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.

Sirtuin 1 (SIRT1) 是一种 NAD ⁺依赖性脱乙酰酶，是一种重要的调节剂，可产生多种生理益处，例如预防癌症和与年龄相关的疾病。SIRT1 被 sirtuin 激活化合物 (STAC) 激活。在这里，我们报道了槲皮素 3,5,7,3',4'-五甲醚 (KPMF-8)，一种来自泰国黑姜的天然 STAC 小花山奈，直接与 SIRT1 相互作用并通过增强 SIRT1 与 Ac-p53 肽（一种不含荧光部分的天然底物肽）的结合亲和力来刺激 SIRT1 活性。SIRT1 和 Ac-p53 肽之间的结合亲和力被 KPMF-8 增强了 8.2 倍，但被白藜芦醇增强了 1.4 倍。KPMF-8 与 SIRT1 的特异性结合位点主要位于 SIRT1 N 末端结构域中的 helix2-turn-helix3 基序。在细胞培养基中补充的 KPMF-8 可将 MCF-7 细胞内的细胞内脱乙酰酶活性提高 1.7 倍，而白藜芦醇仅可提高 1.2 倍。这项工作表明 KPMF-8 比白藜芦醇更有效地激活 SIRT1。