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, 8 (1), 4163

Natural Polyphenols as Sirtuin 6 Modulators

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Natural Polyphenols as Sirtuin 6 Modulators

Minna Rahnasto-Rilla et al. Sci Rep.

Abstract

Flavonoids are polyphenolic secondary metabolites synthesized by plants and fungus with various pharmacological effects. Due to their plethora of biological activities, they have been studied extensively in drug development. They have been shown to modulate the activity of a NAD+-dependent histone deacetylase, SIRT6. Because SIRT6 has been implicated in longevity, metabolism, DNA-repair, and inflammatory response reduction, it is an interesting target in inflammatory and metabolic diseases as well as in cancer. Here we show, that flavonoids can alter SIRT6 activity in a structure dependent manner. Catechin derivatives with galloyl moiety displayed significant inhibition potency against SIRT6 at 10 µM concentration. The most potent SIRT6 activator, cyanidin, belonged to anthocyanidins, and produced a 55-fold increase in SIRT6 activity compared to the 3-10 fold increase for the others. Cyanidin also significantly increased SIRT6 expression in Caco-2 cells. Results from the docking studies indicated possible binding sites for the inhibitors and activators. Inhibitors likely bind in a manner that could disturb NAD+ binding. The putative activator binding site was found next to a loop near the acetylated peptide substrate binding site. In some cases, the activators changed the conformation of this loop suggesting that it may play a role in SIRT6 activation.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
General scaffold of flavonoids (A). The structures of the most potent SIRT6 modulators are displayed, and additional structures are available in supplementary Tables S1 and S2. The yellow background represents inhibitors, gray represents inhibitors and activators and blue represents activators (B).
Figure 2
Figure 2
SIRT6 modulation by selected flavonoids. Inhibition % at the 100 µM concentration (A), at the 10 µM concentration (B) of flavonoids. Black bars indicate ≥60% inhibition. Activation in the presence of 100 µM flavonoids (C). Black bars represent more than 2 -fold activation. The data is presented as mean ± SD, (n = 3).
Figure 3
Figure 3
Caco-2 cells after cyanidin treatment and expression of SIRT6 protein. Cells were exposed to 0.5% DMSO (control) or various concentration of compound 17 (n = 5) for 24 h. (A) Representative light microscopy images of Caco-2 cells after control (Cnt), 100 µM cyanidin or 200 µM cyanidin treatment. (B) Immunoblotting analysis of SIRT6 protein. SIRT6 protein levels (MW: 39 kDa) were normalized relative to α-tubulin (MW: 50 kDa) and quantification is represented as fold change respect to control. Values are expressed as mean ± SEM of four independent experiment (*p values < 0.05; one way-ANOVA). SIRT6 expression were determined by immunoblotting (B).
Figure 4
Figure 4
Cyanidin (compound 17) effect on the expression of FoxO3α (A), Twist1 (B) and GLUT1 (C) protein. Caco-2 cells were treated with DMSO (white bar) or 50 and 100 µM compound 17 (grey bars) for 24 h. FoxO3α, Twist1 and GLUT1 expression were quantified and normalised with α-tubulin or H3. Data represent the mean ± SEM of three independent experiments,*p < 0.05, **p < 0.01 and ***p < 0.001 between the indicated groups.
Figure 5
Figure 5
SIRT6 and locations of binding sites of activators (light turquoise), inhibitors (yellow), peptide substrates (blue) and for NAD+ (brownish gray). Close-up view of the interactions of best inhibitors, compound 4 (A) and compound 5 (B) and best activator, compound 17 (C). The best activators compound 17 (D) and compound 18 (E) induce changes on the β6/α6 loop and the orientation of Trp186 and Glu187 similar to known activators oleic acid (F) and linoleic acid (G). Interactions: Yellow dashes indicate hydrogen-bonding, dark green dashes indicate π-π stacking and light purple dash indicates salt bridge (interaction to Asp185). Pink residues and loops indicate the original residue and loop orientation in the protein structure before inhibitor or activator binding.

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