Structural Bases of Dihydroxy Acid Dehydratase Inhibition and Biodesign for Self-Resistance.

Q2 Agricultural and Biological Sciences 生物设计研究(英文) Pub Date : 2024-11-01 eCollection Date: 2024-01-01 DOI:10.34133/bdr.0046
Xin Zang, Undramaa Bat-Erdene, Weixue Huang, Zhongshou Wu, Steve E Jacobsen, Yi Tang, Jiahai Zhou
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Abstract

Dihydroxy acid dehydratase (DHAD) is the third enzyme in the plant branched-chain amino acid biosynthetic pathway and the target for commercial herbicide development. We have previously reported the discovery of fungal natural product aspterric acid (AA) as a submicromolar inhibitor of DHAD through self-resistance gene directed genome mining. Here, we reveal the mechanism of AA inhibition on DHAD and the self-resistance mechanism of AstD, which is encoded by the self-resistance gene astD. As a competitive inhibitor, the hydroxycarboxylic acid group of AA mimics the binding of the natural substrate of DHAD, while the hydrophobic moiety of AA occupies the substrate entrance cavity. Compared to DHAD, AstD has a relatively narrow substrate channel to prevent AA from binding. Several mutants of DHAD were generated and assayed to validate the self-resistance mechanism and to confer Arabidopsis thaliana DHAD with AA resistance. These results will lead to the engineering of new type of herbicides targeting DHAD and provide direction for the ecological construction of herbicide-resistant crops.

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二羟基酸脱氢酶抑制的结构基础和自我抗性的生物设计
二羟基酸脱水酶(DHAD)是植物支链氨基酸生物合成途径中的第三个酶,也是商业除草剂开发的目标。我们之前报道了通过自抗性基因定向基因组挖掘发现真菌天然产物aspterric acid(AA)是一种亚摩尔级的 DHAD 抑制剂。在此,我们揭示了 AA 对 DHAD 的抑制机制以及 AstD 的自我抗性机理,而 AstD 是由自我抗性基因 astD 编码的。作为一种竞争性抑制剂,AA的羟基羧酸基团模拟了DHAD天然底物的结合,而AA的疏水分子则占据了底物的入口空腔。与 DHAD 相比,AstD 的底物通道相对狭窄,无法与 AA 结合。为了验证 DHAD 的自我抗性机理并赋予拟南芥 DHAD AA 抗性,我们生成并检测了几个 DHAD 突变体。这些研究成果将有助于开发以 DHAD 为靶标的新型除草剂,并为抗除草剂作物的生态建设提供方向。
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CiteScore
3.90
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审稿时长
12 weeks
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