A Molecular Mechanism for Direct Sirtuin Activation by Resveratrol

A Superimposition of Sirt5/FdL1/resveratrol and Sirt5/succinylated H3 peptide/NAD⁺. The movement of the β8/α13 loop is indicated by an arrow. The succinylated H3 peptide and the NAD⁺ molecule are omitted for clarity. B Model for the regulation of Sirtuins by resveratrol-like compounds. After binding of the substrate polypeptide the small molecule attaches to a “docking patch” (DP). It induces ordering of an “adaptable loop” (AL), leading to closure of the peptide exit and stabilization of the enzyme/substrate complex. Depending on the fit between substrate and small-molecule, the substrate is properly oriented in the active site (AS; e.g. Sirt5/Cytochrome c/resveratrol) or adopts a non-productive conformation (e.g. Sirt3/GDH/resveratrol), leading to stimulation or inhibition of turnover, respectively. After deacetylation, the activator dissociates, opening the peptide exit for product release.