Details
| Original language | English |
|---|---|
| Pages (from-to) | 13511-13515 |
| Number of pages | 5 |
| Journal | Angewandte Chemie - International Edition |
| Volume | 59 |
| Issue number | 32 |
| Early online date | 21 Apr 2020 |
| Publication status | Published - 3 Aug 2020 |
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.
Keywords
- Biosynthesis, DMSP, Mass spectrometry, NRPS, Virulence factors
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
- General Chemistry
Sustainable Development Goals
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In: Angewandte Chemie - International Edition, Vol. 59, No. 32, 03.08.2020, p. 13511-13515.
Research output: Contribution to journal › Short/Brief/Rapid Communication › Research › peer review
}
TY - JOUR
T1 - Sulfonium Acids Loaded onto an Unusual Thiotemplate Assembly Line Construct the Cyclopropanol Warhead of a Burkholderia Virulence Factor
AU - Trottmann, Felix
AU - Ishida, Keishi
AU - Franke, Jakob
AU - Stanišić, Aleksa
AU - Ishida-Ito, Mie
AU - Kries, Hajo
AU - Pohnert, Georg
AU - Hertweck, Christian
N1 - Funding Information: We thank A. Perner for LC‐MS measurements. Financial support by the DFG (SFB 1127 ChemBioSys, and Leibniz Award to C.H.) and the European Regional Development Fund (ERDF) (MassNat) is gratefully acknowledged. J.F. acknowledges financial support by the SMART BIOTECS alliance between the Technische Universität Braunschweig and the Leibniz Universität Hannover, supported by the Ministry of Science and Culture (MWK) of Lower Saxony, Germany. H.K. received a fellowship from the Daimler and Benz foundation.
PY - 2020/8/3
Y1 - 2020/8/3
N2 - 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.
AB - 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.
KW - Biosynthesis
KW - DMSP
KW - Mass spectrometry
KW - NRPS
KW - Virulence factors
UR - http://www.scopus.com/inward/record.url?scp=85085516240&partnerID=8YFLogxK
U2 - 10.1002/anie.202003958
DO - 10.1002/anie.202003958
M3 - Short/Brief/Rapid Communication
C2 - 32314848
AN - SCOPUS:85085516240
VL - 59
SP - 13511
EP - 13515
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
SN - 1433-7851
IS - 32
ER -