Cyclic, Hydrophobic Hexapeptide Fusahexin Is the Product of a Nonribosomal Peptide Synthetase in Fusarium graminearum

Klaus Ringsborg Westphal, Simone Bachleitner, Manja Mølgaard Severinsen, Mathias Lehmann Brundtø, Frederik Teilfeldt Hansen, Trine Sørensen, Rasmus Dam Wollenberg, Erik Lysøe, Lena Studt, Jens Laurids Sørensen, Teis Esben Sondergaard, Reinhard Wimmer

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7 Citationer (Scopus)

Abstract

The plant pathogenic fungus Fusarium graminearum is known to produce a wide array of secondary metabolites during plant infection. This includes several nonribosomal peptides. Recently, the fusaoctaxin (NRPS5/9) and gramilin (NRPS8) gene clusters were shown to be induced by host interactions. To widen our understanding of this important pathogen, we investigated the involvement of the NRPS4 gene cluster during infection and oxidative and osmotic stress. Overexpression of NRPS4 led to the discovery of a new cyclic hexapeptide, fusahexin (1), with the amino acid sequence cyclo-(d-Ala-l-Leu-d-allo-Thr-l-Pro-d-Leu-l-Leu). The structural analyses revealed an unusual ether bond between a proline Cδ to Cβ of the preceding threonine resulting in an oxazine ring system. The comparative genomic analyses showed that the small gene cluster only encodes an ABC transporter in addition to the five-module nonribosomal peptide synthetase (NRPS). Based on the structure of fusahexin and the domain architecture of NRPS4, we propose a biosynthetic model in which the terminal module is used to incorporate two leucine units. So far, iterative use of NRPS modules has primarily been described for siderophore synthetases, which makes NRPS4 a rare example of a fungal nonsiderophore NRPS with distinct iterative module usage.
OriginalsprogEngelsk
TidsskriftJournal of Natural Products
Vol/bind84
Udgave nummer8
Sider (fra-til)2070-2080
Antal sider11
ISSN0163-3864
DOI
StatusUdgivet - 31 jul. 2021

Bibliografisk note

Funding Information:
This work was supported by the NovoNordisk Foundation (grant NNF15OC0016186). The NMR laboratory at Aalborg University is supported by the Obel, SparNord, and Carlsberg Foundations. S.B. is the recipient of a PhD fellowship provided by NFB—NÖ Forschung und Bildung (SC16-026).

Funding Information:
This work was supported by the NovoNordisk Foundation (grant NNF15OC0016186). The NMR laboratory at Aalborg University is supported by the Obel, SparNord, and Carlsberg Foundations. S.B. is the recipient of a PhD fellowship provided by NFB'NÖ Forschung und Bildung (SC16-026).

Publisher Copyright:
© 2021 American Chemical Society and American Society of Pharmacognosy.

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