A lead aryl pyrrolidinone anilide identified using high-throughput in vivo screening was optimized for efficacy, crop safety, and weed spectrum, resulting in tetflupyrolimet. Known modes of action were ruled out through in vitro enzyme and in vivo plant-based assays. Genomic sequencing of aryl pyrrolidinone anilide-resistant Arabidopsis thaliana progeny combined with nutrient reversal experiments and metabolomic analyses confirmed that the molecular target of the chemistry was dihydroorotate dehydrogenase (DHODH), the enzyme that catalyzes the fourth step in the de novo pyrimidine biosynthesis pathway. In vitro enzymatic and biophysical assays and a cocrystal structure with purified recombinant plant DHODH further confirmed this enzyme as the target site of this class of chemistry. Like known inhibitors of other DHODH orthologs, these molecules occupy the membrane-adjacent binding site of the electron acceptor ubiquinone. Identification of a new herbicidal chemical scaffold paired with a novel mode of action, the first such finding in over three decades, represents an important leap in combatting weed resistance and feeding a growing worldwide population.

中文翻译：

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通过破坏嘧啶生物合成发挥除草剂作用的新机制

使用高通量体内筛选鉴定的芳基吡咯烷酮苯胺铅，针对功效、作物安全性和杂草谱进行了优化，最终产生了四氟吡咯甲。通过体外酶和体内植物检测排除了已知的作用方式。芳基吡咯烷酮苯胺抗性基因组测序拟南芥后代结合营养逆转实验和代谢组学分析证实，化学的分子靶点是二氢乳清酸脱氢酶（DHODH），这种酶催化嘧啶从头生物合成途径的第四步。体外酶学和生物物理测定以及纯化重组植物 DHODH 的共晶结构进一步证实了该酶是此类化学的靶位点。与其他 DHODH 直系同源物的已知抑制剂一样，这些分子占据电子受体泛醌的膜相邻结合位点。一种新的除草化学支架与一种新颖的作用模式的结合是三十多年来的首次发现，代表着在对抗杂草抗性和养活不断增长的全球人口方面的一个重要飞跃。