Isofunctional but Structurally Different Methyltransferases for Dithiolopyrrolone Diversification
Abstract Dithiolopyrrolone (DTP) natural products are produced by several different bacteria and have potent antibacterial, antifungal and anticancer activities. While the amide of their DTP core can be methylated to fine‐tune bioactivity, the enzyme responsible for the amide N ‐methylation has remained elusive in most taxa. Here, we identified the amide methyltransferase XrdM that is responsible for xenorhabdin (XRD) methylation in Xenorhabdus doucetiae but encoded outside of the XRD gene cluster. XrdM turned out to be isofunctional with the recently reported methyltransferase DtpM, that is involved in the biosynthesis of the DTP thiolutin, although its X‐ray structure is unrelated to that of DtpM. To investigate the structural basis for ligand binding in both enzymes, we used X‐ray crystallography, modeling, site‐directed mutagenesis, and kinetic activity assays. Our study expands the limited knowledge of post‐non‐ribosomal peptide synthetase (NRPS) amide methylation in DTP biosynthesis and reveals an example of convergent evolution of two structurally completely different enzymes for the same reaction in different organisms.
Authors
- Daniel Schindler (ORCID: https://orcid.org/0000-0001-7423-6540)
- Peter Grün
- Mohammad Alanjary (ORCID: https://orcid.org/0000-0001-8420-1325)
- Helge B. Bode (ORCID: https://orcid.org/0000-0001-6048-5909)
- Ли Су (ORCID: https://orcid.org/0000-0002-7787-684X)
- Katarina Cirnski
- Timo Glatter (ORCID: https://orcid.org/0000-0001-8716-8516)
- Edna Bode (ORCID: https://orcid.org/0000-0001-8522-1897)
- M. Groll (ORCID: https://orcid.org/0000-0002-1660-340X)
- Tania S. Köbel
- E.M. Huber (ORCID: https://orcid.org/0000-0001-8018-7204)
- Margaretha Westphalen
- Rolf Müller (ORCID: https://orcid.org/0000-0002-1042-5665)
- Jonas Gellner
Institutions
- Goethe University Frankfurt (DE)
- Philipps University of Marburg (DE)
- Senckenberg - Leibniz Institution for Biodiversity and Earth System Research (DE)
- German Center for Infection Research (DE)
- Helmholtz Centre for Infection Research (DE)
- Helmholtz Institute for Pharmaceutical Research Saarland (DE)
- Loewe Center for Synthetic Microbiology (DE)
- Max Planck Institute for Terrestrial Microbiology (DE)
- Technical University of Munich (DE)
- Wageningen University & Research (NL)
- Saarland University (DE)
Publication Details
- Journal
- Angewandte Chemie
- Published
- 2024-08-26
- DOI
- https://doi.org/10.1002/ange.202410799
- Citations
- 2
- Primary Topic
- Inorganic Fluorides and Related Compounds
- Type
- article
- Field-Weighted Citation Impact
- 0.32
Funders
- Deutsche Forschungsgemeinschaft
- FP7 Ideas: European Research Council
- HORIZON EUROPE European Research Council