Structural analysis of the inhibitory effects of polyphenols, (+)-hopeaphenol and (-)-isohopeaphenol, on human SIRT1.

Human sirtuin 1 (hSIRT1) is a NAD(+)-dependent deacetylase that regulates several cellular processes. Unlike resveratrol, natural polymeric phenolic compounds isolated from Vitaceae are mostly hSIRT1 inhibitors. The resveratrol tetramer, (+)-hopeaphenol ((+)-HP), and its geometric isomer, (-)-isohopeaphenol ((-)-iHP), were tested for inhibitory effects on purified hSIRT1 using a fluorescent derivative of peptide substrate p53-AMC (Fluor de Lys) and a cofactor NAD(+). The Lineweaver-Burk plots indicated that both (+)-HP and (-)-iHP were competitive inhibitors against NAD(+). Computer-assisted modeling of the binding of these molecules with hSIRT1 protein provided the most feasible conformation of the enzyme-inhibitor complex. (c) 2018 BioFactors, 45(2):253-258, 2019