 ΔPKSE mutant strains of the producers of dynemicins and tiancimycins. Additionally, 13C-labeling experiments were performed to track the fate of the PKSE/TE product in the ΔPKSE 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.

Original languageEnglish
Article numbere2220468120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number9
DOIs
StatePublished - Feb 28 2023

Bibliographical note

Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS.

Keywords

  • biosynthesis
  • enediyne
  • natural products
  • polyene
  • polyketide

ASJC Scopus subject areas

  • General

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