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 languageEnglish
JournalAngewandte Chemie - International Edition
Volume60
Issue number43
Pages (from-to)23212-23216
Number of pages5
ISSN1433-7851
DOIs
Publication statusPublished - 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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