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; Max Crüsemann

doi:10.1038/s41467-020-20418-3

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, Max Crüsemann

PHA - Life and Pharmaceutical Science

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	144
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20418-3
Publication status	Published - 2021 Dec

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Hermes, C., Richarz, R., Wirtz, D. A., Patt, J., Hanke, W., Kehraus, S., Voß, J. H., Küppers, J., Ohbayashi, T., Namasivayam, V., Alenfelder, J., Inoue, A., Mergaert, P., Gütschow, M., Müller, C. E., Kostenis, E., König, G. M., & Crüsemann, M. (2021). Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359. Nature communications, 12(1), [144]. https://doi.org/10.1038/s41467-020-20418-3

Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359. / Hermes, Cornelia; Richarz, René; Wirtz, Daniel A.; Patt, Julian; Hanke, Wiebke; Kehraus, Stefan; Voß, Jan Hendrik; Küppers, Jim; Ohbayashi, Tsubasa; Namasivayam, Vigneshwaran; Alenfelder, Judith; Inoue, Asuka; Mergaert, Peter; Gütschow, Michael; Müller, Christa E.; Kostenis, Evi; König, Gabriele M.; Crüsemann, Max.

In: Nature communications, Vol. 12, No. 1, 144, 12.2021.

Research output: Contribution to journal › Article › peer-review

Hermes, C, Richarz, R, Wirtz, DA, Patt, J, Hanke, W, Kehraus, S, Voß, JH, Küppers, J, Ohbayashi, T, Namasivayam, V, Alenfelder, J, Inoue, A, Mergaert, P, Gütschow, M, Müller, CE, Kostenis, E, König, GM & Crüsemann, M 2021, 'Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359', Nature communications, vol. 12, no. 1, 144. https://doi.org/10.1038/s41467-020-20418-3

Hermes, Cornelia ; Richarz, René ; Wirtz, Daniel A. ; Patt, Julian ; Hanke, Wiebke ; Kehraus, Stefan ; Voß, Jan Hendrik ; Küppers, Jim ; Ohbayashi, Tsubasa ; Namasivayam, Vigneshwaran ; Alenfelder, Judith ; Inoue, Asuka ; Mergaert, Peter ; Gütschow, Michael ; Müller, Christa E. ; Kostenis, Evi ; König, Gabriele M. ; Crüsemann, Max. / Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359. In: Nature communications. 2021 ; Vol. 12, No. 1.

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title = "Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359",

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.",

author = "Cornelia Hermes and Ren{\'e} Richarz and Wirtz, {Daniel A.} and Julian Patt and Wiebke Hanke and Stefan Kehraus and Vo{\ss}, {Jan Hendrik} and Jim K{\"u}ppers and Tsubasa Ohbayashi and Vigneshwaran Namasivayam and Judith Alenfelder and Asuka Inoue and Peter Mergaert and Michael G{\"u}tschow and M{\"u}ller, {Christa E.} and Evi Kostenis and K{\"o}nig, {Gabriele M.} and Max Cr{\"u}semann",

note = "Funding Information: We thank the DFG (FOR 2372 grants CR464/7-1 to M.C., KO 902/17-1 and 17-2 to G.M.K., KO 1582/10-1 and 10-2 to E.K., MU 1667/7-1 und 7-2 to C.E.M., GU 345/3-1 to M.G.) and the DBU (PhD scholarship 20018/568 to W.H.) for funding. A.I. was funded by the LEAP JP19gm0010004 from the Japan Agency for Medical Research and Development (AMED). Furthermore, we thank Prof. Dr. Matthias Ullrich, Jacobs University Bremen for the supply of vectors pEX18Tc, pFlp2 and pPS858, Goran Grujicic for help with extractions and G{\"o}ttingen Genomics Laboratory (G2L) for C. vaccinii genome sequencing. Satria Kautsar is acknowledged for advice on bioinformatics and for help with BiG-SLiCE analyses.",

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doi = "10.1038/s41467-020-20418-3",

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AU - Hermes, Cornelia

AU - Richarz, René

AU - Wirtz, Daniel A.

AU - Patt, Julian

AU - Hanke, Wiebke

AU - Kehraus, Stefan

AU - Voß, Jan Hendrik

AU - Küppers, Jim

AU - Ohbayashi, Tsubasa

AU - Namasivayam, Vigneshwaran

AU - Alenfelder, Judith

AU - Inoue, Asuka

AU - Mergaert, Peter

AU - Gütschow, Michael

AU - Müller, Christa E.

AU - Kostenis, Evi

AU - König, Gabriele M.

AU - Crüsemann, Max

N1 - Funding Information: We thank the DFG (FOR 2372 grants CR464/7-1 to M.C., KO 902/17-1 and 17-2 to G.M.K., KO 1582/10-1 and 10-2 to E.K., MU 1667/7-1 und 7-2 to C.E.M., GU 345/3-1 to M.G.) and the DBU (PhD scholarship 20018/568 to W.H.) for funding. A.I. was funded by the LEAP JP19gm0010004 from the Japan Agency for Medical Research and Development (AMED). Furthermore, we thank Prof. Dr. Matthias Ullrich, Jacobs University Bremen for the supply of vectors pEX18Tc, pFlp2 and pPS858, Goran Grujicic for help with extractions and Göttingen Genomics Laboratory (G2L) for C. vaccinii genome sequencing. Satria Kautsar is acknowledged for advice on bioinformatics and for help with BiG-SLiCE analyses.

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N2 - 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.

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