Sulfonium Acids Loaded onto an Unusual Thiotemplate Assembly Line Construct the Cyclopropanol Warhead of a Burkholderia Virulence Factor

authored by

Felix Trottmann, Keishi Ishida, Jakob Franke, Aleksa Stanišić, Mie Ishida-Ito, Hajo Kries, Georg Pohnert, Christian Hertweck

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.

Organisation(s)

Institute of Botany

External Organisation(s)

Leibniz Institute for Natural Product Research and Infection Biology Hans Knöll Institute (HKI)
Friedrich Schiller University Jena

Type

Short/Brief/Rapid Communication

Journal

Angewandte Chemie - International Edition

Volume

59

Pages

13511-13515

No. of pages

5

ISSN

1433-7851

Publication date

03.08.2020

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Catalysis, General Chemistry

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1002/anie.202003958 (Access: Open)
https://doi.org/10.1002/ange.202003958 (Access: Open)
https://doi.org/10.15488/11039 (Access: Open)