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1. Evolution of Distinct Responses to Low NAD+ Stress by Rewiring the Sir2 Deacetylase Network in Yeasts

   https://doi.org/10.1534/genetics.120.303087  

   Humphrey, Kristen M; Zhu, Lisha; Hickman, Meleah A; Hasan, Shirin; Maria, Haniam; Liu, Tao; Rusche, Laura N (April 2020, Genetics)

   Abstract Evolutionary adaptation increases the fitness of a species in its environment. It can occur through rewiring of gene regulatory networks, such that an organism responds appropriately to environmental changes. We investigated whether sirtuin deacetylases, which repress transcription and require NAD+ for activity, serve as transcriptional rewiring points that facilitate the evolution of potentially adaptive traits. If so, bringing genes under the control of sirtuins could enable organisms to mount appropriate responses to stresses that decrease NAD+ levels. To explore how the genomic targets of sirtuins shift over evolutionary time, we compared two yeast species, Saccharomyces cerevisiae and Kluyveromyces lactis, that display differences in cellular metabolism and life cycle timing in response to nutrient availability. We identified sirtuin-regulated genes through a combination of chromatin immunoprecipitation and RNA expression. In both species, regulated genes were associated with NAD+ homeostasis, mating, and sporulation, but the specific genes differed. In addition, regulated genes in K. lactis were associated with other processes, including utilization of nonglucose carbon sources, detoxification of arsenic, and production of the siderophore pulcherrimin. Consistent with the species-restricted regulation of these genes, sirtuin deletion affected relevant phenotypes in K. lactis but not S. cerevisiae. Finally, sirtuin-regulated gene sets were depleted for broadly conserved genes, consistent with sirtuins regulating processes restricted to a few species. Taken together, these results are consistent with the notion that sirtuins serve as rewiring points that allow species to evolve distinct responses to low NAD+ stress. 

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2. Substrate-Dependent Sensitivity of SIRT1 to Nicotinamide Inhibition

   https://doi.org/10.3390/biom11020312  

   Rymarchyk, Stacia; Kang, Wenjia; Cen, Yana (February 2021, Biomolecules)

   null (Ed.)

   SIRT1 is the most extensively studied human sirtuin with a broad spectrum of endogenous targets. It has been implicated in the regulation of a myriad of cellular events, such as gene transcription, mitochondria biogenesis, insulin secretion as well as glucose and lipid metabolism. From a mechanistic perspective, nicotinamide (NAM), a byproduct of a sirtuin-catalyzed reaction, reverses a reaction intermediate to regenerate NAD+ through “base exchange”, leading to the inhibition of the forward deacetylation. NAM has been suggested as a universal sirtuin negative regulator. Sirtuins have evolved different strategies in response to NAM regulation. Here, we report the detailed kinetic analysis of SIRT1-catalyzed reactions using endogenous substrate-based synthetic peptides. A novel substrate-dependent sensitivity of SIRT1 to NAM inhibition was observed. Additionally, SIRT1 demonstrated pH-dependent deacetylation with normal solvent isotope effects (SIEs), consistent with proton transfer in the rate-limiting step. Base exchange, in contrast, was insensitive to pH changes with no apparent SIEs, indicative of lack of proton transfer in the rate-limiting step. Consequently, NAM inhibition was attenuated at a high pH in proteated buffers. Our study provides new evidence for “activation by de-repression” as an effective sirtuin activation strategy. 

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3. Identifying Inhibitors Targeting the Nonstructural Protein 15 and Main Protease of Coronaviruses Using Molecular Docking and Molecular Dynamics Simulation

   Webber, Nakoa K. (January 2021, Rowan digital works)

   The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2020 has impacted daily life globally for over a year. While multiple vaccines have been authorized for emergency use and one oral medication has entered clinical trials, we are still seeking antiviral drugs for a long-term treatment for SARS-CoV-2 as well as other coronaviruses. Computational drug screenings of two SARS-CoV-2 protein target candidates are presented in this thesis: the nidoviral RNA uridylate-specific endoribonuclease (Nsp15) and the main protease (Mpro) of SARS-CoV-2. Nonstructural proteins of coronaviruses were selected as targets as they are more conserved across coronavirus strains than structural proteins. High throughput virtual screening of small molecule libraries including DrugBank and ZINC 15 resulted in several promising compounds for each of these targets. Molecular dynamics simulation allowed us to predict the binding energies for these compounds using molecular mechanics with generalized born surface area solvation calculations (MM-GBSA). Four top compounds were discovered for Nsp15 and eight compounds for Mpro. 

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4. Sirtuins in Epigenetic Silencing and Control of Gene Expression in Model and Pathogenic Fungi

   https://doi.org/10.1146/annurev-micro-041020-100926  

   Zhao, Guolei; Rusche, Laura N (September 2022, Annual Review of Microbiology)

   Fungi, including yeasts, molds, and mushrooms, proliferate on decaying matter and then adopt quiescent forms once nutrients are depleted. This review explores how fungi use sirtuin deacetylases to sense and respond appropriately to changing nutrients. Because sirtuins are NAD⁺-dependent deacetylases, their activity is sensitive to intracellular NAD⁺availability. This allows them to transmit information about a cell's metabolic state on to the biological processes they influence. Fungal sirtuins are primarily known to deacetylate histones, repressing transcription and modulating genome stability. Their target genes include those involved in NAD⁺homeostasis, metabolism, sporulation, secondary metabolite production, and virulence traits of pathogenic fungi. By targeting different genes over evolutionary time, sirtuins serve as rewiring points that allow organisms to evolve novel responses to low NAD⁺stress by bringing relevant biological processes under the control of sirtuins. 

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5. Dietary natural products as epigenetic modifiers in aging-associated inflammation and disease

   https://doi.org/10.1039/c9np00057g  

   Evans, Levi W.; Stratton, Matthew S.; Ferguson, Bradley S. (May 2020, Natural Product Reports)

   Covering: up to 2020 Chronic, low-grade inflammation is linked to aging and has been termed “inflammaging”. Inflammaging is considered a key contributor to the development of metabolic dysfunction and a broad spectrum of diseases or disorders including declines in brain and heart function. Genome-wide association studies (GWAS) coupled with epigenome-wide association studies (EWAS) have shown the importance of diet in the development of chronic and age-related diseases. Moreover, dietary interventions e.g. caloric restriction can attenuate inflammation to delay and/or prevent these diseases. Common themes in these studies entail the use of phytochemicals (plant-derived compounds) or the production of short chain fatty acids (SCFAs) as epigenetic modifiers of DNA and histone proteins. Epigenetic modifications are dynamically regulated and as such, serve as potential therapeutic targets for the treatment or prevention of age-related disease. In this review, we will focus on the role for natural products that include phytochemicals and short chain fatty acids (SCFAs) as regulators of these epigenetic adaptations. Specifically, we discuss regulators of methylation, acetylation and acylation, in the protection from chronic inflammation driven metabolic dysfunction and deterioration of neurocognitive and cardiac function. 

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