1. Plumbagin, a Natural Product with Potent Anticancer Activities, Binds to and Inhibits Dihydroorotase, a Key Enzyme in Pyrimidine Biosynthesis.
- Author
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Guan HH, Huang YH, Lin ES, Chen CJ, and Huang CY
- Subjects
- Antineoplastic Agents, Phytogenic chemistry, Binding Sites, Biological Products chemistry, Catalytic Domain, Dihydroorotase chemistry, Dihydroorotase genetics, Enzyme Inhibitors chemistry, Models, Molecular, Molecular Conformation, Molecular Structure, Mutation, Naphthoquinones chemistry, Protein Binding, Structure-Activity Relationship, Antineoplastic Agents, Phytogenic pharmacology, Biological Products pharmacology, Biosynthetic Pathways drug effects, Dihydroorotase antagonists & inhibitors, Enzyme Inhibitors pharmacology, Naphthoquinones pharmacology, Pyrimidines biosynthesis
- Abstract
Dihydroorotase (DHOase) is the third enzyme in the de novo biosynthesis pathway for pyrimidine nucleotides, and an attractive target for potential anticancer chemotherapy. By screening plant extracts and performing GC-MS analysis, we identified and characterized that the potent anticancer drug plumbagin (PLU), isolated from the carnivorous plant Nepenthes miranda , was a competitive inhibitor of DHOase. We also solved the complexed crystal structure of yeast DHOase with PLU (PDB entry 7CA1), to determine the binding interactions and investigate the binding modes. Mutational and structural analyses indicated the binding of PLU to DHOase through loop-in mode, and this dynamic loop may serve as a drug target. PLU exhibited cytotoxicity on the survival, migration, and proliferation of 4T1 cells and induced apoptosis. These results provide structural insights that may facilitate the development of new inhibitors targeting DHOase, for further clinical anticancer chemotherapies.
- Published
- 2021
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