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Sulfonium Acids Loaded onto an Unusual Thiotemplate Assembly Line Construct the Cyclopropanol Warhead of a
Felix Trottmann1, Keishi Ishida1, Jakob Franke2
1Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstrasse 11a, 07745, Jena, Germany.
Abstract:
Pathogenic bacteria of the Burkholderia pseudomallei group cause severe infectious diseases such as glanders and melioidosis. Malleicyprols were identified as important bacterial virulence factors, yet the biosynthetic origin of their cyclopropanol warhead has remained enigmatic. By a combination of mutational analysis and metabolomics we found that sulfonium acids, dimethylsulfoniumpropionate (DMSP) and gonyol, known as osmolytes and as crucial components in the global organosulfur cycle, are key intermediates en route to the cyclopropanol unit. Functional genetics and in vitro analyses uncover a specialized pathway to DMSP involving a rare prokaryotic SET-domain methyltransferase for a cryptic methylation, and show that DMSP is loaded onto the NRPS-PKS hybrid assembly line by an adenylation domain dedicated to zwitterionic starter units. Then, the megasynthase transforms DMSP into gonyol, as demonstrated by heterologous pathway reconstitution in E. coli.
Insights
Researchers uncovered the origin of malleicyprol
Area of Science:
- Microbiology
- Biochemistry
- Organic Chemistry
Background:
- The Burkholderia pseudomallei group causes serious diseases like melioidosis.
- Malleicyprols are bacterial virulence factors, but their cyclopropanol warhead's origin is unknown.
Purpose of the Study:
- To elucidate the biosynthetic pathway of the cyclopropanol unit in malleicyprols.
Main Methods:
- Mutational analysis
- Metabolomics
- Functional genetics
- In vitro assays
- Heterologous pathway reconstitution in E. coli
Main Results:
- Dimethylsulfoniumpropionate (DMSP) and gonyol are key intermediates in cyclopropanol synthesis.
- A specialized pathway for DMSP production involves a rare prokaryotic SET-domain methyltransferase.
- DMSP is loaded onto a NRPS-PKS hybrid assembly line by a dedicated adenylation domain.
- The megasynthase converts DMSP to gonyol.
Conclusions:
- The study reveals the complete biosynthetic pathway for the cyclopropanol warhead of malleicyprols.
- Dimethylsulfoniumpropionate (DMSP) and gonyol are identified as crucial intermediates.
- This work clarifies a significant gap in understanding bacterial virulence factor biosynthesis.
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