How much successful are the medicinal chemists in modulation of SIRT1: A critical review (original) (raw)
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Analytical Biochemistry, 2009
Sirtuins are nicotinamide adenine dinucleotide (NAD + )-dependent deacetylases that catalyze the deacetylation of proteins such as histones and p53. A sensitive and convenient fluorometric assay for evaluating the SIRT1 enzymatic activity was developed here. Specifically, the remaining NAD + after the deacetylation was determined by converting NAD + to a highly fluorescent cyclized a-adduct compound. By this assay, we found that nicotinamide, Cu 2+ , and Zn 2+ antagonize the activity of SIRT1. Resveratrol stimulates the enzymatic activity specifically with 7-amino-4-methylcoumarin (AMC)-labeled acetylated peptide. Epigallocatechin galate (EGCG) inhibits SIRT1 activity with both AMC-labeled and unlabeled peptide. However, a combination of vitamin C with EGCG can reverse the inhibition of EGCG with the unlabeled peptide or stimulate the deacetylation of AMC-labeled peptide by SIRT1. The assay does not require any isotopic material and thus is biologically safe. It can be adapted to a 96-well microplate for highthroughput screening. Notably, the acetylated peptides with or without fluorescent labels may be used in the assay, which facilitates the substrate specificity study of SIRT1 activators or inhibitors in vitro.
NAD+-dependent histone deacetylases (sirtuins) as novel therapeutic targets
Medicinal Research Reviews, 2009
Histone deacetylases (HDACs) are enzymes that cleave off acetyl groups from acetyl-lysine residues in histones and various nonhistone proteins. Four different classes of HDACs have been identified in humans so far. Although classes I, II, and IV are zinc-dependent amidohydrolases, class III HDACs depend on nicotinamide adenine dinucleotide (NAD 1) for their catalytic activity. According to their homology to Sir2p, a yeast histone deacetylase, the class III is also termed sirtuins. Seven members have been described in humans so far. As sirtuins are involved in many physiological and pathological processes, their activity has been associated with the pathogenesis of cancer, HIV, metabolic, or neurological diseases. Herein, we present an overview over sirtuins including their biology, targets, inhibitors, and activators and their potential as new therapeutic agents.
Function of the SIRT1 protein deacetylase in cancer
Biotechnology Journal, 2007
Targeting apoptotic pathways using specific inhibitors has emerged as a valuable new approach in the treatment of cancer, which may decrease cytotoxicity and therefore side effects due to specificity for tumor cells . SIRT1 belongs to the seven-membered sirtuin family and was the first to be characterized in yeast and then in higher eukaryotic organisms. It is classified as a NAD + -dependent histone deacetylase harboring an additional enzymatic activity, namely that of an ADP-ribosyltransferase [3].
Inhibitors to understand molecular mechanisms of NAD+-dependent deacetylases (sirtuins)
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 2010
Histone deacetylases (HDACs) are enzymes that cleave acetyl groups from acetyl-lysine residues in histones and various nonhistone proteins. Unlike the other three of the four classes of HDACs that have been identified in humans, which are zinc-dependent amidohydrolases, class III HDACs depend on nicotinamide adenine dinucleotide (NAD +) for their catalytic activity. The seven members of the class III HDACs are also named sirtuins for their homology to Sir2p, a yeast histone deacetylase. Sirtuin inhibitors have been critical for the linkage of sirtuin activity to many physiological and pathological processes, and sirtuin activity has been associated with the pathogenesis of cancer, HIV, and metabolic and neurological diseases. Presented here is an overview of the many sirtuin inhibitors that have provided insight into the biological role of sirtuins.
Sirtuin functions and modulation: from chemistry to the clinic
Clinical Epigenetics, 2016
Sirtuins are NAD +-dependent histone deacetylases regulating important metabolic pathways in prokaryotes and eukaryotes and are involved in many biological processes such as cell survival, senescence, proliferation, apoptosis, DNA repair, cell metabolism, and caloric restriction. The seven members of this family of enzymes are considered potential targets for the treatment of human pathologies including neurodegenerative diseases, cardiovascular diseases, and cancer. Furthermore, recent interest focusing on sirtuin modulators as epigenetic players in the regulation of fundamental biological pathways has prompted increased efforts to discover new small molecules able to modify sirtuin activity. Here, we review the role, mechanism of action, and biological function of the seven sirtuins, as well as their inhibitors and activators.
SIRTUIN 1: Regulating the regulator
Biochemical and Biophysical Research Communications, 2008
Earlier analyses on the sirtuin family of histone deacetylases and its well-known member SIRT1 had their primary focus mostly on the identification of cellular targets exploring molecular mechanisms and functional networks in the control of metabolic homeostasis, differentiation, apoptosis and cell survival. However, only little is known about the regulation of SIRT1 itself, so far. Presently, SIRT1 is gaining increasing importance in the development of innovative treatment strategies for cancer, neurodegenerative disorders and metabolic disease. Based on differences in their catalytic activities, SIRT1 and the sirtuins in general, are insensitive to the classical class I and II HDAC inhibitors which are increasingly becoming part of treatment regimens for solid tumors and hematological malignancies. In this review we outline recent research advances on the regulation of SIRT1 which may provide the basis for the development of therapeutic inhibitors with improved specificity.
Biological and Potential Therapeutic Roles of Sirtuin Deacetylases
Cellular and Molecular Life Sciences, 2008
Sirtuins comprise a unique class of nicotinamide adenine dinucleotide (NAD +)-dependent deacetylases that target multiple protein substrates to execute diverse biological functions. These enzymes are key regulators of clinically important cellular and organismal processes, including metabolism, cell division and aging. The desire to understand the important determinants of human health and lifespan has resulted in a firestorm of work on the seven mammalian sirtuins in less than a decade. The implication of sirtuins in medically important areas such as diabetes, cancer, cardiovascular dysfunction and neurodegenerative disease has further catapulted them to a prominent status as potential targets for nutritional and therapeutic development. Here, we present a review of published results on sirtuin biology and its relevance to human disease.
International Journal of Molecular Sciences
Sirtuins (SIRTs), enzymes from the family of NAD+-dependent histone deacetylases, play an important role in the functioning of the body at the cellular level and participate in many biochemical processes. The multi-directionality of SIRTs encourages scientists to undertake research aimed at understanding the mechanisms of their action and the influence that SIRTs have on the organism. At the same time, new substances are constantly being sought that can modulate the action of SIRTs. Extensive research on the expression of SIRTs in various pathological conditions suggests that regulation of their activity may have positive results in supporting the treatment of certain metabolic, neurodegenerative or cancer diseases or this connected with oxidative stress. Due to such a wide spectrum of activity, SIRTs may also be a prognostic markers of selected pathological conditions and prove helpful in assessing their progression, especially by modulating their activity. The article presents and...
Interactomic and pharmacological insights on human Sirt-1
Sirtuin family, in humans as well as in all mammalia, is composed by seven different homologous proteins with NAD-dependent deacetylase/ADP-ribosyltransferase activity. Numerous studies have determined their cellular location and their biological functions. In particular, Sirt-1 is defined as a nuclear protein involved in the molecular mechanisms of inflammation and neurodegeneration through the de-acetylation of many different substrates (PGC-α, FOXOs, NFκB). However experimental data in mouse suggest both its cytoplasmatic presence and nucleo-cytoplasmic shuttling upon oxidative stress. Recently we have modeled the three-dimensional structure of human Sirt-1, and highlighted that it is composed by four different regions: N-terminal region, allosteric site, catalytic core and C-terminal region and underlined that the two terminal regions have high intrinsic disorder propensity. Since Sirt-1 is implicated in various diseases and cancers, many different papers report experimental studies related to its functional activators. The aim of this article is i) to present interactomic studies on human SIRT-1 to understand its most important functional relationships in the light of the gene-protein interactions that control major metabolic pathways and ii) to show how this protein binds some activator molecules in order to evidence structural determinants, physico-chemical features and those residues involved in the formation of complexes. It is believed that these data will be useful to synthesize new effectors through drug design approaches.
Comparative deacetylase activity of wild type and mutants of SIRT1
Biochemical and Biophysical Research Communications, 2010
a b s t r a c t SIRT1, human ortholog of yeast SIR2 protein, deacetylates histones and several other transcription factors. Recently, SIRT1 has emerged as a drug target for treating age related diseases, type II diabetes, neurodegeneration, inflammation and cancer. Here, we have optimized production of functionally active wild type full-length SIRT1 protein and its N-terminal deleted mutants. In a comparative study, we found that the region containing 192-208 amino acids towards the N-terminus is critical for right conformational folding of the protein to retain its deacetylase activity. The EC 50 and IC 50 values obtained with standard modulators showed that the SRT 748 & SRT 556 can deacetylate substrate and are activated by resveratrol, whereas, deacetylase activity of all the other deletion mutants (SRT 540 , SRT 532 , SRT 507 and SRT 503 ) was lost. We further report that the peptide substrate K m for SRT 748 (70 ± 5.2 lM) was comparable to SRT 556 (93 ± 5.4 lM). The K m for NAD + substrate was 176 & 274 lM for SRT 748 and SRT 556 , respectively.