National Key Laboratory of Green Pesticide, Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan 430079, PR China.
National Key Laboratory of Green Pesticide, Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan 430079, PR China.
Trends Biochem Sci. 2023 Jun;48(6):568-584. doi: 10.1016/j.tibs.2023.02.006. Epub 2023 Mar 21.
4-Hydroxyphenylpyruvate dioxygenase (HPPD) plays a key role in tyrosine metabolism and has been identified as a promising target for herbicide and drug discovery. The structures of HPPD complexed with different types of inhibitors have been determined previously. We summarize the structures of HPPD complexed with structurally diverse molecules, including inhibitors, natural products, substrates, and catalytic intermediates; from these structures, the detailed inhibitory mechanisms of different inhibitors were analyzed and compared, and the key structural factors determining the slow-binding behavior of inhibitors were identified. Further, we propose four subpockets that accommodate different inhibitor substructures. We believe that these analyses will facilitate in-depth understanding of the enzymatic reaction mechanism and enable the design of new inhibitors with higher potency and selectivity.
4- 羟苯基丙酮酸双加氧酶（HPPD）在酪氨酸代谢中起着关键作用，已被确定为除草剂和药物发现的有前途的靶标。以前已经确定了与不同类型抑制剂结合的 HPPD 结构。我们总结了与结构多样的分子（包括抑制剂、天然产物、底物和催化中间产物）结合的 HPPD 结构；从这些结构中，分析和比较了不同抑制剂的详细抑制机制，并确定了决定抑制剂慢结合行为的关键结构因素。此外，我们提出了容纳不同抑制剂亚结构的四个亚口袋。我们相信，这些分析将有助于深入了解酶促反应机制，并能够设计出具有更高效力和选择性的新型抑制剂。
