Investigation of the Biosynthetic Mechanism of Bipentaromycin Featuring an Unprecedented Cyclic Head-to-Tail Dimeric Scaffold

Chunshuai Huang, Haiyang Cui, Hengqian Ren, Huimin Zhao

Research output: Contribution to journalArticlepeer-review

Abstract

Bipentaromycins are heterodimeric aromatic polyketides featuring two distinctive 5/6/6/6/5 pentacyclic ring systems and exhibit antibacterial activities. However, their overall biosynthetic mechanism, particularly the mechanism for early-stage modifications, such as hydrogenation and methylation, and late-stage dimerization, remains unknown. Herein, by integrating heterologous expression, isotope labeling, gene knockout and complementation, and computational modeling, we determined the biosynthetic origin of the skeleton, identified the enzymes involved in stereo-/regioselective hydrogenation and methylation, and provided new mechanistic insights into the dimerization. This work not only deciphers the biosynthetic mechanism of bipentaromycins but also provides new strategies for creating biologically active dimeric pharmacophores for drug discovery and development.

Original languageEnglish (US)
Pages (from-to)195-203
Number of pages9
JournalJACS Au
Volume3
Issue number1
DOIs
StatePublished - Jan 23 2023

Keywords

  • biosynthetic origin
  • bipentaromycin
  • computational modeling
  • dimer
  • stereospecific modification

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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