Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives

You, W.; Zheng, Wei; Weiss, Sandra; Chua, Katrin F.; Steegborn, Clemens

doi:10.1038/s41598-019-55654-1

Cited by 69 publications

(89 citation statements)

References 51 publications

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“…A subsequent Xray crystal structure of SIRT6 bound with cyanidin confirmed this binding orientation (Fig. 6) (149). Interestingly, treatment of Caco-2 cells with cyanidin showed a dose-dependent increase (3.5-fold) in SIRT6 protein levels (115).…”

Section: Activationmentioning

confidence: 62%

Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators

Klein

Denu

2020

Journal of Biological Chemistry

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Sirtuin 6 (SIRT6) is a nuclear NAD+-dependent deacetylase of histone H3 that regulates genome stability and gene expression. However, non-histone substrates and additional catalytic activities of SIRT6, including long-chain deacylation and mono-ADP-ribosylation of other proteins have also been reported, but many of these non-canonical roles remain enigmatic. Genetic studies have revealed critical homeostatic cellular functions of SIRT6, underscoring the need to better understand which catalytic functions and molecular pathways are driving SIRT6-associated phenotypes. At the physiological level, SIRT6 activity promotes increased longevity by regulating metabolism andDNA repair. Recent work has identified natural products and synthetic small-molecules capable of activating the inefficient in vitrodeacetylase activity of SIRT6. Here, we discuss the cellular functions of SIRT6 with a focus on attributing its catalytic activity to its proposed biological functions. We cover the molecular architecture and catalytic mechanisms that distinguish SIRT6 from other NAD+-dependent deacylases. We propose that combining specific SIRT6 amino-acid substitutions identified in enzymology studies, and activity-selective compounds could help delineate SIRT6 functions in specific biological contexts and resolve the apparently conflicting roles of SIRT6 in processes such as tumor development. We further highlight the recent development of small-molecule modulators that provide additional biologicalinsight into SIRT6 functions and offer therapeutic approaches to manage metabolic and age-associated diseases.

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Section: Activationmentioning

confidence: 62%

Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators

Klein

Denu

2020

Journal of Biological Chemistry

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“…Interestingly, from Figure 4, we can conclude that the two conformationally similar inhibitors have the same binding mode with SIRT6. In the experiments, You et al [23,25] and Lu et al [43] reported the binding sites of potential inhibitors to SIRT6 (Phe64, Phe82 and Phe86 at N terminus). Our results agree well with the experiments.…”

Section: Resultsmentioning

confidence: 99%

Structural Insight into the Interactions between Structurally Similar Inhibitors and SIRT6

Zhao

Zhu

Wang

et al. 2020

IJMS

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Sirtuin 6 (SIRT6) is an NAD+-dependent deacetylase with a significant role in 20% of all cancers, such as colon cancers and rectal adenocarcinoma. However, there is currently no effective drug for cancers related to SIRT6. To explore potential inhibitors of SIRT6, it is essential to reveal details of the interaction mechanisms between inhibitors and SIRT6 at the atomic level. The nature of small molecules from herbs have many advantages as inhibitors. Based on the conformational characteristics of the inhibitor Compound 9 (Asinex ID: BAS13555470), we explored the natural molecule Scutellarin, one compound of Huang Qin, which is an effective herb for curing cancer that has been described in the Traditional Chinese Medicine (TCMS) library. We investigated the interactions between SIRT6 and the inhibitors using molecular dynamics (MD) simulations. We illustrated that the structurally similar inhibitors have a similar binding mode to SIRT6 with residues-Leu9, Phe64, Val115, His133 and Trp188. Hydrophobic and π-stacking interactions play important roles in the interactions between SIRT6 and inhibitors. In summary, our results reveal the interactive mechanism of SIRT6 and the inhibitors and we also provide Scutellarin as a new potential inhibitor of SIRT6.Our study provides a new potential way to explore potential inhibitors from TCMS.Int. J. Mol. Sci. 2020, 21, 2601 2 of 15 cancers and rectal adenocarcinoma, according to the Cancer Genome Atlas database [17]. Crystal structure of SIRT6 (PDB code 3K35) [23,24] includes the hydrophobic channel, the Rossman fold and the small domain shown in Figure S1A [25]. The Rossman fold is one of the most common and widely distributed super-secondary structures. The dinucleotide such as FAD, NAD and NADP can bind in the domain [26]. There is a long hydrophobic-channel pocket that binds the small molecules [27].Probing potential inhibitors has become essential for the development of cancer drug design [4,28,29]. Several potential inhibitors of SIRT6 have been reported, such as Compound 9 [3,30], trichostatin A [23] and inhibitors with a salicylate-linked structure [31]. Parenti et al. synthesized three (SYN17739303, BAS13555470 or Compound 9 and BAS00417531) potential inhibitors for SIRT6 [30]. Interestingly we found that the three inhibitors have similar chemical structure. The structures of these inhibitors can give insight into the direction of the design of improved inhibitors. However, the mechanism of interactions between the inhibitors and SIRT6 is still elusive. The relationship between the interactions and the bioactivity of SIRT6 is also not clear.Small molecules from herbs have many advantages as inhibitors. For example, herbal medicine has low toxicity and can be easily absorbed and easily expelled from the body. In this investigation, we therefore sought to probe structure-based inhibitors similar to Compound 9 [30] from Traditional Chinese Medicines (TCMS). Scutellarin is one compound of Scutellaria baicalensis Georgi, named Huang Qin in TCMS. It has been reported that ...

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“…Several amino acid residues (e.g., Ile 61, Pro62, Phe64/82/86, Val70, Asn114, Val115, and Asp116) form a hydrophobic pocket to anchor the molecules in the pocket with polar contact and potential H‐bonds. Most modulators binding in the active site have partial overlap with the pocket where NAM moiety of NAD + occupies (Figure 1A, C site), and thus no ADPr competition but statistically significant NAD + or NAM competition with them are detected in the activity assays 54,296–300 . Importantly, SIRT6 activators binding in this pocket primarily exerts concentration‐dependent deacetylation activity.…”

Section: Sirt6 Modulatorsmentioning

confidence: 99%

“…Importantly, SIRT6 activators binding in this pocket primarily exerts concentration‐dependent deacetylation activity. Some of them has no improvement to or even inhibits the SIRT6‐dependent demyristoylation activity, likely due to the compatible binding of activators with that of acetylated substrates and overlapping with longer acylated substrate 34,35,296,296,300,301 …”

Section: Sirt6 Modulatorsmentioning

confidence: 99%

Emerging roles of SIRT6 in human diseases and its modulators

Liu

Chen

Liu

et al. 2020

Medicinal Research Reviews

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The biological functions of sirtuin 6 (SIRT6; e.g., deacetylation, defatty‐acylation, and mono‐ADP‐ribosylation) play a pivotal role in regulating lifespan and several fundamental processes controlling aging such as DNA repair, gene expression, and telomeric maintenance. Over the past decades, the aberration of SIRT6 has been extensively observed in diverse life‐threatening human diseases. In this comprehensive review, we summarize the critical roles of SIRT6 in the onset and progression of human diseases including cancer, inflammation, diabetes, steatohepatitis, arthritis, cardiovascular diseases, neurodegenerative diseases, viral infections, renal and corneal injuries, as well as the elucidation of the related signaling pathways. Moreover, we discuss the advances in the development of small molecule SIRT6 modulators including activators and inhibitors as well as their pharmacological profiles toward potential therapeutics for SIRT6‐mediated diseases.

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Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives

Cited by 69 publications

References 51 publications

Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators

Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators

Structural Insight into the Interactions between Structurally Similar Inhibitors and SIRT6

Emerging roles of SIRT6 in human diseases and its modulators

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