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Xiangying Guan, Alok Upadhyay, Sudipto Munshi, Raj Chakrabarti
Across all families of enzymes, only a dozen or so distinct classes of non-natural small molecule activators have been characterized, with only four known modes of activation among them. All of these modes of activation rely on naturally evolved binding sites that trigger global conformational changes. Among the enzymes that are of greatest interest for small molecule activation are the seven sirtuin enzymes, nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylases that play a central role in the regulation of healthspan and lifespan in organisms ranging from yeast to mammals...
2018: PloS One
Ana Trapero, Angela Pacitto, Vinayak Singh, Mohamad Sabbah, Anthony G Coyne, Valerie Mizrahi, Tom L Blundell, David B Ascher, Chris Abell
Tuberculosis (TB) remains a major cause of mortality worldwide, and improved treatments are needed to combat emergence of drug resistance. Inosine 5´-monophosphate dehydrogenase (IMPDH), a crucial enzyme required for de novo synthesis of guanine nucleotides, is an attractive TB drug target. Herein, we describe the identification of potent IMPDH inhibitors using fragment-based screening and structure-based design techniques. Screening of a fragment library for Mycobacterium thermoresistible (Mth) IMPDH(ΔCBS) inhibitors identified a low affinity phenylimidazole derivative...
March 16, 2018: Journal of Medicinal Chemistry
Min-Hui Tang, Nan Gao, Jiao Zhou, Yan Zhao, Jing-Sheng Cheng, Wen-Kun Su, Ying-Jin Yuan
Sulfamethoxazole (SMX) has frequently been detected in aquatic environments. In natural environment, not only individual microorganism but also microbial consortia are involved in some biotransformation of pollutants. The competition for space under consortia causing cell-cell contact inhibition changes the cellular behaviors. Herein, the membrane bioreactor system (MBRS) was applied to improve SMX elimination thorough exchanging the cell-free broths (CFB). The removal efficiency of SMX was increased by more than 24% whether under the pure culture of A...
March 15, 2018: Biodegradation
Angela Contreras, Magdalena Ribbeck, Guillermo D Gutiérrez, Pablo M Cañon, Sebastián N Mendoza, Eduardo Agosin
The effect of ethanol on the metabolism of Oenococcus oeni , the bacterium responsible for the malolactic fermentation (MLF) of wine, is still scarcely understood. Here, we characterized the global metabolic response in O. oeni PSU-1 to increasing ethanol contents, ranging from 0 to 12% (v/v). We first optimized a wine-like, defined culture medium, MaxOeno, to allow sufficient bacterial growth to be able to quantitate different metabolites in batch cultures of O. oeni . Then, taking advantage of the recently reconstructed genome-scale metabolic model iSM454 for O...
2018: Frontiers in Microbiology
Megerditch Kiledjian
A hallmark of eukaryotic mRNAs has long been the 5'-end m7 G cap. This paradigm was recently amended by recent reports that Saccharomyces cerevisiae and mammalian cells also contain mRNAs carrying a novel nicotinamide adenine dinucleotide (NAD+ ) cap at their 5'-end. The presence of an NAD+ cap on mRNA uncovers a previously unknown mechanism for controlling gene expression through nucleotide metabolite-directed mRNA turnover. In contrast to the m7 G cap that stabilizes mRNA, the NAD+ cap targets RNA for rapid decay in mammalian cells through the DXO non-canonical decapping enzyme which removes intact NAD+ from RNA in a process termed 'deNADding'...
March 12, 2018: Trends in Cell Biology
Miguel R Lugo, Bronwyn Lyons, Cristina Lento, Derek J Wilson, A Rod Merrill
Scabin is a mono-ADP-ribosyltransferase enzyme and is a putative virulence factor produced by the plant pathogen, Streptomyces scabies. Previously, crystal structures of Scabin were solved in the presence and absence of substrate analogues and inhibitors. Herein, experimental (hydrogen-deuterium exchange), simulated (molecular dynamics), and theoretical (Gaussian Network Modeling) approaches were systematically applied to study the dynamics of apo-Scabin in the context of a Scabin·NAD+·DNA model. MD simulations revealed that the apo-Scabin solution conformation correlates well with the X-ray crystal structure, beyond the conformation of the exposed, mobile regions...
2018: PloS One
Céline Ronin, David Mendes Costa, Joana Tavares, Joana Faria, Fabrice Ciesielski, Paola Ciapetti, Terry K Smith, Jane MacDougall, Anabela Cordeiro-da-Silva, Iain K Pemberton
The de novo crystal structure of the Leishmania infantum Silent Information Regulator 2 related protein 1 (LiSir2rp1) has been solved at 1.99Å in complex with an acetyl-lysine peptide substrate. The structure is broadly commensurate with Hst2/SIRT2 proteins of yeast and human origin, reproducing many of the structural features common to these sirtuin deacetylases, including the characteristic small zinc-binding domain, and the larger Rossmann-fold domain involved in NAD+-binding interactions. The two domains are linked via a cofactor binding loop ordered in open conformation...
2018: PloS One
Natthakan Thongon, Chiara Zucal, Vito Giuseppe D'Agostino, Toma Tebaldi, Silvia Ravera, Federica Zamporlini, Francesco Piacente, Ruxanda Moschoi, Nadia Raffaelli, Alessandro Quattrone, Alessio Nencioni, Jean-Francois Peyron, Alessandro Provenzani
Background: Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. However, continuous exposure to NAMPT inhibitors, such as FK866, can induce acquired resistance. Methods: We developed FK866-resistant CCRF-CEM (T cell acute lymphoblastic leukemia) and MDA MB231 (breast cancer) models, and by exploiting an integrated approach based on genetic, biochemical, and genome wide analyses, we annotated the drug resistance mechanisms...
2018: Cancer & Metabolism
Yannan Zhao, Lilan Luo, Jiesi Xu, Peiyong Xin, Hongyan Guo, Jian Wu, Lin Bai, Guodong Wang, Jinfang Chu, Jianru Zuo, Hong Yu, Xun Huang, Jiayang Li
Programmed cell death (PCD) is a fundamental biological process. Deficiency in MOSAIC DEATH 1 (MOD1), a plastid-localized enoyl-ACP reductase, leads to the accumulation of reactive oxygen species (ROS) and PCD, which can be suppressed by mitochondrial complex I mutations, indicating a signal from chloroplasts to mitochondria. However, this signal remains to be elucidated. In this study, through cloning and analyzing a series of mod1 suppressors, we reveal a comprehensive organelle communication pathway that regulates the generation of mitochondrial ROS and triggers PCD...
March 14, 2018: Cell Research
Nanako Kanno, Katsumi Matsuura, Shin Haruta
Purple photosynthetic bacteria utilize light energy for growth. We previously demonstrated that light energy contributed to prolonging the survival of multiple purple bacteria under carbon-starved conditions. In order to clarify the effects of illumination on metabolic states under carbon-starved, non-growing conditions, we herein compared the metabolic profiles of starved cells in the light and dark using the purple bacterium, Rhodopseudomonas palustris. The metabolic profiles of starved cells in the light were markedly different from those in the dark...
March 13, 2018: Microbes and Environments
Sang-Won Min, Peter Dongmin Sohn, Yaqiao Li, Nino Devidze, Jeffrey R Johnson, Nevan J Krogan, Eliezer Masliah, Sue-Ann Mok, Jason E Gestwicki, Li Gan
Hyperacetylation of tau has been implicated in neurodegeneration and cognitive decline in tauopathy brains. The NAD-dependent class III protein deacetylase SIRT1 is one of major enzymes involved in removal of acetyl groups from tau in vitro However, whether SIRT1 regulates acetylation of pathogenic tau and ameliorates tau-mediated pathogenesis remains unclear. Here, we report deacetylating activity of SIRT1 for acetylated Lys174 (K174) of tau in tauP301S transgenic mice with a brain-specific SIRT1 deletion...
March 14, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Katsuaki Kobayashi, Take-Aki Koizumi, Debashis Ghosh, Takashi Kajiwara, Susumu Kitagawa, Koji Tanaka
A RhCp* (Cp* = pentamethylcyclopentadienyl) complex bearing an NAD+ /NADH-functionalized ligand, [RhCp*(pbn)Cl]Cl ([1]Cl, pbn = (2-(2-pyridyl)benzo[b]-1,5-naphthyridine)), was synthesized. The cyclic voltammogram of [1]Cl in CH3 CN shows two reversible redox waves at E1/2 = -0.58 and -1.53 V (vs. the saturated calomel electrode (SCE)), which correspond to the RhIII /RhI and pbn/pbn˙- redox couples, respectively. The addition of acetic acid to the solution afforded the proton-coupled two-electron reduction of [1]Cl at -0...
March 14, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
Mingming Pu, Lili Sheng, Sooyeon Song, Ting Gong, Thomas K Wood
Pseudomonas aeruginosa causes many biofilm infections, and the rugose small-colony variants (RSCVs) of this bacterium are important for infection. We found here that inactivation of PA2444, which we determined to be a serine hydroxymethyltransferase (SHMT), leads to the RSCV phenotype of P. aeruginosa PA14. In addition, loss of PA2444 increases biofilm formation by two orders of magnitude, increases exopolysaccharide by 45-fold, and abolishes swarming. The RSCV phenotype is related to higher cyclic diguanylate concentrations due to increased activity of the Wsp chemosensory system, including diguanylate cyclase WspR...
2018: Frontiers in Microbiology
Jiangying Kuang, Lei Chen, Qin Tang, Jinhang Zhang, Yanping Li, Jinhan He
Sirt6 is one of the sirtuin family members, a kind of NAD+-dependent histone deacetylase and ADP-ribose transferase enzyme. It has an important role in physiological and pathological processes, regulating aging, cancer, obesity, insulin resistance, inflammation, and energy metabolism. Recent studies have suggested that reduced Sirt6 action is related to obesity and diabetes. Aging and overnutrition, two major risk factors for obesity and diabetes, lead to decreased Sirt6 level and function, which results in abnormal glucose and lipid metabolism...
2018: Frontiers in Physiology
George Cătălin Marinescu, Roua-Gabriela Popescu, Anca Dinischiotu
Over 12% of the world's health resources are spent on treating diabetes, as high blood glucose is the third cause of mortality worldwide. Insulin resistance is the basis of the most common form of diabetes: type 2 diabetes. Recent animal studies report successful attempts at reversing type 2 diabetes by the administering of the NAD+ precursor nicotinamide mononucleotide (NMN). However, the current high price of this molecule urges for more efficient and cost-effective production methods. This work proposes a method for purifying NMN by Size Exclusion Chromatography (SEC) on silica with a covalently attached coating of poly(2-hydroxyethyl aspartamide) (PolyHEA) stationary phase using an isocratic elution with a denaturing mobile phase (50 mM formic acid) from a complex molecular mixture such as a fermentation broth...
March 13, 2018: Scientific Reports
Ying-Chun Shih, Chao-Ling Chen, Yan Zhang, Rebecca L Mellor, Evelyn M Kanter, Yun Fang, Hua-Chi Wang, Chen-Ting Hung, Jing-Yi Nong, Hui-Ju Chen, Tzu-Han Lee, Yi-Shuan Tseng, Chiung-Nien Chen, Chau-Chung Wu, Shuei-Liong Lin, Kathryn A Yamada, Jeanne M Nerbonne, Kai-Chien Yang
<u>Rationale:</u> Cardiac fibrosis plays a critical role in the pathogenesis of heart failure (HF). Excessive accumulation of extracellular matrix (ECM) resulting from cardiac fibrosis impairs cardiac contractile function and increases arrhythmogenicity. Current treatment options for cardiac fibrosis, however, are limited and there is a clear need to identify novel mediators of cardiac fibrosis to facilitate the development of better therapeutics. Exploiting co-expression gene network analysis on RNA sequencing data from failing human heart, we identified thioredoxin domain containing 5 (TXNDC5), a cardiac fibroblast (CF)-enriched endoplasmic reticulum (ER) protein, as a potential novel mediator of cardiac fibrosis and we completed experiments to test this hypothesis directly...
March 13, 2018: Circulation Research
Adejoke N Kolawole, Valentine T Akinladejo, Olusola O Elekofehinti, Afolabi C Akinmoladun, Ayodele O Kolawole
Aldehyde dehydrogenases (ALDHs) are a diverse family of enzymes that catalyze the NAD(P)+ -dependent detoxification of toxic aldehyde compounds. ALDHs are also involved in non-enzymatic ligand binding to endobiotics and xenobiotics. Here, the enzyme crucial non-canonical and non-catalytic interaction with kolaflavanone, a component of kolaviron, and a major bioflavonoid isolated from Garcinia kola (Bitter kola) was characterized by various spectroscopic and in silico approaches under stimulated physiological condition...
February 27, 2018: Bioorganic Chemistry
Jasmin Frey, Fabian Schneider, Thomas Huhn, Dieter Spiteller, Bernhard Schink, David Schleheck
Degradation of acetone by the sulfate-reducing bacterium Desulfococcus biacutus involves an acetone-activation reaction different from that used by aerobic or nitrate-reducing bacteria, because the small energy budget of sulfate-reducing bacteria does not allow for major expenditures into ATP-consuming carboxylation reactions. In the present study, an inducible coenzyme B12 -dependent conversion of 2-hydroxyisobutyryl-CoA to 3-hydroxybutyryl-CoA was demonstrated in cell-free extracts of acetone-grown D. biacutus cells, together with a NAD+ -dependent oxidation of 3-hydroxybutyryl-CoA to acetoacetyl-CoA...
March 12, 2018: Environmental Microbiology Reports
Taofeek O Ajiboye, Evelyn Skiebe, Gottfried Wilharm
Phenolic acids with catechol groups are good prooxidants because of their low redox potential. In this study, we provided data showing that phenolic acids, caffeic acid, gallic acid and protocatechuic acid, enhanced colistin-mediated bacterial death by inducing redox imbalance. The minimum inhibitory concentrations of these phenolic acids against Acinetobacter baumannii AB5075 were considerably lowered for ΔsodB and ΔkatG mutants. Checkerboard assay shows synergistic interactions between colistin and phenolic acids...
March 7, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Filipa V Sena, Filipe M Sousa, A Sofia F Oliveira, Cláudio M Soares, Teresa Catarino, Manuela M Pereira
Type-II NADH:quinone oxidoreductases (NDH-2s) are membrane proteins involved in respiratory chains and the only enzymes with NADH:quinone oxidoreductase activity expressed in Staphylococcus aureus (S. aureus), one of the most common causes of clinical infections. NDH-2s are members of the two-Dinucleotide Binding Domains Flavoprotein (tDBDF) superfamily, having a flavin adenine dinucleotide, FAD, as prosthetic group and NAD(P)H as substrate. The establishment of a Charge-Transfer Complex (CTC) between the isoalloxazine ring of the reduced flavin and the nicotinamide ring of NAD+ in NDH-2 was described, and in this work we explored its role in the kinetic mechanism using different electron donors and electron acceptors...
February 17, 2018: Redox Biology
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