Protein Adducts and Protein Oxidation as Molecular Mechanisms of Flavonoid Bioactivity

Molecules. 2021 Aug 23;26(16):5102. doi: 10.3390/molecules26165102.


There are tens of thousands of scientific papers about flavonoids and their impacts on human health. However, despite the vast amount of energy that has been put toward studying these compounds, a unified molecular mechanism that explains their bioactivity remains elusive. One contributing factor to the absence of a general mechanistic explanation of their bioactivity is the complexity of flavonoid chemistry in aqueous solutions at neutral pH. Flavonoids have acidic protons, are redox active, and frequently auto-oxidize to produce an array of degradation products including electrophilic quinones. Flavonoids are also known to interact with specificity and high affinity with a variety of proteins, and there is evidence that some of these interactions may be covalent. This review summarizes the mechanisms of flavonoid oxidation in aqueous solutions at neutral pH and proposes the formation of protein-flavonoid adducts or flavonoid-induced protein oxidation as putative mechanisms of flavonoid bioactivity in cells. Nucleophilic residues in proteins may be able to form covalent bonds with flavonoid quinones; alternatively, specific amino acid residues such as cysteine, methionine, or tyrosine in proteins could be oxidized by flavonoids. In either case, these protein-flavonoid interactions would likely occur at specific binding sites and the formation of these types of products could effectively explain how flavonoids modify proteins in cells to induce downstream biochemical and cellular changes.

Keywords: EGCG; flavonoid bioactivity; flavonoid biological mechanisms; flavonoids; protein adducts; protein-flavonoid interactions; quercetin; quinones.

Publication types

  • Review

MeSH terms

  • Animals
  • Flavonoids / chemistry
  • Flavonoids / pharmacology*
  • Humans
  • Models, Molecular
  • Oxidation-Reduction
  • Proteins / metabolism*
  • Solutions


  • Flavonoids
  • Proteins
  • Solutions