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Plumbagin, a Natural Product with Potent Anticancer Activities, Binds to and Inhibits Dihydroorotase, a Key Enzyme in Pyrimidine Biosynthesis
- Source :
- International Journal of Molecular Sciences, Volume 22, Issue 13, International Journal of Molecular Sciences, Vol 22, Iss 6861, p 6861 (2021)
- Publication Year :
- 2021
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2021.
-
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.
- Subjects :
- Models, Molecular
crystal structure
QH301-705.5
drug design
Protein Data Bank (RCSB PDB)
Molecular Conformation
pyrimidine biosynthesis
anticancer
dihydropyrimidinase
Catalysis
Article
allantoinase
Inorganic Chemistry
chemistry.chemical_compound
Structure-Activity Relationship
4T1 cell
Biosynthesis
Catalytic Domain
CAD
Biology (General)
Physical and Theoretical Chemistry
Enzyme Inhibitors
QD1-999
Molecular Biology
Spectroscopy
plumbagin
chemistry.chemical_classification
Biological Products
Natural product
Binding Sites
Molecular Structure
Organic Chemistry
General Medicine
Plumbagin
Antineoplastic Agents, Phytogenic
Computer Science Applications
Biosynthetic Pathways
Chemistry
Enzyme
Dihydroorotase
Pyrimidines
chemistry
Biochemistry
Dihydropyrimidinase
Pyrimidine metabolism
Mutation
dihydroorotase
Naphthoquinones
Protein Binding
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....387824f2a7437c714da99ff23a714122
- Full Text :
- https://doi.org/10.3390/ijms22136861