Journal
JOURNAL OF NATURAL PRODUCTS
Volume 84, Issue 8, Pages 2070-2080Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jnatprod.0c00947
Keywords
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Funding
- NovoNordisk Foundation [NNF15OC0016186]
- Obel Foundation
- Carlsberg Foundation
- NFB-NO Forschung und Bildung [SC16-026]
- SparNord Foundation
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The plant pathogenic fungus Fusarium graminearum was found to produce a new cyclic hexapeptide named fusahexin, and a biosynthetic model for it was proposed based on the structure of fusahexin and the domain architecture of NRPS4. NRPS4 gene cluster plays a significant role during infection and oxidative and osmotic stress, making it an important pathogen in plant infection.
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 C-delta to C-beta 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.
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