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

verfasst von

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.

Organisationseinheit(en)

Institut für Botanik

Externe Organisation(en)

Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V.Hans-Knöll-Institut
Friedrich-Schiller-Universität Jena

Typ

Kurzmitteilung

Journal

Angewandte Chemie - International Edition

Band

59

Seiten

13511-13515

Anzahl der Seiten

5

ISSN

1433-7851

Publikationsdatum

03.08.2020

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Katalyse, Chemie (insg.)

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1002/anie.202003958 (Zugang: Offen)
https://doi.org/10.1002/ange.202003958 (Zugang: Offen)
https://doi.org/10.15488/11039 (Zugang: Offen)