Kokkonen Piia, Rahnasto-Rilla Minna, Mellini Paolo, Jarho Elina, Lahtela-Kakkonen Maija, Kokkola Tarja
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
Eur J Pharm Sci. 2014 Oct 15;63:71-6. doi: 10.1016/j.ejps.2014.06.015. Epub 2014 Jul 6.
SIRT6 is a modulator of chromatin structure having an important role in healthy ageing, and there is a crucial need to find specific modulators for it. Therefore, the activity of SIRT6 should be studied using a variety of methods. We examined the capability of SIRT6 to deacetylate a set of five fluorogenic substrates based on p53 and histone H3 sequences. The substrate designed around H3K56 deacetylation site exhibited the best signal-to-background ratio and was chosen for further studies. Nicotinamide is a known inhibitor for sirtuins, and it was found to be less potent inhibitor for SIRT6 than it is for SIRT1. In addition, we studied 15 other small molecule sirtuin modulators using the H3K56 based substrate. EX-527, quercetin and three pseudopeptidic compounds were found to be the most potent SIRT6 inhibitors, exhibiting over 50% deacetylation inhibition. These findings describe the first modulators of SIRT6 activity at the physiologically important H3K56 deacetylation site.
SIRT6是一种染色质结构调节剂，在健康衰老过程中发挥着重要作用，因此迫切需要找到其特异性调节剂。所以，应该使用多种方法来研究SIRT6的活性。我们检测了SIRT6对一组基于p53和组蛋白H3序列的五种荧光底物进行去乙酰化的能力。围绕H3K56去乙酰化位点设计的底物表现出最佳的信噪比，并被选用于进一步研究。烟酰胺是一种已知的sirtuin抑制剂，结果发现它对SIRT6的抑制作用比对SIRT1的抑制作用弱。此外，我们使用基于H3K56的底物研究了其他15种小分子sirtuin调节剂。发现EX-527、槲皮素和三种假肽化合物是最有效的SIRT6抑制剂，去乙酰化抑制率超过50%。这些发现描述了在生理上重要的H3K56去乙酰化位点上SIRT6活性的首批调节剂。
