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https://www.readbyqxmd.com/read/28213125/reduced-bioavailable-manganese-causes-striatal-urea-cycle-pathology-in-huntington-s-disease-mouse-model
#1
Terry Jo V Bichell, Michal Wegrzynowicz, K Grace Tipps, Emma M Bradley, Michael A Uhouse, Miles Bryan, Kyle Horning, Nicole Fisher, Karrie Dudek, Timothy Halbesma, Preethi Umashanker, Andrew D Stubbs, Hunter K Holt, Gunnar F Kwakye, Andrew M Tidball, Roger J Colbran, Michael Aschner, M Diana Neely, Alba Di Pardo, Vittorio Maglione, Alexander Osmand, Aaron B Bowman
Huntington's disease (HD) is caused by a mutation in the huntingtin gene (HTT), resulting in profound striatal neurodegeneration through an unknown mechanism. Perturbations in the urea cycle have been reported in HD models and in HD patient blood and brain. In neurons, arginase is a central urea cycle enzyme, and the metal manganese (Mn) is an essential cofactor. Deficient biological responses to Mn, and reduced Mn accumulation have been observed in HD striatal mouse and cell models. Here we report in vivo and ex vivo evidence of a urea cycle metabolic phenotype in a prodromal HD mouse model...
February 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28212523/redox-regulation-in-metabolic-programming-and-inflammation
#2
REVIEW
Helen R Griffiths, Dan Gao, Chathyan Pararasa
Energy metabolism and redox state are intrinsically linked. In order to mount an adequate immune response, cells must have an adequate and rapidly available energy resource to migrate to the inflammatory site, to generate reactive oxygen species using NADPH as a cofactor and to engulf bacteria or damaged tissue. The first responder cells of the innate immune response, neutrophils, are largely dependent on glycolysis. Neutrophils are relatively short-lived, dying via apoptosis in the process of bacterial killing through production of hypochlorous acid and release of extracellular NETs...
February 12, 2017: Redox Biology
https://www.readbyqxmd.com/read/28212376/the-legionella-pneumophila-genome-evolved-to-accommodate-multiple-regulatory-mechanisms-controlled-by-the-csra-system
#3
Tobias Sahr, Christophe Rusniok, Francis Impens, Giulia Oliva, Odile Sismeiro, Jean-Yves Coppée, Carmen Buchrieser
The carbon storage regulator protein CsrA regulates cellular processes post-transcriptionally by binding to target-RNAs altering translation efficiency and/or their stability. Here we identified and analyzed the direct targets of CsrA in the human pathogen Legionella pneumophila. Genome wide transcriptome, proteome and RNA-Co-immunoprecipitaion followed by deep sequencing of a wild type and a csrA mutant strain identified 479 RNAs with potential CsrA interaction sites located in the untranslated and/or coding regions of mRNAs or of known non-coding sRNAs...
February 17, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28211871/expression-level-is-a-key-determinant-of-e2f1-mediated-cell-fate
#4
Igor Shats, Michael Deng, Adam Davidovich, Carolyn Zhang, Jungeun S Kwon, Dinesh Manandhar, Raluca Gordân, Guang Yao, Lingchong You
The Rb/E2F network has a critical role in regulating cell cycle progression and cell fate decisions. It is dysfunctional in virtually all human cancers, because of genetic lesions that cause overexpression of activators, inactivation of repressors, or both. Paradoxically, the downstream target of this network, E2F1, is rarely strongly overexpressed in cancer. E2F1 can induce both proliferation and apoptosis but the factors governing these critical cell fate decisions remain unclear. Previous studies have focused on qualitative mechanisms such as differential cofactors, posttranslational modification or state of other signaling pathways as modifiers of the cell fate decisions downstream of E2F1 activation...
February 17, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28211163/new-functional-assays-to-selectively-quantify-the-apc-and-tfpi-cofactor-activities-of-protein-s-in-plasma
#5
N Alshaikh, J Rosing, M C L G D Thomassen, E Castoldi, P Simioni, T M Hackeng
BACKGROUND: Protein S plays an important role in the down-regulation of coagulation as cofactor for activated protein C (APC) and tissue factor pathway inhibitor (TFPI). AIM: To develop functional assays to quantify the APC- and TFPI-cofactor activities of protein S in plasma. METHODS: APC- and TFPI-cofactor activities of protein S in plasma were measured using calibrated automated thrombography in protein S-depleted plasma supplemented with a small amount of sample plasma either in the presence of anti-TFPI antibodies and APC (APC-cofactor activity) or at excess full-length TFPI without APC (TFPI-cofactor activity)...
February 17, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28211124/in-planta-expression-searching-for-the-genuine-chromophores-of-cryptochrome-3-from-arabidopsis-thaliana
#6
Wolfgang Gärtner
Göbel et al. present in this issue an exemplary study of identification of chromophores from Arabidopsis thaliana cryptochrome-3. Usually taken for granted, proteins and cofactors, respective chromophores, from heterologous expression are considered identical to material isolated from their genuine host. Cryptochromes carry two chromophores, an antenna cofactor and a functional flavin chromophore, both noncovalently embedded into the protein. In particular the antenna chromophore is loosely bound and often lost during protein purification...
January 2017: Photochemistry and Photobiology
https://www.readbyqxmd.com/read/28202758/endogenous-brain-lipids-inhibit-prion-amyloid-formation-in-vitro
#7
Clare E Hoover, Kristen A Davenport, Davin M Henderson, Mark D Zabel, Edward A Hoover
The normal cellular prion protein (PrP(C)) resides in detergent-resistant outer membrane lipid rafts in which conversion to the pathogenic misfolded form is believed to occur. Once misfolding occurs, the pathogenic isoform polymerizes into highly stable amyloid fibrils. In vitro assays have demonstrated an intimate association between prion conversion and lipids, specifically phosphatidylethanolamine, which is a critical cofactor in the formation of synthetic infectious prions. In the current work, we demonstrate an alternative inhibitory function of lipids in the prion conversion process as assessed in vitro by real-time, quaking induced conversion (RT-QuIC)...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28202538/targeting-rna-for-processing-or-destruction-by-the-eukaryotic-rna-exosome-and-its-cofactors
#8
REVIEW
John C Zinder, Christopher D Lima
The eukaryotic RNA exosome is an essential and conserved protein complex that can degrade or process RNA substrates in the 3'-to-5' direction. Since its discovery nearly two decades ago, studies have focused on determining how the exosome, along with associated cofactors, achieves the demanding task of targeting particular RNAs for degradation and/or processing in both the nucleus and cytoplasm. In this review, we highlight recent advances that have illuminated roles for the RNA exosome and its cofactors in specific biological pathways, alongside studies that attempted to dissect these activities through structural and biochemical characterization of nuclear and cytoplasmic RNA exosome complexes...
January 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28202332/cdc20-at-the-crossroads-between-chromosome-segregation-and-mitotic-exit
#9
REVIEW
Maria Kapanidou, Natalie L Curtis, Victor M Bolanos-Garcia
Cell-division cycle protein 20 homologue (Cdc20) has important functions in chromosome segregation and mitotic exit. Cdc20 is the target of the spindle assembly checkpoint (SAC) and a key cofactor of the anaphase-promoting complex or cyclosome (APC/C) E3 ubiquitin ligase, thus regulating APC/C ubiquitin activity on specific substrates for their subsequent degradation by the proteasome. Here we discuss the roles of Cdc20 in SAC signalling and mitotic exit, describe how the integration of traditional approaches with emerging technologies has revealed new details of Cdc20 functions, comment about the potential of Cdc20 as a therapeutic target for the treatment of human malignancies, and discuss recent advances and controversies in the mechanistic understanding of the control of chromosome segregation during cell division...
February 12, 2017: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/28201792/engineering-the-cofactor-specificity-of-an-alcohol-dehydrogenase-via-single-mutations-or-insertions-distal-to-the-2-phosphate-group-of-nadp-h
#10
Kusum Solanki, Walaa Abdallah, Scott Banta
No abstract text is available yet for this article.
February 15, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/28198360/secreted-clic3-drives-cancer-progression-through-its-glutathione-dependent-oxidoreductase-activity
#11
Juan R Hernandez-Fernaud, Elena Ruengeler, Andrea Casazza, Lisa J Neilson, Ellie Pulleine, Alice Santi, Shehab Ismail, Sergio Lilla, Sandeep Dhayade, Iain R MacPherson, Iain McNeish, Darren Ennis, Hala Ali, Fernanda G Kugeratski, Heba Al Khamici, Maartje van den Biggelaar, Peter V E van den Berghe, Catherine Cloix, Laura McDonald, David Millan, Aoisha Hoyle, Anna Kuchnio, Peter Carmeliet, Stella M Valenzuela, Karen Blyth, Huabing Yin, Massimiliano Mazzone, Jim C Norman, Sara Zanivan
The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2)...
February 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28198056/vitamin-b12-catalysis-probing-the-structure-efficacy-relationship
#12
Maksymilian Karczewski, Michał Ociepa, Katarzyna Pluta, Keith óProinsias, Dorota Gryko
Vitamin B12 is a cofactor for many enzymes but it also functions as a catalyst in C-C bond forming reactions. In the present study, the impact of corrin structural modifications on their catalytic efficacy was examined. Derivatives with various substituents at c-, d-, and meso-positions were synthesized using traditional and new microwave methodologies and then tested in the model reaction of 1,1-diphenylethylene with EDA. To complement our experimental data, CV and DFT calculations were performed. Mainly alterations at the c- or d-positions influence both the reaction yield and selectivity...
February 14, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28196881/engineered-holocytochrome-c-synthases-that-biosynthesize-new-cytochromes-c
#13
Deanna L Mendez, Shalon E Babbitt, Jeremy D King, John D'Alessandro, Michael B Watson, Robert E Blankenship, Liviu M Mirica, Robert G Kranz
Cytochrome c (cyt c), required for electron transport in mitochondria, possesses a covalently attached heme cofactor. Attachment is catalyzed by holocytochrome c synthase (HCCS), leading to two thioether bonds between heme and a conserved CXXCH motif of cyt c In cyt c, histidine (His19) of CXXCH acts as an axial ligand to heme iron and upon release of holocytochrome c from HCCS, folding leads to formation of a second axial interaction with methionine (Met81). We previously discovered mutations in human HCCS that facilitate increased biosynthesis of cyt c in recombinant Escherichia coli Focusing on HCCS E159A, novel cyt c variants in quantities that are sufficient for biophysical analysis are biosynthesized...
February 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28196028/evaluation-of-suppressive-effects-of-tranilast-on-the-invasion-metastasis-mechanism-in-a-murine-pancreatic-cancer-cell-line
#14
Munehisa Kaneda, Hideaki Obara, Keiichi Suzuki, Osamu Takeuchi, Asako Takizawa, Masayoshi Osaku, Hajime Matsubara, Yuko Kitagawa
OBJECTIVES: Numerous studies have investigated the mechanism of the antitumor effect of tranilast, well known as an antiallergic drug. Herein, we investigated the mechanism of the antitumor effects of tranilast using murine Pan02 cell line. METHODS: In an allograft mouse model, the number of metastatic sites in the liver was counted. Wound healing and chemoinvasion assay were performed to evaluate migration and invasive ability of Pan02, respectively. Activities of matrix metalloproteinases (MMPs) were evaluated by gelatin zymography...
February 14, 2017: Pancreas
https://www.readbyqxmd.com/read/28194496/impact-of-pulmonary-hypertension-on-outcome-in-patients-with-severe-aortic-stenosis-and-preserved-left-ventricular-ejection-fraction
#15
Julien Magne, Dania Mohty, Alessandro Piccardo, Cyrille Boulogne, Mathieu Deltreuil, Vincent Petitalot, Najmeddine Echahidi, Nicole Darodes, Patrice Virot, Thibaud Damy, Victor Aboyans
AIMS: The prognostic impact of elevated pulmonary arterial pressure (PAP) remains controversial in aortic stenosis (AS) and few studies focused on patients with preserved left ventricular ejection fraction (LVEF). We aimed to investigate the impact of pulmonary hypertension (PH), invasively derived, on survival in severe AS with preserved LVEF. METHODS AND RESULTS: Between 2000 and 2010, 749 patients (74 ± 8 years, 57% males) with preserved LVEF and severe AS without other valvular heart disease underwent cardiac catheterization...
February 14, 2017: Clinical Research in Cardiology: Official Journal of the German Cardiac Society
https://www.readbyqxmd.com/read/28193327/cloning-expression-and-biochemical-characterization-of-a-novel-nadp-dependent-7%C3%AE-hydroxysteroid-dehydrogenase-from-clostridium-difficile-and-its-application-for-the-oxidation-of-bile-acids
#16
Daniel Bakonyi, Werner Hummel
A gene encoding a novel 7α-specific NADP(+)-dependent hydroxysteroid dehydrogenase from Clostridium difficile was cloned and heterologously expressed in Escherichia coli. The enzyme was purified using an N-terminal hexa-his-tag and biochemically characterized. The optimum temperature is at 60°C, but the enzyme is inactivated at this temperature with a half-life time of 5min. Contrary to other known 7α-HSDHs, for example from Clostridium sardiniense or E. coli, the enzyme from C. difficile does not display a substrate inhibition...
April 2017: Enzyme and Microbial Technology
https://www.readbyqxmd.com/read/28192411/the-glcn6p-cofactor-plays-multiple-catalytic-roles-in-the-glms-ribozyme
#17
Jamie L Bingaman, Sixue Zhang, David R Stevens, Neela H Yennawar, Sharon Hammes-Schiffer, Philip C Bevilacqua
RNA enzymes (ribozymes) have remarkably diverse biological roles despite having limited chemical diversity. Protein enzymes enhance their reactivity through recruitment of cofactors; likewise, the naturally occurring glmS ribozyme uses the glucosamine-6-phosphate (GlcN6P) organic cofactor for phosphodiester bond cleavage. Prior structural and biochemical studies have implicated GlcN6P as the general acid. Here we describe new catalytic roles of GlcN6P through experiments and calculations. Large stereospecific normal thio effects and a lack of metal-ion rescue in the holoribozyme indicate that nucleobases and the cofactor play direct chemical roles and align the active site for self-cleavage...
February 13, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28191958/specific-ligation-of-two-multimeric-enzymes-with-native-peptides-and-immobilization-with-controlled-molar-ratio
#18
Kun Du, Jinjin Zhao, Jian Sun, Wei Feng
D-amino acid oxidases (DAAOs) are flavor enzymes and have been used in resolution of racemic amino acids and manufacturing of pharmaceuticals. However, the evolved H2O2 during the catalysis has deleterious and inhibitory effects. Decomposition of the hydrogen peroxide by catalase (CAT) can eliminate the negative effects. DAAO and CAT are dimeric and tetrameric proteins, respectively. Here the N-terminus of the DAAO subunits has been specifically ligated to the C-terminus of the CAT subunits with native peptides through intein-mediated in vivo protein splicing...
February 13, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28190770/nuclear-rna-decay-pathways-aid-rapid-remodeling-of-gene-expression-in-yeast
#19
Stefan Bresson, Alex Tuck, Desislava Staneva, David Tollervey
In budding yeast, the nuclear RNA surveillance system is active on all pre-mRNA transcripts and modulated by nutrient availability. To test the role of nuclear surveillance in reprogramming gene expression, we identified transcriptome-wide binding sites for RNA polymerase II and the exosome cofactors Mtr4 (TRAMP complex) and Nab3 (NNS complex) by UV crosslinking immediately following glucose withdrawal (0, 4, and 8 min). In glucose, mRNA binding by Nab3 and Mtr4 was mainly restricted to promoter-proximal sites, reflecting early transcription termination...
January 27, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28188871/cloning-characterization-and-subcellular-localization-of-nuclear-lim-interactor-interacting-factor-gene-from-leishmania-donovani
#20
R Ravinder, N Goyal
LIM domains are zinc-binding motifs that mediate protein-protein interactions and are found in a wide variety of cytoplasmic and nuclear proteins. The nuclear LIM domain family members have a number of different functions including transcription factors, gene regulation, cell fate determination, organization of the cytoskeleton and tumour formation exerting their function through various LIM domain interacting protein partners/cofactors. Nuclear LIM domain interacting proteins/factors have not been reported in any protozoan parasites including Leishmania...
February 7, 2017: Gene
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