The Structure of Cyclodecatriene Collinolactone, its Biosynthesis, and Semisynthetic Analogues: Effects of Monoastral Phenotype and Protection from Intracellular Oxidative Stress

Julian C. Schmid; Kerstin Frey; Matthias Scheiner; Jaime Felipe Guerrero Garzón; Luise Stafforst; Jan-Niklas Fricke; Michaela Schuppe; Hajo Schiewe; Axel Zeeck; Tilmann Weber; Isabel Usón; Ralf Kemkemer; Michael Decker; Stephanie Grond

doi:10.1002/anie.202106802

The Structure of Cyclodecatriene Collinolactone, its Biosynthesis, and Semisynthetic Analogues: Effects of Monoastral Phenotype and Protection from Intracellular Oxidative Stress

Julian C. Schmid, Kerstin Frey, Matthias Scheiner, Jaime Felipe Guerrero Garzón, Luise Stafforst, Jan-Niklas Fricke, Michaela Schuppe, Hajo Schiewe, Axel Zeeck, Tilmann Weber, Isabel Usón, Ralf Kemkemer, Michael Decker, Stephanie Grond^*

^*Corresponding author for this work

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Abstract

Recently described rhizolutin and collinolactone isolated from Streptomyces Gö 40/10 share the same novel carbon scaffold. Analyses by NMR and X-Ray crystallography verify the structure of collinolactone and propose a revision of rhizolutin's stereochemistry. Isotope-labeled precursor feeding shows that collinolactone is biosynthesized via type I polyketide synthase with Baeyer–Villiger oxidation. CRISPR-based genetic strategies led to the identification of the biosynthetic gene cluster and a high-production strain. Chemical semisyntheses yielded collinolactone analogues with inhibitory effects on L929 cell line. Fluorescence microscopy revealed that only particular analogues induce monopolar spindles impairing cell division in mitosis. Inspired by the Alzheimer-protective activity of rhizolutin, we investigated the neuroprotective effects of collinolactone and its analogues on glutamate-sensitive cells (HT22) and indeed, natural collinolactone displays distinct neuroprotection from intracellular oxidative stress.

Original language	English
Journal	Angewandte Chemie - International Edition
Volume	60
Issue number	43
Pages (from-to)	23212-23216
Number of pages	5
ISSN	1433-7851
DOIs	https://doi.org/10.1002/anie.202106802
Publication status	Published - 2021

Bibliographical note

Funding Information:
J.F.G.G. and T.W. were supported by the Novo Nordisk Foundation [grants NNF16OC0021746, NNF20CC0035580 to T.W.]. R.K., K.F. and S.G. are part of the graduation program IPMB funded by the MWK Baden‐Württemberg. L.S. was funded by SFB 416. The work was further supported by infrastructural funding from Eberhard Karls University of Tuebingen. We especially thank Prof. Dr. Oh and co‐workers from the Natural Products Research Institute, Seoul National University, Korea, who kindly provided NMR data of rhizolutin for a final comparison. Also, we thank Pascal Rath for NMR measurements, José. M. Beltrán‐Beleña Nagel for LC–MS measurements, and Hans‐Jörg Langer for excellent technical assistance. Open Access funding enabled and organized by Projekt DEAL.

Publisher Copyright:
© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH

Keywords

Alzheimer's disease
Biosynthesis
Natural products
Neuroprotection
Polyketide

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Schmid, J. C., Frey, K., Scheiner, M., Garzón, J. F. G., Stafforst, L., Fricke, J.-N., Schuppe, M., Schiewe, H., Zeeck, A., Weber, T., Usón, I., Kemkemer, R., Decker, M., & Grond, S. (2021). The Structure of Cyclodecatriene Collinolactone, its Biosynthesis, and Semisynthetic Analogues: Effects of Monoastral Phenotype and Protection from Intracellular Oxidative Stress. Angewandte Chemie - International Edition, 60(43), 23212-23216. https://doi.org/10.1002/anie.202106802

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abstract = "Recently described rhizolutin and collinolactone isolated from Streptomyces G{\"o} 40/10 share the same novel carbon scaffold. Analyses by NMR and X-Ray crystallography verify the structure of collinolactone and propose a revision of rhizolutin's stereochemistry. Isotope-labeled precursor feeding shows that collinolactone is biosynthesized via type I polyketide synthase with Baeyer–Villiger oxidation. CRISPR-based genetic strategies led to the identification of the biosynthetic gene cluster and a high-production strain. Chemical semisyntheses yielded collinolactone analogues with inhibitory effects on L929 cell line. Fluorescence microscopy revealed that only particular analogues induce monopolar spindles impairing cell division in mitosis. Inspired by the Alzheimer-protective activity of rhizolutin, we investigated the neuroprotective effects of collinolactone and its analogues on glutamate-sensitive cells (HT22) and indeed, natural collinolactone displays distinct neuroprotection from intracellular oxidative stress.",

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author = "Schmid, {Julian C.} and Kerstin Frey and Matthias Scheiner and Garz{\'o}n, {Jaime Felipe Guerrero} and Luise Stafforst and Jan-Niklas Fricke and Michaela Schuppe and Hajo Schiewe and Axel Zeeck and Tilmann Weber and Isabel Us{\'o}n and Ralf Kemkemer and Michael Decker and Stephanie Grond",

note = "Funding Information: J.F.G.G. and T.W. were supported by the Novo Nordisk Foundation [grants NNF16OC0021746, NNF20CC0035580 to T.W.]. R.K., K.F. and S.G. are part of the graduation program IPMB funded by the MWK Baden‐W{\"u}rttemberg. L.S. was funded by SFB 416. The work was further supported by infrastructural funding from Eberhard Karls University of Tuebingen. We especially thank Prof. Dr. Oh and co‐workers from the Natural Products Research Institute, Seoul National University, Korea, who kindly provided NMR data of rhizolutin for a final comparison. Also, we thank Pascal Rath for NMR measurements, Jos{\'e}. M. Beltr{\'a}n‐Bele{\~n}a Nagel for LC–MS measurements, and Hans‐J{\"o}rg Langer for excellent technical assistance. Open Access funding enabled and organized by Projekt DEAL. Publisher Copyright: {\textcopyright} 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH",

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Schmid, JC, Frey, K, Scheiner, M, Garzón, JFG, Stafforst, L, Fricke, J-N, Schuppe, M, Schiewe, H, Zeeck, A, Weber, T, Usón, I, Kemkemer, R, Decker, M & Grond, S 2021, 'The Structure of Cyclodecatriene Collinolactone, its Biosynthesis, and Semisynthetic Analogues: Effects of Monoastral Phenotype and Protection from Intracellular Oxidative Stress', Angewandte Chemie - International Edition, vol. 60, no. 43, pp. 23212-23216. https://doi.org/10.1002/anie.202106802

The Structure of Cyclodecatriene Collinolactone, its Biosynthesis, and Semisynthetic Analogues: Effects of Monoastral Phenotype and Protection from Intracellular Oxidative Stress. / Schmid, Julian C.; Frey, Kerstin; Scheiner, Matthias et al.
In: Angewandte Chemie - International Edition, Vol. 60, No. 43, 2021, p. 23212-23216.

Research output: Contribution to journal › Journal article › Research › peer-review

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AU - Scheiner, Matthias

AU - Garzón, Jaime Felipe Guerrero

AU - Stafforst, Luise

AU - Fricke, Jan-Niklas

AU - Schuppe, Michaela

AU - Schiewe, Hajo

AU - Zeeck, Axel

AU - Weber, Tilmann

AU - Usón, Isabel

AU - Kemkemer, Ralf

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AB - Recently described rhizolutin and collinolactone isolated from Streptomyces Gö 40/10 share the same novel carbon scaffold. Analyses by NMR and X-Ray crystallography verify the structure of collinolactone and propose a revision of rhizolutin's stereochemistry. Isotope-labeled precursor feeding shows that collinolactone is biosynthesized via type I polyketide synthase with Baeyer–Villiger oxidation. CRISPR-based genetic strategies led to the identification of the biosynthetic gene cluster and a high-production strain. Chemical semisyntheses yielded collinolactone analogues with inhibitory effects on L929 cell line. Fluorescence microscopy revealed that only particular analogues induce monopolar spindles impairing cell division in mitosis. Inspired by the Alzheimer-protective activity of rhizolutin, we investigated the neuroprotective effects of collinolactone and its analogues on glutamate-sensitive cells (HT22) and indeed, natural collinolactone displays distinct neuroprotection from intracellular oxidative stress.

KW - Alzheimer's disease

KW - Biosynthesis

KW - Natural products

KW - Neuroprotection

KW - Polyketide

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DO - 10.1002/anie.202106802

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ER -

The Structure of Cyclodecatriene Collinolactone, its Biosynthesis, and Semisynthetic Analogues: Effects of Monoastral Phenotype and Protection from Intracellular Oxidative Stress

Abstract

Bibliographical note

Keywords

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