Quercetin 3,5,7,3′,4′-pentamethyl ether from Kaempferia parviflora directly and effectively activates human SIRT1

Sirtuin 1 (SIRT1), an NAD + -dependent deacetylase, is a crucial regulator that produces multiple physiological benefits, such as the prevention of cancer and age-related diseases. SIRT1 is activated by sirtuin-activating compounds (STACs). Here, we report that quercetin 3,5,7,3′,4′-pentamethyl ether (KPMF-8), a natural STAC from Thai black ginger Kaempferia parviflora , interacts with SIRT1 directly and stimulates SIRT1 activity by enhancing the binding affinity of SIRT1 with Ac-p53 peptide, a native substrate peptide without a fluorogenic moiety. The binding affinity between SIRT1 and Ac-p53 peptide was enhanced 8.2-fold by KPMF-8 but only 1.4-fold by resveratrol. The specific binding sites of KPMF-8 to SIRT1 were mainly localized to the helix2–turn–helix3 motif in the N-terminal domain of SIRT1. Intracellular deacetylase activity in MCF-7 cells was promoted 1.7-fold by KPMF-8 supplemented in the cell medium but only 1.2-fold by resveratrol. This work reveals that KPMF-8 activates SIRT1 more effectively than resveratrol does. A compound from Thai black ginger, KPMF-8, was previously found to dramatically promote activation of SIRT1 towards a peptide substrate. Zhang et al. now show that KPMF-8 can be taken up by cells through culture media, directly interacts with SIRT1, and promotes its deacetylation activity toward native substrate more effectively than resveratrol.