Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives.

ABSTRACT: Mammalian Sirtuin 6 (Sirt6) is an NAD⁺-dependent protein deacylase regulating metabolism and chromatin homeostasis. Sirt6 activation protects against metabolic and aging-related diseases, and Sirt6 inhibition is considered a cancer therapy. Available Sirt6 modulators show insufficient potency and specificity, and even partially contradictory Sirt6 effects were reported for the plant flavone quercetin. To understand Sirt6 modulation by quercetin-based compounds, we analysed their binding and activity effects on Sirt6 and other Sirtuin isoforms and solved crystal structures of compound complexes with Sirt6 and Sirt2. We find that quercetin activates Sirt6 via the isoform-specific binding site for pyrrolo[1,2-a]quinoxalines. Its inhibitory effect on other isoforms is based on an al

SUBMITTER: You W 

PROVIDER: S-EPMC6914789 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature