Harzianic Acid from Trichoderma afroharzianum Is a Natural Product Inhibitor of Acetohydroxyacid Synthase,Journal of the American Chemical Society

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Harzianic Acid from Trichoderma afroharzianum Is a Natural Product Inhibitor of Acetohydroxyacid Synthase
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2021-06-16 , DOI: 10.1021/jacs.1c03988
Linan Xie ₁ , Xin Zang ₂ , Wei Cheng ₃ , Zhuan Zhang ₄ , Jiahai Zhou _{2,

5} , Mengbin Chen , Yi Tang

Affiliation

Acetohydroxyacid synthase (AHAS) is the first enzyme in the branched-chain amino acid biosynthetic pathway and is a validated target for herbicide and fungicide development. Here we report harzianic acid (HA, 1) produced by the biocontrol fungus Trichoderma afroharzianum t-22 (Tht22) as a natural product inhibitor of AHAS. The biosynthetic pathway of HA was elucidated with heterologous reconstitution. Guided by a putative self-resistance enzyme in the genome, HA was biochemically demonstrated to be a selective inhibitor of fungal AHAS, including those from phytopathogenic fungi. In addition, HA can inhibit a common resistant variant of AHAS in which the active site proline is mutated. Structural analysis of AHAS complexed with HA revealed the molecular basis of competitive inhibition, which differs from all known commercial AHAS inhibitors. The alternative binding mode also rationalizes the selectivity of HA, as well as effectiveness toward resistant mutants. A proposed role of HA biosynthesis by Tht22 in the rhizosphere is discussed based on the data.

中文翻译：

非洲木霉中的哈茨酸是乙酰羟酸合酶的天然产物抑制剂

乙酰羟酸合酶 (AHAS) 是支链氨基酸生物合成途径中的第一种酶，是除草剂和杀菌剂开发的经过验证的靶标。在这里，我们报道了生物防治真菌木霉 afroharzianum t-22 (Tht22) 产生的哈茨酸 (HA, 1 ) 作为 AHAS 的天然产物抑制剂。通过异源重建阐明了 HA 的生物合成途径。在基因组中假定的自抗性酶的指导下，HA 被生化证明是真菌 AHAS（包括来自植物病原真菌的 AHAS）的选择性抑制剂。此外，HA 还可抑制 AHAS 的常见耐药变体，其中活性位点脯氨酸发生突变。 AHAS 与 HA 复合物的结构分析揭示了竞争性抑制的分子基础，这与所有已知的商业 AHAS 抑制剂不同。替代结合模式也合理化了 HA 的选择性以及对耐药突变体的有效性。根据数据讨论了 Tht22 在根际中 HA 生物合成的拟议作用。

更新日期：2021-06-30

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