Structure and biosynthesis of polycyclic tetramate macrolactams

• Applicant: Professor Dr. Tobias A. M. Gulder
• Subject Area: Biological and Biomimetic Chemistry
• Term: from 2013 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 241369642

• Final Report Year: 2025

Final Report Abstract

Polycyclic Tetramate-Containing Macrolactams (PoTeMs) are an expanding class of microbial natural products (NPs). All PoTeMs share a tetramic acid moiety integrated into a macrolactam. The core structural diversity of PoTeMs arises from an additional carbocyclic element fused to this macrolactam, which typically consists of two to three cyclohexane / cyclopentane units. Variations in the degree of saturation, oxygenation, and alkylation patterns further expand the structural and hence functional diversity of PoTeMs. As a result, these compounds exhibit a broad range of biological activities, from antibiotic and fungicidal effects to potent cytotoxicity. These remarkable functions highlight the significant potential of PoTeMs in biomedical research, underscoring their promise for applications in drug development. Despite the fascinating structural, biosynthetic, and pharmacological properties of PoTeMs, little was known about their biosynthetic assembly at the outset of this project. Using ikarugamycin, the first member of this NP class ever reported, as a model system, we aimed to close this knowledge gap. This resulted, among other achievements, in the elucidation of PoTeM biosynthetic assembly setting the stage for the targeted discovery of new PoTeMs by genome mining, their production by (chemo-)enzymatic and biotechnological approaches, their late-stage oxidative functionalization, and even the engineering of their core structural composition. Overall, this project has provided valuable tools for PoTeM discovery and biosynthetic engineering, which can now be harnessed by the research community to tailor this fascinating NP class for potential biomedical applications.

Publications

• Genome analysis of Pseudoalteromonas flavipulchra JG1 reveals various survival advantages in marine environment. BMC Genomics, 14(1).
  Yu, Min; Tang, Kaihao; Liu, Jiwen; Shi, Xiaochong; Gulder, Tobias AM & Zhang, Xiao-Hua
  
• Heterologous Reconstitution of Ikarugamycin Biosynthesis in E. coli. Angewandte Chemie International Edition, 53(11), 3011-3014.
  Antosch, Janine; Schaefers, Françoise & Gulder, Tobias A. M.
  
• Promiscuous hydroxylases for the functionalization of polycyclic tetramate macrolactams – conversion of ikarugamycin to butremycin. Chemical Communications, 51(25), 5334-5336.
  Greunke, Christian; Antosch, Janine & Gulder, Tobias A. M.
  
• Biocatalytic Total Synthesis of Ikarugamycin. Angewandte Chemie International Edition, 56(15), 4351-4355.
  Greunke, Christian; Glöckle, Anna; Antosch, Janine & Gulder, Tobias A. M.
  
• A Plug-and-Play System for Polycyclic Tetramate Macrolactam Expression and Functionalization. openRxiv.
  Glöckle, Anna; Schuler, Sebastian; Einsiedler, Manuel & Gulder, Tobias A. M.
  
• Expanding Polycyclic Tetramate Macrolactam (PoTeM) Core Structure Diversity by Chemo-Enzymatic Synthesis and Bioengineering. American Chemical Society (ACS).
  Schuler, Sebastian; Einsiedler, Manuel; Evers, Julia; Malay, Mert; Uka, Valdet; Schneider, Sabine & Gulder, Tobias
  
• Heterologous expression and optimization of fermentation conditions for recombinant ikarugamycin production. openRxiv.
  Evers, Julia K.; Glöckle, Anna; Wiegand, Monique; Schuler, Sebastian; Einsiedler, Manuel & Gulder, Tobias A. M.
  
• A plug-and-play system for polycyclic tetramate macrolactam production and functionalization. Microbial Cell Factories, 24(1).
  Glöckle, Anna; Schuler, Sebastian; Einsiedler, Manuel & Gulder, Tobias A. M.
  
• Expanding Polycyclic Tetramate Macrolactam (PoTeM) Core Structure Diversity by Chemo‐Enzymatic Synthesis and Bioengineering. Angewandte Chemie International Edition, 64(13).
  Schuler, Sebastian; Einsiedler, Manuel; Evers, Julia K.; Malay, Mert; Uka, Valdet; Schneider, Sabine & Gulder, Tobias A. M.
  
• Heterologous Expression and Optimization of Fermentation Conditions for Recombinant Ikarugamycin Production. Biotechnology and Bioengineering, 122(4), 974-982.
  Evers, Julia K.; Glöckle, Anna; Wiegand, Monique; Schuler, Sebastian; Einsiedler, Manuel & Gulder, Tobias A. M.