Identification, structure and function of the methyltransferase involved in the 
biosynthesis of the dithiolopyrrolone antibiotic xenorhabdin

Su, Li; Huber, Eva M.; Westphalen, Margaretha; Gellner, Jonas; Bode, Edna; Köbel, Tania; Grün, Peter; Alanjary, Mohammad M.; Glatter, Timo; Schindler, Daniel; Groll, Michael; Bode, Helge B.

doi:10.1101/2024.01.12.575338

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Identification, structure and function of the methyltransferase involved in the biosynthesis of the dithiolopyrrolone antibiotic xenorhabdin

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Su, Li
Natural Product Function and Engineering, Department of Natural Products in Organismic Interactions, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

/persons/resource/persons264335

Bode, Edna
Natural Product Function and Engineering, Department of Natural Products in Organismic Interactions, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

Köbel, Tania
Core Facility MPG MAXGenesys DNAfoundry, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

Grün, Peter
Natural Product Function and Engineering, Department of Natural Products in Organismic Interactions, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

/persons/resource/persons261236

Glatter, Timo
Core Facility Mass Spectrometry and Proteomics, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

/persons/resource/persons261244

Schindler, Daniel
Core Facility MPG MAXGenesys DNAfoundry, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

/persons/resource/persons256033

Bode, Helge B.
Natural Product Function and Engineering, Department of Natural Products in Organismic Interactions, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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https://doi.org/10.1101/2024.01.12.575338
(Preprint)

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Citation

Su, L., Huber, E. M., Westphalen, M., Gellner, J., Bode, E., Köbel, T., et al. (2024). Identification, structure and function of the methyltransferase involved in the biosynthesis of the dithiolopyrrolone antibiotic xenorhabdin. bioRxiv: the preprint server for biology, doi: 10.1101/2024.01.12.575338.

Cite as: https://hdl.handle.net/21.11116/0000-000E-745F-6

Abstract

Xenorhabdins (XRDs) are produced by Xenorhabdus species and are members of the dithiopyrrolone (DTP) class of natural products that have potent antibacterial, antifungal and anticancer activity. The amide moiety of their DTP core can be methylated or not to fine-tune the bioactivity properties. However, the enzyme responsible for the amide N-methylation remained elusive. Here, we identified and characterized the amide methyltransferase XrdM that is encoded nearly 600 kb away from the XRD gene cluster using proteomic analysis, methyltransferase candidate screening, gene deletion, and allied approaches. In addition, crystallographic analysis and site-directed mutagenesis proved that XrdM is completely distinct from the recently reported DTP methyltransferase DtpM, and that both have been tailored in a species-specific manner for DTP biosynthesis in Gram-negative/positive organisms. Our study expands the limited knowledge of post-NRPS amide methylation in DTP biosynthesis and reveals the evolution of two structurally completely different enzymes for the same reaction in different organisms.Competing Interest StatementThe authors have declared no competing interest.