Author
Listed:
- Cornelia Hermes
(University of Bonn)
- René Richarz
(University of Bonn)
- Daniel A. Wirtz
(University of Bonn)
- Julian Patt
(University of Bonn)
- Wiebke Hanke
(University of Bonn)
- Stefan Kehraus
(University of Bonn)
- Jan Hendrik Voß
(University of Bonn)
- Jim Küppers
(University of Bonn)
- Tsubasa Ohbayashi
(University of Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)
Institute for Agro-Environmental Sciences, National Agriculture and Food Research Organization (NARO))
- Vigneshwaran Namasivayam
(University of Bonn)
- Judith Alenfelder
(University of Bonn)
- Asuka Inoue
(Tohoku University)
- Peter Mergaert
(University of Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC))
- Michael Gütschow
(University of Bonn)
- Christa E. Müller
(University of Bonn)
- Evi Kostenis
(University of Bonn)
- Gabriele M. König
(University of Bonn)
- Max Crüsemann
(University of Bonn)
Abstract
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.
Suggested Citation
Cornelia Hermes & René Richarz & Daniel A. Wirtz & Julian Patt & Wiebke Hanke & Stefan Kehraus & Jan Hendrik Voß & Jim Küppers & Tsubasa Ohbayashi & Vigneshwaran Namasivayam & Judith Alenfelder & Asuk, 2021.
"Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359,"
Nature Communications, Nature, vol. 12(1), pages 1-12, December.
Handle:
RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20418-3
DOI: 10.1038/s41467-020-20418-3
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