論文

国際誌
2021年1月8日

Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359.

Nature communications
  • Cornelia Hermes
  • René Richarz
  • Daniel A Wirtz
  • Julian Patt
  • Wiebke Hanke
  • Stefan Kehraus
  • Jan Hendrik Voß
  • Jim Küppers
  • Tsubasa Ohbayashi
  • Vigneshwaran Namasivayam
  • Judith Alenfelder
  • Asuka Inoue
  • Peter Mergaert
  • Michael Gütschow
  • Christa E Müller
  • Evi Kostenis
  • Gabriele M König
  • Max Crüsemann
  • 全て表示

12
1
開始ページ
144
終了ページ
144
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/s41467-020-20418-3

The potent and selective Gq protein inhibitor depsipeptide FR900359 (FR), originally discovered as the product of an uncultivable plant endosymbiont, is synthesized by a complex biosynthetic system comprising two nonribosomal peptide synthetase (NRPS) assembly lines. Here we characterize a cultivable bacterial FR producer, enabling detailed investigations into biosynthesis and attachment of the functionally important FR side chain. We reconstitute side chain assembly by the monomodular NRPS FrsA and the non-heme monooxygenase FrsH, and characterize intermolecular side chain transesterification to the final macrocyclic intermediate FR-Core, mediated by the FrsA thioesterase domain. We harness FrsA substrate promiscuity to generate FR analogs with altered side chains and demonstrate indispensability of the FR side chain for efficient Gq inhibition by comparative bioactivity, toxicity and docking studies. Finally, evolution of FR and side chain biosynthesis is discussed based on bioinformatics analyses. Side chain transesterification boosts potency and target affinity of selective Gq inhibitor natural products.

リンク情報
DOI
https://doi.org/10.1038/s41467-020-20418-3
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/33420046
ID情報
  • DOI : 10.1038/s41467-020-20418-3
  • PubMed ID : 33420046

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