title: Naturally occurring polyphenol, morin hydrate, inhibits enzymatic activity of N-methylpurine DNA glycosylase, a DNA repair enzyme with various roles in human disease.
abstract: Interest in the mechanisms of DNA repair pathways, including the base excision repair (BER) pathway specifically, has heightened since these pathways have been shown to modulate important aspects of human disease. Modulation of the expression or activity of a particular BER enzyme, N-methylpurine DNA glycosylase (MPG), has been demonstrated to play a role in carcinogenesis and resistance to chemotherapy as well as neurodegenerative diseases, which has intensified the focus on studying MPG-related mechanisms of repair. A specific small molecule inhibitor for MPG activity would be a valuable biochemical tool for understanding these repair mechanisms. By screening several small molecule chemical libraries, we identified a natural polyphenolic compound, morin hydrate, which inhibits MPG activity specifically (IC50=2.6μM). Detailed mechanism analysis showed that morin hydrate inhibited substrate DNA binding of MPG, and eventually the enzymatic activity of MPG. Computational docking studies with an x-ray derived MPG structure as well as comparison studies with other structurally-related flavonoids offer a rationale for the inhibitory activity of morin hydrate observed. The results of this study suggest that the morin hydrate could be an effective tool for studying MPG function and it is possible that morin hydrate and its derivatives could be utilized in future studies focused on the role of MPG in human disease.
authors: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, United States.
authors: Monica
authors: M
authors: Dixon
authors: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, United States.
authors: Jordan
authors: J
authors: Woodrick
authors: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, United States.
authors: Suhani
authors: S
authors: Gupta
authors: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, United States.
authors: Soumendra Krishna
authors: SK
authors: Karmahapatra
authors: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, United States.
authors: Stephen
authors: S
authors: Devito
authors: Department of Biochemistry, Georgetown University Medical School, Washington, DC 20057, United States.
authors: Sona
authors: S
authors: Vasudevan
authors: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, United States.
authors: Sivanesan
authors: S
authors: Dakshanamurthy
authors: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, United States.
authors: Sanjay
authors: S
authors: Adhikari
authors: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, United States.
authors: Venkata M
authors: VM
authors: Yenugonda
authors: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, United States. Electronic address: rr228@georgetown.edu.
authors: Rabindra
authors: R
authors: Roy
mesh_terms: D045744:Cell Line, Tumor; D045647:DNA Glycosylases / Q000037:antagonists & inhibitors*; D004260:DNA Repair; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D047309:Flavones
chemical_list: D045647:DNA Glycosylases; D004791:Enzyme Inhibitors; D005419:Flavonoids; C008548:morin; D047309:Flavones; C076131:DNA-3-methyladenine glycosidase II
keywords: Base excision repair; Carcinogenesis; Chemosensitization; Enzyme inhibitors; Neurodegeneration
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