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

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 and Max Crüsemann ()
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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)
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

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20418-3

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DOI: 10.1038/s41467-020-20418-3

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