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https://www.readbyqxmd.com/read/28346407/insights-into-activity-and-inhibition-from-the-crystal-structure-of-human-o-glcnacase
#1
Nathaniel L Elsen, Sangita B Patel, Rachael E Ford, Dawn L Hall, Fred Hess, Hari Kandula, Maria Kornienko, John Reid, Harold Selnick, Jennifer M Shipman, Sujata Sharma, Kevin J Lumb, Stephen M Soisson, Daniel J Klein
O-GlcNAc hydrolase (OGA) catalyzes removal of βα-linked N-acetyl-D-glucosamine from serine and threonine residues. We report crystal structures of Homo sapiens OGA catalytic domain in apo and inhibited states, revealing a flexible dimer that displays three unique conformations and is characterized by subdomain α-helix swapping. These results identify new structural features of the substrate-binding groove adjacent to the catalytic site and open new opportunities for structural, mechanistic and drug discovery activities...
March 27, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28346405/structural-and-functional-insight-into-human-o-glcnacase
#2
Christian Roth, Sherry Chan, Wendy A Offen, Glyn R Hemsworth, Lianne I Willems, Dustin T King, Vimal Varghese, Robert Britton, David J Vocadlo, Gideon J Davies
O-GlcNAc hydrolase (OGA) removes O-linked N-acetylglucosamine (O-GlcNAc) from a myriad of nucleocytoplasmic proteins. Through co-expression and assembly of OGA fragments, we determined the three-dimensional structure of human OGA, revealing an unusual helix-exchanged dimer that lays a structural foundation for an improved understanding of substrate recognition and regulation of OGA. Structures of OGA in complex with a series of inhibitors define a precise blueprint for the design of inhibitors that have clinical value...
March 27, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28339907/o-linked-%C3%AE-n-acetylglucosamine-modification-of-proteins-is-essential-for-foot-process-maturation-and-survival-in-podocytes
#3
Shinya Ono, Shinji Kume, Mako Yasuda-Yamahara, Kosuke Yamahara, Naoko Takeda, Masami Chin-Kanasaki, Hisazumi Araki, Osamu Sekine, Hideki Yokoi, Masashi Mukoyama, Takashi Uzu, Shin-Ichi Araki, Hiroshi Maegawa
Background.: O-linked β- N -acetylglucosamine modification O-GlcNAcylation) is a post-translational modification of intracellular proteins, serving as a nutrient sensor. Growing evidence has demonstrated its physiological and pathological importance in various mammalian tissues. This study examined the physiological role of O-GlcNAcylation in podocyte function and development. Methods.: O-GlcNAc transferase (Ogt) is a critical enzyme for O-GlcNAcylation and resides on the X chromosome...
February 27, 2017: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/28336748/the-sweet-side-of-ampk-signaling-regulation-of-gfat1
#4
John W Scott, Jonathan S Oakhill
Maintaining a steady balance between nutrient supply and energy demand is essential for all living organisms and is achieved through the dynamic control of metabolic processes that produce and consume adenosine-5'-triphosphate (ATP), the universal currency of energy in all cells. A key sensor of cellular energy is the adenosine-5'-monophosphate (AMP)-activated protein kinase (AMPK), which is the core component of a signaling network that regulates energy and nutrient metabolism. AMPK is activated by metabolic stresses that decrease cellular ATP, and functions to restore energy balance by orchestrating a switch in metabolism away from anabolic pathways toward energy-generating catabolic processes...
March 23, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28319083/structures-of-human-o-glcnacase-and-its-complexes-reveal-a-new-substrate-recognition-mode
#5
Baobin Li, Hao Li, Lei Lu, Jiaoyang Jiang
Human O-GlcNAcase (hOGA) is the unique enzyme responsible for the hydrolysis of the O-linked β-N-acetyl glucosamine (O-GlcNAc) modification, an essential protein glycosylation event that modulates the function of numerous cellular proteins in response to nutrients and stress. Here we report crystal structures of a truncated hOGA, which comprises the catalytic and stalk domains, in apo form, in complex with an inhibitor, and in complex with a glycopeptide substrate. We found that hOGA forms an unusual arm-in-arm homodimer in which the catalytic domain of one monomer is covered by the stalk domain of the sister monomer to create a substrate-binding cleft...
March 20, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28314751/identification-of-glycopeptides-as-post-translationally-modified-neoantigens-in-leukemia
#6
Stacy A Malaker, Sarah A Penny, Lora G Steadman, Paisley T Myers, Justin Loke, Manoj Raghavan, Dina L Bai, Jeffery Shabanowitz, Donald Hunt, Mark Cobbold
Leukemias are highly immunogenic but have a low mutational load, providing few mutated peptide targets. Thus, the identification of alternative neoantigens is a pressing need. Here, we identify 36 MHC class I-associated peptide antigens with O-linked β-N-acetylglucosamine (O-GlcNAc) modifications as candidate neoantigens, using three experimental approaches. Thirteen of these peptides were also detected with disaccharide units on the same residues and two contain either mono- and/or di-methylated arginine residues...
March 17, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28302723/identification-and-characterization-of-a-missense-mutation-in-the-o-glcnac-transferase-gene-that-segregates-with-x-linked-intellectual-disability
#7
Krithika Vaidyanathan, Tejasvi Niranjan, Nithya Selvan, Chin Fen Teo, Melanie May, Sneha Patel, Brent Weatherly, Cindy Skinner, John Opitz, John Carey, David Viskochil, Jozef Gecz, Marie Shaw, Yunhui Peng, Emil Alexov, Tao Wang, Charles Schwartz, Lance Wells
O-GlcNAc is a regulatory post-translational modification of nucleocytoplasmic proteins that has been implicated in multiple biological processes including transcription. In humans, single genes encode enzymes for its attachment [O-GlcNAc transferase (OGT)] and removal [O-GlcNAcase (OGA)]. An X-chromosome exome screen identified a missense mutation, that encodes an amino acid in the tetratricopeptide repeat, in OGT (759G>T (p.L254F)) that segregates with X-linked intellectual disability (XLID) in an affected family...
March 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28299467/cardiomyocyte-ogt-limits-ventricular-dysfunction-in-mice-following-pressure-overload-without-affecting-hypertrophy
#8
Sujith Dassanayaka, Robert E Brainard, Lewis J Watson, Bethany W Long, Kenneth R Brittian, Angelica M DeMartino, Allison L Aird, Anna M Gumpert, Timothy N Audam, Peter J Kilfoil, Senthilkumar Muthusamy, Tariq Hamid, Sumanth D Prabhu, Steven P Jones
The myocardial response to pressure overload involves coordination of multiple transcriptional, posttranscriptional, and metabolic cues. The previous studies show that one such metabolic cue, O-GlcNAc, is elevated in the pressure-overloaded heart, and the increase in O-GlcNAcylation is required for cardiomyocyte hypertrophy in vitro. Yet, it is not clear whether and how O-GlcNAcylation participates in the hypertrophic response in vivo. Here, we addressed this question using patient samples and a preclinical model of heart failure...
May 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/28296566/a-new-elisa-based-method-for-detection-of-o-glcnac-transferase-activity-in-vitro
#9
Jieqiong Qi, Ruihong Wang, Yazhen Zeng, Wengong Yu, Yuchao Gu
O-GlcNAcylation is a dynamic, reversible, post-translational modification that regulates many cellular processes. O-GlcNAc transferase (OGT) is the sole enzyme transferring N-acetylglucosamine from UDP-GlcNAc to selected Ser/Thr residues of cytoplasm and nucleus proteins. Aberrant of OGT activity is associated with a number of diseases, suggesting OGT as a novel therapeutic target. In this study, we created a new ELISA-based method for detection of OGT activity. First, CKII, a well-known OGT substrate, was coated onto ELISA plate...
March 15, 2017: Preparative Biochemistry & Biotechnology
https://www.readbyqxmd.com/read/28280036/myeloid-derived-cullin-3-promotes-stat3-phosphorylation-by-inhibiting-ogt-expression-and-protects-against-intestinal-inflammation
#10
Xinghui Li, Zhibin Zhang, Lupeng Li, Wei Gong, Audrey J Lazenby, Benjamin J Swanson, Laura E Herring, John M Asara, Jeffrey D Singer, Haitao Wen
Signal transducer and activator of transcription 3 (STAT3) is a key mediator of intestinal inflammation and tumorigenesis. However, the molecular mechanism that modulates STAT3 phosphorylation and activation is not fully understood. Here, we demonstrate that modification of STAT3 with O-linked β-N-acetylglucosamine (O-GlcNAc) on threonine 717 (T717) negatively regulates its phosphorylation and targets gene expression in macrophages. We further found that cullin 3 (CUL3), a cullin family E3 ubiquitin ligase, down-regulates the expression of the O-GlcNAc transferase (OGT) and inhibits STAT3 O-GlcNAcylation...
March 9, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28272406/o-glcnacylation-of-skn-1-modulates-the-lifespan-and-oxidative-stress-resistance-in-caenorhabditis-elegans
#11
Hongyuan Li, Xin Liu, Dan Wang, Liangping Su, Tingting Zhao, Zhongwei Li, Cong Lin, Yu Zhang, Baiqu Huang, Jun Lu, Xiaoxue Li
In C. elegans, the transcription factor skinhead-1 (SKN-1), the ortholog of human NF-E2-related factor 2 (Nrf-2), plays important roles in oxidative stress defense and aging processes. It has been documented that the activity of SKN-1 is regulated by its phosphorylation modification. However, whether other posttranslational modifications of SKN-1 affect its function remains unclear to date. Here we report, for the first time, that SKN-1 is O-GlcNAcylated at Ser470 and Thr493 by O-GlcNActransferase OGT-1. By generating the double mutations of Ser470/Thr493 in the wild type and skn-1(zu67) worms, respectively, we found that disruption of O-GlcNAc modification on SKN-1 repressed the accumulation of SKN-1 in the intestinal nuclei, and decreased the activities of SKN-1 in modulating lifespan and oxidative stress resistance...
March 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28263870/yeast-cells-as-an-assay-system-for-in-vivo-o-glcnac-modification
#12
Hideki Nakanishi, Feng Li, Baoxian Han, Seisuke Arai, Xiao-Dong Gao
BACKGROUND: O-GlcNAcylation is a reversible protein post-translational modification, where O-GlcNAc moiety is attached to nucleocytoplasmic protein by O-GlcNAc transferase (OGT) and removed by O-GlcNAcase (OGA). Although O-GlcNAc modification widely occurs in eukaryotic cells, the budding yeast Saccharomyces cerevisiae notably lacks this protein modification and the genes for the GlcNAc transferase and hydrolase. METHODS: Human OGT isoforms and OGA were ectopically expressed in S...
March 2, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28262738/high-glucose-levels-boost-the-aggressiveness-of-highly-metastatic-cholangiocarcinoma-cells-via-o-glcnacylation
#13
Chatchai Phoomak, Kulthida Vaeteewoottacharn, Atit Silsirivanit, Charupong Saengboonmee, Wunchana Seubwai, Kanlayanee Sawanyawisuth, Chaisiri Wongkham, Sopit Wongkham
Increased glucose utilization is a feature of cancer cells to support cell survival, proliferation, and metastasis. An association between diabetes mellitus and cancer progression was previously demonstrated in cancers including cholangiocarcinoma (CCA). This study was aimed to determine the effects of high glucose on protein O-GlcNAcylation and metastatic potentials of CCA cells. Two pairs each of the parental low metastatic and highly metastatic CCA sublines were cultured in normal (5.6 mM) or high (25 mM) glucose media...
March 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28259907/o-glcnacylation-promotes-migration-and-invasion-in-human-ovarian-cancer-cells-via-the-rhoa-rock-mlc-pathway
#14
Yichao Niu, Ye Xia, Jingyun Wang, Xiaofei Shi
O-GlcNAcylation is a dynamic and reversible post-translational modification associated with the regulation of multiple cellular functions. The addition and removal of O‑Linked β-N-acetylglucosamine (O‑GlcNAc) on target proteins is catalyzed by O‑GlcNAc transferase (OGT) and O‑GlcNAcase (OGA), respectively. Accumulating evidence suggests that O-GlcNAcylation is associated with the malignancy of several types of human cancer. To investigate the effect of O-GlcNAcylation on ovarian cancer phenotypes, global O‑GlcNAc levels were decreased by OGT silencing through RNA interference and increased by inhibiting OGA activity with Thiamet‑G...
April 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28246173/nutrient-driven-o-glcnac-cycling-impacts-neurodevelopmental-timing-and-metabolism
#15
Stephanie Olivier-Van Stichelen, Peng Wang, Marcy Comly, Dona C Love, John A Hanover
Nutrient-driven O-GlcNAcylation is strikingly abundant in the brain and has been linked to development and neurodegenerative disease. We selectively targeted the O-GlcNAcase (Oga) gene in the mouse brain to define the role of O-GlcNAc cycling in the central nervous system. The brain-knockout animals exhibited dramatically increased brain O-GlcNAc levels and pleiotropic phenotypes including early onset obesity, growth defects, and metabolic dysregulation. Anatomical defects in the Oga knockout included delayed brain differentiation and neurogenesis as well as abnormal proliferation accompanying a developmental delay...
February 28, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28242721/a-putative-o-linked-%C3%AE-n-acetylglucosamine-transferase-is-essential-for-hormogonium-development-and-motility-in-the-filamentous-cyanobacterium-nostoc-punctiforme
#16
Behzad Khayatan, Divleen K Bains, Monica H Cheng, Ye Won Cho, Jessica Huynh, Rachelle Kim, Osagie H Omoruyi, Adriana P Pantoja, Jun Sang Park, Julia K Peng, Samantha D Splitt, Mason Y Tian, Douglas D Risser
Most species of filamentous cyanobacteria are capable of gliding motility, likely via a conserved type IV pilus-like system that may also secrete a motility associated polysaccharide. In a subset of these organisms, motility is only achieved after the transient differentiation of hormogonia, specialized filaments that enter a non-growth state dedicated to motility. Despite the fundamental importance of hormogonia to the life cycle of many filamentous cyanobacteria, the molecular regulation of hormogonium development is largely undefined...
February 27, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/28238085/o-glcnac-glycosylation-of-nnos-promotes-neuronal-apoptosis-following-glutamate-excitotoxicity
#17
Rongrong Chen, Peipei Gong, Tao Tao, Yilu Gao, Jianhong Shen, Yaohua Yan, Chengwei Duan, Jun Wang, Xiaojuan Liu
Ischemic stroke is a dominant health problem with extremely high rates of mortality and disability. The main mechanism of neuronal injury after stroke is excitotoxicity, during which the activation of neuronal nitric oxide synthase (nNOS) exerts a vital role. However, directly blocking N-methyl-D-aspartate receptors or nNOS can lead to severe undesirable effects since they have crucial physiological functions in the central nervous system. Here, we report that nNOS undergoes O-linked-β-N-acetylglucosamine (O-GlcNAc) modification via interacting with O-GlcNAc transferase, and the O-GlcNAcylation of nNOS remarkably increases during glutamate-induced excitotoxicity...
February 25, 2017: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/28228555/microrna-15b-suppresses-th17-differentiation-and-is-associated-with-pathogenesis-of-multiple-sclerosis-by-targeting-o-glcnac-transferase
#18
Ruiqiong Liu, Xiaofeng Ma, Li Chen, Yang Yang, Yi Zeng, Jie Gao, Wei Jiang, Fang Zhang, Daojing Li, Bin Han, Ranran Han, Rongfang Qiu, Wei Huang, Yan Wang, Junwei Hao
IL-17-producing Th17 cells have gradually become considered as key factors in the pathogenesis of many autoimmune diseases, including multiple sclerosis (MS). Although the involvement of certain microRNAs in the development of MS has been reported, their role in Th17-driven autoimmunity is still poorly understood. In this study, we identified microRNA (miR)-15b as an important factor in Th17-associated effects and determined that the expression of miR-15b is significantly downregulated in MS patients and in mice with experimental autoimmune encephalomyelitis...
February 22, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28202678/stress-induced-o-glcnacylation-an-adaptive-process-of-injured-cells
#19
REVIEW
Marissa R Martinez, Thiago Braido Dias, Peter S Natov, Natasha E Zachara
In the 30 years, since the discovery of nucleocytoplasmic glycosylation, O-GlcNAc has been implicated in regulating cellular processes as diverse as protein folding, localization, degradation, activity, post-translational modifications, and interactions. The cell co-ordinates these molecular events, on thousands of cellular proteins, in concert with environmental and physiological cues to fine-tune epigenetics, transcription, translation, signal transduction, cell cycle, and metabolism. The cellular stress response is no exception: diverse forms of injury result in dynamic changes to the O-GlcNAc subproteome that promote survival...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28195695/o-glcnacylation-of-%C3%AE-synuclein-at-serine-87-reduces-aggregation-without-affecting-membrane-binding
#20
Yuka E Lewis, Ana Galesic, Paul M Levine, Cesar A De Leon, Natalie Lamiri, Caroline K Brennan, Matthew R Pratt
The aggregation of neurodegenerative-disease associated proteins can be affected by many factors, including a variety of post-translational modifications. One such modification, O-GlcNAcylation, has been found on some of these aggregation prone proteins, including α-synuclein, the major protein that plays a causative role in synucleinopathies like Parkinson's disease. We previously used synthetic protein chemistry to prepare α-synuclein bearing a homogeneous O-GlcNAc modification at threonine 72 and showed that this modification inhibits protein aggregation...
February 22, 2017: ACS Chemical Biology
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