Natural polyphenols convert proteins into histone-binding ligands

Antioxidants are sensitive to oxidation and are immediately converted into their oxidized forms that can react with pro-teins. We have recently found that proteins incubated with oxidized vitamin C (dehydroascorbate) gain a new function as a histone-binding ligand. This finding led us to predict that an-tioxidants, through conversion to their oxidized forms, may generally have similar functions. In the present study, we identified several natural polyphenols as a source of histone ligands and characterized the mechanism for the interaction of protein-bound polyphenols with histone. Through screening of 25 plant-derived polyphenols by assessing their ability to convert bovine serum albumin into histone ligands, we iden-tified seven polyphenols, including (-)-epigallocatechin-3-O-gallate (EGCG). Additionally, we found that the histone tail domain, which is a highly charged and conformationally flex-ible region, is involved in the interaction with the polyphenol-modified proteins. Further mechanistic studies showed the involvement of a complex heterogeneous group of the polyphenol-derived compounds bound to proteins as histone-binding elements. We also determined that the interaction of polyphenol-modified proteins with histones formed aggregates and exerted a protective effect against histone-mediated cyto-toxicity toward endothelial cells. These findings demonstrated that histones are one of the major targets of polyphenol-modified proteins and provide important insights into the chemoprotective functions of dietary polyphenols.