期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 59, 期 32, 页码 13511-13515出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202003958
关键词
Biosynthesis; DMSP; Mass spectrometry; NRPS; Virulence factors
资金
- DFG [SFB 1127 ChemBioSys]
- European Regional Development Fund (ERDF) (MassNat)
- SMART BIOTECS alliance
- Ministry of Science and Culture (MWK) of Lower Saxony, Germany
- Daimler and Benz foundation
- DFG (Leibniz Award)
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.
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