A1 Journal article (refereed)
Direct pathway cloning and expression of the radiosumin biosynthetic gene cluster (2023)

Ouyang, X., D'Agostino, P. M., Wahlsten, M., Delbaje, E., Jokela, J., Permi, P., Gaiani, G., Poso, A., Bartos, P., Gulder, T. A. M., Koistinen, H., & Fewer, D. P. (2023). Direct pathway cloning and expression of the radiosumin biosynthetic gene cluster. Organic and Biomolecular Chemistry, 21(23), 4893-4908. https://doi.org/10.1039/d3ob00385j

JYU authors or editors

Publication details

All authors or editors: Ouyang, Xiaodan; D'Agostino, Paul M.; Wahlsten, Matti; Delbaje, Endrews; Jokela, Jouni; Permi, Perttu; Gaiani, Greta; Poso, Antti; Bartos, Piia; Gulder, Tobias A. M.; et al.

Journal or series: Organic and Biomolecular Chemistry

ISSN: 1477-0520

eISSN: 1477-0539

Publication year: 2023

Volume: 21

Issue number: 23

Pages range: 4893-4908

Publisher: Royal Society of Chemistry (RSC)

Publication country: United Kingdom

Publication language: English

DOI: https://doi.org/10.1039/d3ob00385j

Publication open access: Openly available

Publication channel open access: Partially open access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/87470

Abstract

Radiosumins are a structurally diverse family of low molecular weight natural products that are produced by cyanobacteria and exhibit potent serine protease inhibition. Members of this family are dipeptides characterized by the presence of two similar non-proteinogenic amino acids. Here we used a comparative bioinformatic analysis to identify radiosumin biosynthetic gene clusters from the genomes of 13 filamentous cyanobacteria. We used direct pathway cloning to capture and express the entire 16.8 kb radiosumin biosynthetic gene cluster from Dolichospermum planctonicum UHCC 0167 in Escherichia coli. Bioinformatic analysis demonstrates that radiosumins represent a new group of chorismate-derived non-aromatic secondary metabolites. High-resolution liquid chromatography-mass spectrometry, nuclear magnetic resonance spectroscopy and chemical degradation analysis revealed that cyanobacteria produce a cocktail of novel radiosumins. We report the chemical structure of radiosumin D, an N-methyl dipeptide, containing a special Aayp (2-amino-3-(4-amino-2-cyclohexen-1-ylidene) propionic acid) with R configuration that differs from radiosumin A–C, an N-Me derivative of Aayp (Amyp) and two acetyl groups. Radiosumin C inhibits all three human trypsin isoforms at micromolar concentrations with preference for trypsin-1 and -3 (IC50 values from 1.7 μM to >7.2 μM). These results provide a biosynthetic logic to explore the genetic and chemical diversity of the radiosumin family and suggest that these natural products may be a source of drug leads for selective human serine proteases inhibitors.

Keywords: cyanobacteria; genetic polymorphism; DNA

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Related projects

Ministry reporting: Yes

Reporting Year: 2023

Preliminary JUFO rating: 2