Naturally occurring polyphenol, morin hydrate, inhibits enzymatic activity of N-methylpurine DNA glycosylase, a DNA repair enzyme with various roles in human disease

Monica Dixon, Jordan Woodrick, Suhani Gupta, Soumendra Krishna Karmahapatra, Stephen Devito, Sona Vasudevan, Sivanesan Dakshanamurthy, Sanjay Adhikari, Venkata M. Yenugonda, Rabindra Roy

Research output: Contribution to journalArticle

11 Scopus citations

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 = 2.6 μM). 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.

Original languageEnglish (US)
Pages (from-to)1102-1111
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number5
DOIs
StatePublished - Mar 1 2015

Keywords

  • Base excision repair
  • Carcinogenesis
  • Chemosensitization
  • Enzyme inhibitors
  • Neurodegeneration

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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