Validamycin A (VMA) is an antifungal antibiotic derived from Streptomyces hygroscopicus commonly used in plant disease management. Surprisingly, VMA was discovered to impede the production of fumonisin B1 (FB₁) in agricultural settings. However, the specific target of VMA in Fusarium verticillioides remained unclear. To unravel the molecular mechanism of VMA, ultrastructural observations unveiled damage to mitochondrial membranes. Trehalase (FvNth) was pinpointed as the target of VMA by utilizing a 3D-printed surface plasmon resonance sensor. Molecular docking identified Trp²⁸⁵, Arg⁴⁴⁷, Asp⁴⁵², and Phe⁶⁶⁵ as the binding sites between VMA and FvNth. A ΔFvnth mutant lacking amino acids 250–670 was engineered through homologous recombination. Transcriptome analysis indicated that samples treated with VMA and ΔFvnth displayed similar expression patterns, particularly in the suppression of the FUM gene cluster. VMA treatment resulted in reduced trehalase and ATPase activity as well as diminished production of glucose, pyruvic acid, and acetyl-CoA. Conversely, these effects were absent in samples treated with ΔFvnth. This research proposes that VMA hinders acetyl-CoA synthesis by trehalase, thereby suppressing the FB₁ biosynthesis. These findings present a novel target for the development of mycotoxin control agents.

中文翻译：

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有效霉素 A 通过靶标 FvNth 抑制轮枝镰刀菌中 FB1 生物合成


Validamycin A (VMA) 是一种源自吸水链霉菌的抗真菌抗生素，常用于植物病害管理。令人惊讶的是，VMA 被发现会阻碍农业环境中伏马菌素 B1 (FB ₁ ) 的生产。然而，VMA在轮枝镰刀菌中的具体作用靶点仍不清楚。为了揭示 VMA 的分子机制，超微结构观察揭示了线粒体膜的损伤。利用 3D 打印的表面等离子共振传感器，将海藻糖酶 (FvNth) 确定为 VMA 的靶标。分子对接确定Trp ²⁸⁵ 、Arg ⁴⁴⁷ 、Asp ⁴⁵² 和Phe ⁶⁶⁵ 为VMA和FvNth之间的结合位点。通过同源重组设计了缺乏氨基酸 250-670 的 ΔFvnth 突变体。转录组分析表明，用 VMA 和 ΔFvnth 处理的样品表现出相似的表达模式，特别是在 FUM 基因簇的抑制方面。 VMA 处理导致海藻糖酶和 ATP 酶活性降低，以及葡萄糖、丙酮酸和乙酰辅酶 A 的产生减少。相反，用 ΔFvnth 处理的样品中不存在这些影响。本研究提出VMA阻碍海藻糖酶合成乙酰辅酶A，从而抑制FB ₁ 生物合成。这些发现为霉菌毒素控制剂的开发提供了新的靶点。