N‐Acylethanolamines Bind to SIRT6

Sirtuin 6 (SIRT6) is an NAD+‐dependent histone deacetylase enzyme that is involved in multiple molecular pathways related to aging. Initially, it was reported that SIRT6 selectively deacetylated H3K9Ac and H3K56Ac; however, it has more recently been shown to preferentially hydrolyze long‐chain fatty acyl groups over acetyl groups in vitro. Subsequently, fatty acids were demonstrated to increase the catalytic activity of SIRT6. In this study, we investigated whether a series of N‐acylethanolamines (NAEs), quercetin, and luteolin could regulate SIRT6 activity. NAEs increased SIRT6 activity, with oleoylethanolamide having the strongest activity (EC₅₀ value of 3.1 μm ). Quercetin and luteolin were demonstrated to have dual functionality with respect to SIRT6 activity; namely, they inhibited SIRT6 activity with IC₅₀ values of 24 and 2 μm , respectively, and stimulated SIRT6 activity more than sixfold (EC₅₀ values of 990 and 270 μm , respectively).