Insights into 4-hydroxyphenylpyruvate dioxygenase-inhibitor interactions from comparative structural biology

作者：Lin, Hong-Yan; Dong, Jin; Dong, Jiangqing; Yang, Wen-Chao; Yang, Guang-Fu^*

来源：Trends in Biochemical Sciences, 2023, 48(6): 568-584.

DOI：10.1016/j.tibs.2023.02.006

• P-HYDROXYPHENYLPYRUVATE DIOXYGENASE
• 2-HIS-1-CARBOXYLATE FACIAL TRIAD
• TYROSINEMIA TYPE-III
• HYDROXYMANDELATE SYNTHASE
• HERBICIDAL ACTIVITY
• (4-HYDROXYPHENYL)PYRUVATE DIOXYGENASE
• CATALYTIC-REACTION
• CRYSTAL-STRUCTURES
• ACTIVE-SITE
• TRIKETONE

4-Hydroxyphenylpyruvate dioxygenase (HPPD) plays a key role in tyrosine me-tabolism 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 com-plexed with structurally diverse molecules, including inhibitors, natural products, substrates, and catalytic intermediates; from these structures, the detailed inhib-itory 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 in-hibitor substructures. We believe that these analyses will facilitate in-depth un-derstanding of the enzymatic reaction mechanism and enable the design of new inhibitors with higher potency and selectivity.