Structural analysis of the inhibitory effects of polyphenols, (+)‐hopeaphenol and (−)‐isohopeaphenol, on human SIRT1 (original) (raw)
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Natural Product Communications
SIRT1 is a mammalian ortholog of the yeast enzyme Sir2, which is an NAD+-dependent deacetylase of histones, p53, FOXO, NF-κB, PGC-1α, and other transcription factors. The Sir2 protein is reported as a longevity protein in yeast. Resveratrol, a polyphenol isolated from various types of plant families, particularly the Vitaceae family, is a known naturally occurring SIRT1 activator. In this study, we evaluated the effects of four types of resveratrol dimers and four types of tetramers isolated from vitaceous plants, and one type of resveratrol tetramer isolated from a dipterocarpaceous plant on purified human SIRT1 enzyme activity. Of the resveratrol dimers examined, (+)-ε-viniferin and pallidol exhibited no effect on SIRT1 enzyme activity, whereas (+)-ampelopsin B and (-)-ampelopsin F showed inhibitory activity on SIRT1. However, all the resveratrol tetramers examined, i.e., (+)-vitisin A, (-)-vitisin B, (+)-hopeaphenol, (-)-hopeaphenol, and (-)-isohopeaphenol markedly inhibited the ...
Resveratrol-like Compounds as SIRT1 Activators
International Journal of Molecular Sciences, 2022
The sirtuin 1 (SIRT1) activator resveratrol has emerged as a promising candidate for the prevention of vascular oxidative stress, which is a trigger for endothelial dysfunction. However, its clinical use is limited by low oral bioavailability. In this work, we have applied a previously developed computational protocol to identify the most promising derivatives from our in-house chemical library of resveratrol derivatives. The most promising compounds in terms of SIRT1 activation and oral bioavailability, predicted in silico, were evaluated for their ability to activate the isolated SIRT1 enzyme. Then, we assessed the antioxidant effects of the most effective derivative, compound 3d, in human umbilical vein endothelial cells (HUVECs) injured with H2O2 100 µM. The SIRT1 activator 3d significantly preserved cell viability and prevented an intracellular reactive oxygen species increase in HUVECs exposed to the oxidative stimulus. Such effects were partially reduced in the presence of a sirtuin inhibitor, sirtinol, confirming the potential role of sirtuins in the activity of resveratrol and its derivatives. Although 3d appeared less effective than resveratrol in activating the isolated enzyme, the effects exhibited by both compounds in HUVECs were almost superimposable, suggesting a higher ability of 3d to cross cell membranes and activate the intracellular target SIRT1.
A Molecular Mechanism for Direct Sirtuin Activation by Resveratrol
PLoS ONE, 2012
Sirtuins are protein deacetylases regulating metabolism, stress responses, and aging processes, and they were suggested to mediate the lifespan extending effect of a low calorie diet. Sirtuin activation by the polyphenol resveratrol can mimic such lifespan extending effects and alleviate metabolic diseases. The mechanism of Sirtuin stimulation is unknown, hindering the development of improved activators. Here we show that resveratrol inhibits human Sirt3 and stimulates Sirt5, in addition to Sirt1, against fluorophore-labeled peptide substrates but also against peptides and proteins lacking the non-physiological fluorophore modification. We further present crystal structures of Sirt3 and Sirt5 in complex with fluorogenic substrate peptide and modulator. The compound acts as a top cover, closing the Sirtuin's polypeptide binding pocket and influencing details of peptide binding by directly interacting with this substrate. Our results provide a mechanism for the direct activation of Sirtuins by small molecules and suggest that activators have to be tailored to a specific Sirtuin/substrate pair.
Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol
Genes & development, 2015
Sirtuins with an extended N-terminal domain (NTD), represented by yeast Sir2 and human SIRT1, harbor intrinsic mechanisms for regulation of their NAD-dependent deacetylase activities. Elucidation of the regulatory mechanisms is crucial for understanding the biological functions of sirtuins and development of potential therapeutics. In particular, SIRT1 has emerged as an attractive therapeutic target, and the search for SIRT1-activating compounds (STACs) has been actively pursued. However, the effectiveness of a class of reported STACs (represented by resveratrol) as direct SIRT1 activators is under debate due to the complication involving the use of fluorogenic substrates in in vitro assays. Future efforts of SIRT1-based therapeutics necessitate the dissection of the molecular mechanism of SIRT1 stimulation. We solved the structure of SIRT1 in complex with resveratrol and a 7-amino-4-methylcoumarin (AMC)-containing peptide. The structure reveals the presence of three resveratrol mol...
Natural polyphenols as sirtuin 6 modulators
Scientific reports, 2018
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 stud...
Biomolecules
Resveratrol, the most widely studied natural phytochemical, has been shown to interact with different target proteins. Previous studies show that resveratrol binds and inhibits DNA polymerases and some other enzymes; however, the binding and functioning mechanisms remain unknown. The elucidated knowledge of inhibitory mechanisms of resveratrol will assist us in new drug discovery. We utilized molecular docking and molecular dynamics (MD) simulation to reveal how resveratrol and structurally similar compounds bind to various nucleotide-dependent enzymes, specifically, DNA polymerases, HIV-1 reverse transcriptase, and ribonucleotide reductase. The results show that resveratrol and its analogs exert their inhibitory effects by competing with the substrate dNTPs in these enzymes and blocking elongation of chain polymerization. In addition, the results imply that resveratrol binds to a variety of other ATP-/NTP-binding proteins.
Sirt1 activation by resveratrol is substrate sequence-selective
Aging, 2013
Sirtuins are protein deacetylases used as therapeutic targets. Pharmacological Sirt1 activation has been questioned since the in vitro activator resveratrol failed to stimulate deacetylation of several physiological substrates. We tested the influence of substrate sequence by analyzing resveratrol effects on Sirt1-dependent deacetylation of 6802 physiological acetylation sites using peptide microarrays. Resveratrol stimulated deacetylation of a small set of sites and inhibited deacetylation of another set, whereas most substrates were hardly affected. Solution assays confirmed these substrate categories, and statistical analysis revealed their sequence features. Our results reveal substrate sequence dependence for Sirt1 modulation and suggest substrates contributing to resveratrol effects.
Journal of Biological Chemistry, 2001
Resveratrol (3,4,5-trihydroxy-trans-stilbene) is a natural phytoalexin found in grapes and wine, which shows antioxidant and antiproliferative activities. In this study we have investigated whether these properties are dependent on similar or different structural determinants of the molecule. To this purpose, resveratrol derivatives, in which all or each single hydroxylic function were selectively substituted with methyl groups, were synthesized. Analogues with the stilbenic double bond reduced or with the stereoisomery modified were also investigated. The antioxidant activity of these compounds was evaluated by measuring the inhibition of citronellal thermo-oxidation, or the reduction of 2,2-diphenyl-1-picrylhydrazyl radical. In addition, the protection against lipid peroxidation was determined in rat liver microsomes, and in human primary cell cultures. The antiproliferative activity was evaluated by a clonogenic assay, and by analysis of cell cycle progression and DNA synthesis. The results showed that the hydroxyl group in 4 position is not the sole determinant for antioxidant activity. In contrast, the presence of 4-OH together with stereoisomery in the trans-conformation (4-hydroxystyryl moiety) was absolutely required for inhibition of cell proliferation. Enzymatic assays in vitro demonstrated that inhibition of DNA synthesis was induced by a direct interaction of resveratrol with DNA polymerases ␣ and ␦.
Resveratrol and SIRT1 Activators for the Treatment of Aging and Age-Related Diseases
Resveratrol - Adding Life to Years, Not Adding Years to Life, 2019
Reduced calorie intake is a religious and medical practice known since very old times, but its direct influence on life span in all organisms, included humans, has been demonstrated in the modern era. Not only periodic fasting, but also natural or synthetic compounds that mimic this phenomenon are growing to slow aging and the onset of chronic morbidities. Resveratrol (RSV), a plant polyphenol, is an elixir of longevity for simple organisms and preclinical rodent models even if a beneficial role in humans is still debated. Its main rejuvenating mechanism copes with the activation of specific longevity genes called sirtuins. Among seven known mammalian sirtuins, sirtuin 1 is the most studied. This pleiotropic nicotinamide adenine dinucleotide (NAD)-based deacetylase maintains longevity by removing acetyl group in nuclear histones, transcription factors, and other DNA repairing proteins. Actually, an exciting challenge is to discover and test novel sirtuin 1 activators to extend life span and to treat age-associated disabilities. This chapter updates on the antiaging effect of RSV and sirtuin 1 activators in experimental animals and in humans. Finally, pros and cons on RSV analogues and sirtuin 1 activators tested in preclinical and clinical trials to hamper neurological deficit, cardiovascular complications, diabetes, bone and muscle deterioration, and cancer are discussed.