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BBA - Proteins and Proteomics (v.1804, #8)
Regulation of yeast sirtuins by NAD+ metabolism and calorie restriction by Shu-Ping Lu; Su-Ju Lin (pp. 1567-1575).
The Sir2 family proteins (sirtuins) are evolutionally conserved NAD+ (nicotinamide adenine dinucleotide)-dependent protein deacetylases and ADP-ribosylases, which have been shown to play important roles in the regulation of stress response, gene transcription, cellular metabolism and longevity. Recent studies have also suggested that sirtuins are downstream targets of calorie restriction (CR), which mediate CR-induced beneficial effects including life span extension in an NAD+-dependent manner. CR extends life span in many species and has been shown to ameliorate many age-associated disorders such as diabetes and cancers. Understanding the mechanisms of CR as well as the regulation of sirtuins will therefore provide insights into the molecular basis of these age-associated metabolic diseases. This review focuses on discussing advances in studies of sirtuins and NAD+ metabolism in genetically tractable model system, the budding yeast Saccharomyces cerevisiae. These studies have unraveled key metabolic longevity factors in the CR signaling and NAD+ biosynthesis pathways, which may also contribute to the regulation of sirtuin activity. Many components of the NAD+ biosynthesis pathway and CR signaling pathway are conserved in yeast and higher eukaryotes including humans. Therefore, these findings will help elucidate the mechanisms underlying age-associated metabolic disease and perhaps human aging.
Keywords: Sir2; NAD; +; Calorie restriction; Longevity regulation; Aging
Sirtuin regulation in calorie restriction by Xiaolei Qiu; Katharine V. Brown; Yehu Moran; Danica Chen (pp. 1576-1583).
The beneficial effects of calorie restriction diet in extending lifespan and preventing diseases have long been recognized. Recent genetic and molecular studies in model organisms began to uncover the molecular regulation of calorie restriction response, with the gene SIR2 playing an essential role. This article summarizes the latest development on how mammalian SIR2 homologs coordinately regulate the calorie restriction response.
Keywords: Sirtuin; Calorie restriction; Aging
“Clocks” in the NAD World: NAD as a metabolic oscillator for the regulation of metabolism and aging by Shin-ichiro Imai (pp. 1584-1590).
SIR2 ( silent information regulator 2) proteins, now called “sirtuins,” are an evolutionarily conserved family of NAD-dependent protein deacetylases/ADP-ribosyltransferases. Sirtuins have recently attracted major attention in the field of aging research, and it has been demonstrated that SIR2 and its orthologs regulate aging and longevity in yeast, worms, and flies. In mammals, the SIR2 ortholog SIRT1 coordinates important metabolic responses to nutritional availability in multiple tissues. Most recently, it has been demonstrated that SIRT1 regulates the amplitude and the duration of circadian gene expression through the interaction and the deacetylation of key circadian clock regulators, such as BMAL1 and PER2. More strikingly, we and others have discovered a novel circadian clock feedback loop in which both the rate-limiting enzyme in mammalian NAD biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), and NAD levels display circadian oscillations and modulate CLOCK:BMAL1-mediated circadian transcriptional regulation through SIRT1, demonstrating a new function of NAD as a “metabolic oscillator.” These findings reveal a novel system dynamics of a recently proposed systemic regulatory network regulated by NAMPT-mediated NAD biosynthesis and SIRT1, namely, the NAD World. In the light of this concept, a new connection between physiological rhythmicity, metabolism, and aging will be discussed.
Keywords: SIRT1; NAMPT; NAD biosynthesis; Circadian rhythm; CLOCK; BMAL1; NAD; Metabolic oscillator; NAD World; Metabolism; Aging; Aging clock
Sirtuin chemical mechanisms by Anthony A. Sauve (pp. 1591-1603).
Sirtuins are ancient proteins widely distributed in all lifeforms of earth. These proteins are universally able to bind NAD+, and activate it to effect ADP-ribosylation of cellular nucleophiles. The most commonly observed sirtuin reaction is the ADP-ribosylation of acetyllysine, which leads to NAD+-dependent deacetylation. Other types of ADP-ribosylation have also been observed, including protein ADP-ribosylation, NAD+ solvolysis and ADP-ribosyltransfer to 5,6-dimethylbenzimidazole, a reaction involved in eubacterial cobalamin biosynthesis. This review broadly surveys the chemistries and chemical mechanisms of these enzymes.
Keywords: Sirtuin; AADPR; Protein deacetylation; Enzyme mechanism; NAD
Structural basis for sirtuin function: What we know and what we don't by Brandi D. Sanders; Brittany Jackson; Ronen Marmorstein (pp. 1604-1616).
The sirtuin (silent information regulator 2) proteins are NAD+-dependent deacetylases that are implicated in diverse biological processes including DNA regulation, metabolism, and longevity. Homologues of the prototypic yeast Sir2p have been identified in all three kingdoms of life, and while bacteria and archaea typically contain one to two sirtuins, eukaryotic organisms contain multiple members. Sirtuins are regulated in part by the cellular concentrations of the noncompetitive inhibitor, nicotinamide, and several synthetic modulators of these enzymes have been identified. The x-ray crystal structures of several sirtuin proteins in various liganded forms have been determined. This wealth of structural information, together with related biochemical studies, have provided important insights into the catalytic mechanism, substrate specificity, and inhibitory mechanism of sirtuin proteins. Implications for future structural studies to address outstanding questions in the field are also discussed.
Keywords: Sirtuins; Histone deacetylases; Structure
Function and metabolism of sirtuin metabolite O-acetyl-ADP-ribose by Lei Tong; John M. Denu (pp. 1617-1625).
Sirtuins catalyze the NAD+-dependent deacetylation of target proteins, which are regulated by this reversible lysine modification. During deacetylation, the glycosidic bond of the nicotinamide ribose is cleaved to yield nicotinamide and the ribose accepts the acetyl group from substrate to produce O-acetyl-ADP-ribose ( OAADPr), which exists as an ∼50:50 mixture of 2′ and 3′ isomers at neutral pH. Discovery of this metabolite has fueled the idea that OAADPr may play an important role in the biology associated with sirtuins, acting as a signaling molecule and/or an important substrate for downstream enzymatic processes. Evidence for OAADPr-metabolizing enzymes indicates that at least three distinct activities exist that could modulate the cellular levels of this NAD+-derived metabolite. In Sacc ha romyces cerevisiae, NUDIX hydrolase Ysa1 cleaves OAADPr to AMP and 2- and 3- O-acetylribose-5-phosphate, lowering the cellular levels of OAADPr. A buildup of OAADPr and ADPr has been linked to a metabolic shift that lowers endogenous reactive oxygen species and diverts glucose towards preventing oxidative damage. In vitro, the mammalian enzyme ARH3 hydrolyzes OAADPr to acetate and ADPr. A third nuclear-localized activity appears to utilize OAADPr to transfer the acetyl-group to another small molecule, whose identity remains unknown. Recent studies suggest that OAADPr may regulate gene silencing by facilitating the assembly and loading of the Sir2–4 silencing complex onto nucleosomes. In mammalian cells, the Trpm2 cation channel is gated by both OAADPr and ADP-ribose. Binding is mediated by the NUDIX homology (NudT9H) domain found within the intracellular portion of the channel. OAADPr is capable of binding the Macro domain of splice variants from histone protein MacroH2A, which is highly enriched at heterochromatic regions. With recently developed tools, the pace of new discoveries of OAADPr-dependent processes should facilitate new molecular insight into the diverse biological processes modulated by sirtuins.
Keywords: Sirtuin; Sir2; NAD; Deacetylation; Deacetylase; O; -acetyl-ADP-ribose
Biochemical effects of SIRT1 activators by Joseph A. Baur (pp. 1626-1634).
SIRT1 is the closest mammalian homologue of enzymes that extend life in lower organisms. Its role in mammals is incompletely understood, but includes modulation of at least 34 distinct targets through its nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase activity. Recent experiments using small molecule activators and genetically engineered mice have provided new insight into the role of this enzyme in mammalian biology and helped to highlight some of the potentially relevant targets. The most widely employed activator is resveratrol, a small polyphenol that improves insulin sensitivity and vascular function, boosts endurance, inhibits tumor formation, and ameliorates the early mortality associated with obesity in mice. Many of these effects are consistent with modulation of SIRT1 targets, such as PGC1α and NFκB, however, resveratrol can also activate AMPK, inhibit cyclooxygenases, and influence a variety of other enzymes. A novel activator, SRT1720, as well as various methods to manipulate NAD+ metabolism, are emerging as alternative methods to increase SIRT1 activity, and in many cases recapitulate effects of resveratrol. At present, further studies are needed to more directly test the role of SIRT1 in mediating beneficial effects of resveratrol, to evaluate other strategies for SIRT1 activation, and to confirm the specific targets of SIRT1 that are relevant in vivo. These efforts are especially important in light of the fact that SIRT1 activators are entering clinical trials in humans, and “nutraceutical” formulations containing resveratrol are already widely available.
Keywords: SIRT1; Resveratrol; SRT1720; Longevity; Sirtuin; Polyphenol; Nad
Sirtuins inhibitors: The approach to affinity and selectivity by Yana Cen (pp. 1635-1644).
Accumulating evidence has indicated the importance of sirtuins (class III histone deacetylases) in various biological processes. Their potential roles in metabolic and neurodegenerative diseases have encouraged scientists to seek potent and selective sirtuin inhibitors to investigate their biological functions with a view to eventual new therapeutic treatments. This article surveys current knowledge of sirtuin inhibitors including those discovered via high-throughput screening (HST) or via mechanism-based drug design from synthetic or natural sources. Their inhibitory affinity, selectivities, and possible inhibition mechanisms are discussed.
Keywords: Sirtuins; Inhibitor; NAD; +; Metabolism; Selectivity
Mitochondrial sirtuins by Jing-Yi Huang; Matthew D. Hirschey; Tadahiro Shimazu; Linh Ho; Eric Verdin (pp. 1645-1651).
Sirtuins have emerged as important proteins in aging, stress resistance and metabolic regulation. Three sirtuins, SIRT3, 4 and 5, are located within the mitochondrial matrix. SIRT3 and SIRT5 are NAD+-dependent deacetylases that remove acetyl groups from acetyllysine-modified proteins and yield 2′-O-acetyl-ADP-ribose and nicotinamide. SIRT4 can transfer the ADP-ribose group from NAD+ onto acceptor proteins. Recent findings reveal that a large fraction of mitochondrial proteins are acetylated and that mitochondrial protein acetylation is modulated by nutritional status. This and the identification of targets for SIRT3, 4 and 5 support the model that mitochondrial sirtuins are metabolic sensors that modulate the activity of metabolic enzymes via protein deacetylation or mono-ADP-ribosylation. Here, we review and discuss recent progress in the study of mitochondrial sirtuins and their targets.
Keywords: Mitochondria; Sirtuin; SIRT3; SIRT4; SIRT5; O-Acetyl-ADP-ribose; Acetylation
Sirtuins regulate key aspects of lipid metabolism by David J. Lomb; Gaëlle Laurent; Marcia C. Haigis (pp. 1652-1657).
Members of the sirtuin family of NAD+-dependent protein deacetylases are important regulators of longevity in yeast, worms, and flies. Mammals have seven sirtuins (SIRT1-7), each characterized by differences in subcellular localization, substrate preference, and biological function. While it is unclear whether sirtuins regulate aging in mammals, it is clear that sirtuins influence diverse aspects of their metabolism. Indeed, SIRT1 promotes oxidation of fatty acids in liver and skeletal muscle, cholesterol metabolism in liver, and lipid mobilization in white adipose tissue. Moreover, small-molecule activators of SIRT1 have recently been shown to protect mice from the negative effects of a high-fat diet. These findings suggest that sirtuins might provide important new targets for the treatment of obesity and related diseases. In this review, we discuss the major findings linking sirtuins with the regulation of lipid metabolism.
Keywords: SIRT1; Lipid; Metabolism; PPARα; PGC-1α; LXR
Function and regulation of the mitochondrial Sirtuin isoform Sirt5 in Mammalia by Melanie Gertz; Clemens Steegborn (pp. 1658-1665).
Sirtuins are a family of protein deacetylases that catalyze the nicotinamide adenine dinucleotide (NAD+)-dependent removal of acetyl groups from modified lysine side chains in various proteins. Sirtuins act as metabolic sensors and influence metabolic adaptation but also many other processes such as stress response mechanisms, gene expression, and organismal aging. Mammals have seven Sirtuin isoforms, three of them – Sirt3, Sirt4, and Sirt5 – located to mitochondria, our centers of energy metabolism and apoptosis initiation. In this review, we shortly introduce the mammalian Sirtuin family, with a focus on the mitochondrial isoforms. We then discuss in detail the current knowledge on the mitochondrial isoform Sirt5. Its physiological role in metabolic regulation has recently been confirmed, whereas an additional function in apoptosis regulation remains speculative. We will discuss the biochemical properties of Sirt5 and how they might contribute to its physiological function. Furthermore, we discuss the potential use of Sirt5 as a drug target, structural features of Sirt5 and of an Sirt5/inhibitor complex as well as their differences to other Sirtuins and the current status of modulating Sirt5 activity with pharmacological compounds.
Keywords: Deacetylase; Function; Metabolism; Mitochondria; Sirt5; Sirtuin
SIRT1-dependent regulation of chromatin and transcription: Linking NAD+ metabolism and signaling to the control of cellular functions by Tong Zhang; W. Lee Kraus (pp. 1666-1675).
Sirtuins comprise a family of NAD+-dependent protein deacetylases and ADP-ribosyltransferases. Mammalian SIRT1 – a homolog of yeast Sir2, the prototypical member of the sirtuin family – is an important regulator of metabolism, cell differentiation and senescence, stress response, and cancer. As an NAD+-dependent enzyme, SIRT1 regulates gene expression programs in response to cellular metabolic status, thereby coordinating metabolic adaptation of the whole organism. Several important mechanisms have emerged for SIRT1-dependent regulation of transcription. First, SIRT1 can modulate chromatin function through direct deacetylation of histones as well as by promoting alterations in the methylation of histones and DNA, leading to the repression of transcription. The latter is accomplished through the recruitment of other nuclear enzymes to chromatin for histone methylation and DNA CpG methylation, suggesting a broader role of SIRT1 in epigenetic regulation. Second, SIRT1 can interact and deacetylate a broad range of transcription factors and coregulators, thereby regulating target gene expression both positively and negatively. Cellular energy state, specifically NAD+ metabolism, plays a major role in the regulation of SIRT1 activity. Recent studies on the NAD+ biosynthetic enzymes in the salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide mononucleotide adenylyltransferase 1 (NMNAT-1), have revealed important functions for these enzymes in SIRT1-dependent transcription regulation. The collective molecular actions of SIRT1 control specific patterns of gene expression that modulate a wide variety of physiological outcomes.
Keywords: SIRT1; NAD; +; Deacetylation; Transcription; Chromatin; Metabolism
Nutrient-dependent regulation of PGC-1α's acetylation state and metabolic function through the enzymatic activities of Sirt1/GCN5 by John E. Dominy Jr.; Yoonjin Lee; Zachary Gerhart-Hines; Pere Puigserver (pp. 1676-1683).
Mammals possess an intricate regulatory system for controlling flux through fuel utilization pathways in response to the dietary availability of particular macronutrients. Under fasting conditions, for instance, mammals initiate a whole body metabolic response that limits glucose utilization and favors fatty acid oxidation. Understanding the underlying mechanisms by which this process occurs will facilitate the development of new treatments for metabolic disorders such as type II diabetes and obesity. One of the recently identified components of the signal transduction pathway involved in metabolic reprogramming is PGC-1α. This transcriptional coactivator is able to coordinate the expression of a wide array of genes involved in glucose and fatty acid metabolism. The nutrient-mediated control of PGC-1α activity is tightly correlated with its acetylation state. In this review, we evaluate how the nutrient regulation of PGC-1α activity squares with the regulation of its acetylation state by the deacetylase Sirt1 and the acetyltransferase GCN5. We also propose an outline of additional experimental directives that will help to shed additional light on this very powerful transcriptional coactivator.
Keywords: PGC-1α; GCN5; Sirt1; Acetylation
SIRT1 and p53, effect on cancer, senescence and beyond by Jingjie Yi; Jianyuan Luo (pp. 1684-1689).
NAD+-dependent Class III histone deacetylase SIRT1 is a multiple function protein critically involved in stress responses, cellular metabolism and aging through deacetylating a variety of substrates including p53, forkhead-box transcription factors, PGC-1α, NF-κB, Ku70 and histones. The first discovered non-histone target of SIRT1, p53, is suggested to play a central role in SIRT1-mediated functions in tumorigenesis and senescence. SIRT1 was originally considered to be a potential tumor promoter since it negatively regulates the tumor suppressor p53 and other tumor suppressors. There is new evidence that SIRT1 acts as a tumor suppressor based on its role in negatively regulating β-catenin and survivin. This review provides an overview of current knowledge of SIRT1-p53 signaling and controversies regarding the functions of SIRT1 in tumorigenesis.
Keywords: SIRT1; p53; Acetylation; Deacetylation; Cancer; Senescence
The role of Sirt1: At the crossroad between promotion of longevity and protection against Alzheimer's disease neuropathology by Jun Wang; Hayley Fivecoat; Lap Ho; Yong Pan; Emi Ling; Giulio Maria Pasinetti (pp. 1690-1694).
Sirt1, a mammalian member of the sirtuin gene family, holds great potential for promoting longevity, preventing against disease and increasing cell survival. For example, studies suggest that the beneficial impact of caloric restriction in promoting longevity and cellular function may be mediated, in part, by Sirt1 through mechanisms involving PGC-1α, which plays important role in the regulation of cellular metabolism and inflammatory and antioxidant responses. Sirt1 may also interfere with mechanisms implicated in pathological disorders. We will present recent evidence indicating that Sirt1 may protect against Alzheimer's disease by interfering with the generation of β-amyloid peptides. We will discuss Sirt1 as a potential novel target, in addition to the development of Sirt1 activators for the prevention and treatment of Alzheimer's disease.
Keywords: Sirtuins; Caloric restriction; Neurodegeneration; Alzheimer's disease; Dementia