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^δ to C^β 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.

中文翻译：

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环状疏水六肽 Fusahexin 是禾谷镰刀菌中非核糖体肽合成酶的产物

已知植物病原真菌禾谷镰刀菌在植物感染期间会产生多种次生代谢物。这包括几种非核糖体肽。最近，fusaoctaxin ( NRPS5 /9 ) 和短杆菌肽 ( NRPS8 ) 基因簇被证明是由宿主相互作用诱导的。为了扩大我们对这一重要病原体的理解，我们研究了NRPS4基因簇在感染和氧化和渗透应激过程中的参与。NRPS4 的过度表达导致发现了一种新的环状六肽，fusahexin ( 1 )，其氨基酸序列为环-( d -Ala- l -Leu- d -allo -Thr -l -Pro- d -Leu- l -Leu)。结构分析揭示了前面苏氨酸的脯氨酸 C ^δ到 C ^β之间的不寻常的醚键，导致了恶嗪环系统。比较基因组分析表明，除了五模块非核糖体肽合成酶 (NRPS) 外，小基因簇仅编码 ABC 转运蛋白。基于fusahexin和域结构的结构NRPS4，我们提出了一种生物合成模型，其中所述终端模块用于包括两个亮氨酸单元。到目前为止，主要针对铁载体合成酶描述了 NRPS 模块的迭代使用，这使得NRPS4 具有独特迭代模块使用的真菌非铁载体 NRPS 的罕见示例。