Moreover, there are a number of mechanistically similar related enzymes such as β‐hexosaminidases (Hex), and the concomitant inhibition of these enzymes leads to undesirable lysosomal‐storage disorders. Epub 2016 Aug 4. Cleaves GlcNAc but not GalNAc from O-glycosylated proteins. Pharmacological inhibition of O-GlcNAcase (OGA), the sole enzyme that removes O-GlcNAc, reproducibly slows neurodegeneration in various Alzheimer’s disease (AD) mouse models manifesting either tau or amyloid pathology. 2 Protects cardiac function after trauma-hemorrhage which is mediated by increased protein O-GlcNAc levels. We report the discovery of nanomolar OGA inhibitors that are up to 900,000-fold selective over the related lysosomal hexosaminidases. (2010) Inhibition of O-GlcNAcase using a potent and cell-permeable inhibitor does not induce insulin resistance in 3T3-L1 adipocytes. 4 O-GlcNAcylation is a post-translational modification consisting of the addition of a single N-acetyl-glucosamine residue (GlcNAc) to specific serine/threonine residues of proteins.The addition of GlcNAc has been compared to phosphorylation, and there may be significant interplay between the two … 2020 Aug;374(2):252-263. doi: 10.1124/jpet.120.266122. Can use p-nitrophenyl-beta-GlcNAc and 4-methylumbelliferone-GlcNAc as substrates but not p-nitrophenyl-beta-GalNAc or p-nitrophenyl-alpha-GlcNAc (in vitro) (PubMed:11148210). O-GLCNACASE Inhibitors The Biocompare Inhibitor Search lets researchers browse thousands of compounds by searching not only by inhibitor name, but also by its target enzyme. Thiamet-G is a recently synthesized potent OGA inhibitor, and initial studies suggest it can influence O-GlcNAc levels in the brain, allowing OGA inhibition to be a potential route to altering disease progression in AD. O-GlcNAcylation: New Tools to Investigate this Important Post-Translational Modification. Learn more. COVID-19 is an emerging, rapidly evolving situation. We focus on the catalytic mechanism and substrate recognition by OGA. Increases O-GlcNAc-modified protein levels (EC 50 = 30 nM). Irregular O‐GlcNAcylation is linked to several diseases including cancer, diabetes and neurodegeneration. 2017 May 18;12(1):39. doi: 10.1186/s13024-017-0181-0. This site needs JavaScript to work properly. This protein modification is mainly governed by a pair of enzymes: O‐GlcNAc transferase (OGT) adds the N‐acetylglucosamine moiety to acceptor proteins, and O‐GlcNAcase (OGA) hydrolyses the sugar moiety from protein acceptors. 2020 Oct 19;21(20):7739. doi: 10.3390/ijms21207739. 108155 Ensembl ENSG00000147162 ENSMUSG00000034160 UniProt O15294 Q8CGY8 RefSeq (mRNA) NM_003605 NM_181672 NM_181673 NM_001290535 NM_139144 RefSeq (protein) NP_858058 NP_858059 NP_001277464 NP_631883 Location (UCSC) Chr X: 71.53 – 71.58 Mb Chr X: 101.64 – 101.68 Mb PubMed search Wikidata View/Edit Human View/Edit Mouse Protein O -GlcNAc … PUGNAc (CAS 132489-69-1) is an O-GlcNAcase (O-GlcNAc-β-N-acetylglucosaminidase) and β-hexosaminidase inhibitor (K i =46 and 36 nM, respectively). 3 Induces insulin resistance in rat skeletal muscle. Epub 2020 Jun 3. CNS Neurosci Ther. Epub 2014 Apr 24. Inhibition of O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc modification, has been shown to reduce tau pathology in several transgenic models.  |  We have painstakingly mapped out these targets for your convenience, so that you may quickly and painlessly find and decide the right inhibitor for your work. The reagent su O-GlcNAc and neurodegeneration: biochemical mechanisms and potential roles in Alzheimer's disease and beyond. Molecular Interrogation to Crack the Case of O-GlcNAc. These data have stimulated interest in the possibility of using OGA-selective inhibitors as pharmaceuticals to alter the progression of AD. In order to identify new human O‐GlcNAcase inhibitors, a high‐throughput screening assay was performed based on the release of 4‐methylumbelliferol (4MU) from the pseudo substrate 4MU‐GlcNAc, initially using the bacterial OGA homologue from C. perfringens (CpOGA) which has recently been shown to be a good model of hOGA . CAS Number. NIH Please check your email for instructions on resetting your password. Chemical structure. Acutely elevated O-GlcNAcylation suppresses hippocampal activity by modulating both intrinsic and synaptic excitability factors. Would you like email updates of new search results? Hastings NB, Wang X, Song L, Butts BD, Grotz D, Hargreaves R, Fred Hess J, Hong KK, Huang CR, Hyde L, Laverty M, Lee J, Levitan D, Lu SX, Maguire M, Mahadomrongkul V, McEachern EJ, Ouyang X, Rosahl TW, Selnick H, Stanton M, Terracina G, Vocadlo DJ, Wang G, Duffy JL, Parker EM, Zhang L. Mol Neurodegener. Shows antitauopathic effects in vivo. The inhibitors goblin1 (OGT bisubstrate-linked inhibitor 1; Figure 1) and goblin2 have been created by connecting an acceptor peptide to a UDP through a short linker that replaces the GlcNAc moiety. 88 Biochemical Society Transactions (2016) Volume 44, part 1 O-GlcNAc transferase inhibitors: current tools and future challenges Riccardo Trapannone*1, Karim Rafie*1 and Daan M.F. Request PDF | O-GlcNAcase inhibitors | O-GlcN Acylation is a newly discovered protein post-translational modification on Ser/Thr. These results strongly suggest that OGA inhibitors act within brain through a mechanism involving enhancement of autophagy, which aids the brain in combatting the accumulation of toxic protein species. HHS  |  O-GlcNAcylation is an essential posttranslational modification in metazoa. Wang X, Li W, Marcus J, Pearson M, Song L, Smith K, Terracina G, Lee J, Hong KK, Lu SX, Hyde L, Chen SC, Kinsley D, Melchor JP, Rubins DJ, Meng X, Hostetler E, Sur C, Zhang L, Schachter JB, Hess JF, Selnick HG, Vocadlo DJ, McEachern EJ, Uslaner JM, Duffy JL, Smith SM. The mechanisms mediating the neuroprotective effects of OGA inhibitors, … Recently, the discovery of small‐molecule OGA inhibitors has enabled the physiological function of O‐GlcNAcylation to be investigated. Potent, selective O-GlcNAcase inhibitor (K i = 21 nM). These findings should aid the advancement of OGA inhibitors within the clinic. Chemical name . O-GlcNAcase Inhibitor Alzheimer's Oxyntomodulin Diabetes PACAP38 Antibody Pain PD-1 Antibody Agonist Immunology ... Lilly defines First Human Dose as the date of the first dose administered in the initial clinical study of the molecule given to healthy volunteers. Modulation of O-GlcNAcylation Regulates Autophagy in Cortical Astrocytes. We discuss inhibitor structures, binding modes, and selectivity towards the enzyme, and potential outcomes in probing O‐GlcNAcylation at cellular levels. This review highlights recent insights into the structure of human O‐GlcNAcase and its isoforms. This enzyme catalyses the removal of the O-GlcNAc post-translational modification in the following chemical reaction: -3-O--L-serine + H2O ⇌ -L-serine + N-acetyl-D-glucosamine -3-O--L-threonine + H2O ⇌ -L-threonine + N-acetyl-D-glucosamine USA.gov. Keywords: Here, we report the pharmacokinetics of … For the biopharma industry investment, business development and competitive intelligence professionals who require information to support financing, partnering and licensing activities, BCIQ provides accurate information and context to support profitable and strategic decision making. Consistent with this proposal, 1,2-dideoxy-2′-methyl-α-d-glucopyranoso-[2,1-d]-Δ2′-thiazoline, an inhibitor that mimics the oxazoline intermediate proposed in the catalytic mechanism of family 20 glycoside hydrolases, is shown to act as a potent competitive inhibitor of both O-GlcNAcase (K I I = 0.070 μ m) and β-hexosaminidase (K = 0.070 μ m). We find that short OGA, which possesses O-GlcNAcase catalysis machinery like that of long OGA, exhibits comparative resistance to previously described potent inhibitors of long OGA and lysosomal hexosaminidases, including PUGNAc and NAG-thiazoline, suggesting a role for the HAT domain in O-GlcNAcase catalysis. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. The mechanisms mediating the neuroprotective effects of OGA inhibitors, however, remain poorly understood. OGA is encoded by the MGEA5 gene. Novel non-carbohydrate O-GlcNAcase inhibitors with CNS drug properties as potential treatment for Alzheimer’s disease and tauopathies. 2012;7(4):e35277. Epub 2012 Apr 19. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high … ABSTRACT: Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer’s disease and progressive supranuclear palsy. 2014 Oct 7;43(19):6839-58. doi: 10.1039/c4cs00038b. We found that … O-GlcNAcase Inhibitors as Tools to Study O-GlcNAc Signaling The elucidation of the OGA catalytic mechanism has enabled the development of potent and selective inhibitors that have subsequently been used to study O-GlcNAcylation in cells and organisms. Alzheimer’s disease; O-GlcNAc; Thiamet-G; autophagy; glycosylation; neurodegeneration. These compounds exhibited low micromolar affinity for OGT and inhibited O-GlcNAcylation of peptides and protein substrates in vitro (IC 50 =18 μM for goblin1) [ 44 ]. Does not bind acetyl-CoA and does not have histone acetyltransferase activity (PubMed:24088714). Blood-brain barrier permeable. Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer’s disease and progressive supranuclear palsy. van Aalten* Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK article info Article history: Received 16 October 2009 Revised 1 December 2009 Accepted 13 December 2009 Available online 16 December 2009 Edited by Judit … O-GLCNACASE INH Alzheimer’s GGG TRI-AGONIST Diabetes CDK7 INHIBITOR Cancer CONNECTED CARE PREFILLED INSULIN PEN Diabetes GLP-1R NPA Diabetes TRPA1 ANTAGONIST Pain SSTR4 AGONIST Pain D1 PAM II Dementia ANGPTL3/8 MAB CVD SERD Cancer TIRZEPATIDE Obesity LEBRIKIZUMAB Atopic Dermatitis SELPERCATINIB 1L Med Thyroid Cancer SELPERCATINIB 1L … 2017 Jul;133:80-87. doi: 10.1016/j.brainresbull.2016.08.002. Use the link below to share a full-text version of this article with your friends and colleagues. O‐GlcNAcylation is the dynamic and ubiquitous post‐translational glycosylation of nucleocytoplasmic proteins on serine/threonine residues; it is implicated in regulation of the cell cycle. If you do not receive an email within 10 minutes, your email address may not be registered, Blocks tau phosphorylation. In this study, we injected thiamet-G into the lateral ventricle of mice to increase O-GlcNAcylation of proteins and investigated the resulting effects on site-specific tau phosphorylation. In addition, it presents an updated overview of small‐molecule OGA inhibitors, with either carbohydrate or noncarbohydrate scaffolds. Working off-campus? Orally active. van Aalten*†2 *Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K. NLM PLoS One. For the biopharma industry investment, business development and competitive intelligence professionals who require information to support financing, partnering and licensing activities, BCIQ provides accurate information and context to support profitable and strategic decision making. Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice. Brain Res Bull. and you may need to create a new Wiley Online Library account. Properties. Learn about our remote access options, Center for Neuro-Medicine Brain Science Institute, Korea Institutes of Science and Technology, Seoul, 02792 (Republic of Korea, Division of Bio-Med KIST school, Korea University of Science and Technology (UST), Gajungro 217 Youseong-gu, Daejeon (Republic of, Korea, Daegu University, Department of Science Education-Chemistry, Gyeongsan-si, Gyeongsangbuk-do, Gyeongbuk, 38453 (Republic of Korea. However, the design of highly potent and selective inhibitors faces several challenges as no full structural data of human OGA has been discovered to date. The available inhibitors … Exploring the bi-directional relationship between autophagy and Alzheimer's disease. Pharmacological inhibition of O-GlcNAcase (OGA), the sole enzyme that removes O-GlcNAc, reproducibly slows neurodegeneration in various Alzheimer's disease (AD) mouse models manifesting either tau or amyloid pathology. Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. A widely used tool for increasing cellular levels of O-GlcNAc. doi: 10.1371/journal.pone.0035277. Moreover, O-GlcNAc is implicated in various diseases including cancers, diabetes, cardiac dysfunction, and neurodegenerative diseases. Moreover, these data suggest more targeted strategies to stimulate autophagy in an mTOR-independent manner may be found within the O-GlcNAc pathway. Sci Rep. 2019 May 13;9(1):7287. doi: 10.1038/s41598-019-43017-9.  |  Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice | springermedizin.de Skip to main content Clarifying the underlying mechanism by which OGA inhibition leads to the reduction of pathological tau and identifying translatable measures to guide human dosing and efficacy determination would significantly facilitate … Accumulation of hyperphosphorylated tau, a microtubule-associated protein, plays an important role in the progression of Alzheimer disease. eCollection 2019. Protein O-GlcNAcase is an enzyme with systematic name -3-O--L-serine/threonine N-acetylglucosaminyl hydrolase. Clipboard, Search History, and several other advanced features are temporarily unavailable. These data have stimulated interest in the possibility of using OGA-selective inhibitors as pharmaceuticals to alter the progression of AD. Chem Soc Rev. Macauley MS, He Y, Gloster TM, Stubbs KA, Davies GJ, et al. An O-GlcNAcase-specific inhibitor and substrate are engineered by the extension of the N-Acetyl Moiety of O-(2-acet-amido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc). Inhibitors of O-GlcNAcase, the enzyme removing O-GlcNAc, are useful tools for studying the role of O-GlcNAc in a range of cellular processes. Irregular O‐GlcNAcylation is linked to several diseases including cancer, diabetes and neurodegeneration. Beginning with carbohydrate-based lead molecules, we … Here, we show that Thiamet‐G, a highly selective pharmacological agent that inhibits the glycoside hydrolase O‐GlcNAcase (OGA), blunts the cellular uptake of α‐syn fibrils. When applied at nanomolar concentrations on live cells, these cell-penetrant molecules shift the Bukke VN, Villani R, Archana M, Wawrzyniak A, Balawender K, Orkisz S, Ferraro L, Serviddio G, Cassano T. Int J Mol Sci. View Article Google Scholar 41. Number of times cited according to CrossRef: Biological evaluation and molecular modeling of peptidomimetic compounds as inhibitors for O-GlcNAc transferase (OGT). Estevez A, Zhu D, Blankenship C, Jiang J. Chemistry. J Pharmacol Exp Ther. NCI CPTC Antibody Characterization Program. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. Recently, the discovery of small‐molecule OGA inhibitors has enabled the physiological function of O‐GlcNAcylation … Modulation of O-GlcNAc levels with small molecule inhibitors of O-GlcNAc hydrolase (OGA) is a useful strategy to probe the role of this modification in a range of cellular processes. Enter your email address below and we will send you your username, If the address matches an existing account you will receive an email with instructions to retrieve your username, orcid.org/http://orcid.org/0000-0001-6339-1190, I have read and accept the Wiley Online Library Terms and Conditions of Use. The glycosylation of nucleocytoplasmic proteins with O-linked N-acetylglucosamine residues (O-GlcNAc) is conserved among metazoans and is particularly abundant within brain. Oxid Med Cell Longev. 2020 Feb;26(2):155-166. doi: 10.1111/cns.13216. Screening-based discovery of drug-like O-GlcNAcase inhibitor scaffolds Helge C. Dorfmueller, Daan M.F. Epub 2020 Jul 20. 2020 Sep 21;26(53):12086-12100. doi: 10.1002/chem.202000155. This protein modification is mainly governed by a pair of enzymes: O‐GlcNAc transferase (OGT) adds the N‐acetylglucosamine moiety to acceptor proteins, and O‐GlcNAcase (OGA) hydrolyses the sugar moiety from protein acceptors. 1009816-48-1. Drug design targeting active posttranslational modification protein isoforms. Inhibition of O -GlcNAcase (OGA), the enzyme that removes O -GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. Kuang H, Tan CY, Tian HZ, Liu LH, Yang MW, Hong FF, Yang SL. 2019 Nov 13;2019:6279313. doi: 10.1155/2019/6279313. O-GlcNAc is involved in diverse cellular processes ranging from the regulation of gene expression to stress response. Differential effects of an O-GlcNAcase inhibitor on tau phosphorylation. IDO1 INHIBITOR Cancer ERK INHIBITOR Cancer DACRA-089 Diabetes BAFF/IL-17 Immunology IL-23/CGRP Immunology IL-2 CONJUGATE Immunology AUTOMATED INSULIN DELIVERY SYS Diabetes IL-33 MAB Immunology BASAL INSULIN-FC Diabetes TIM-3 MAB Cancer OXYNTOMODULIN Diabetes CXCR1/2L MAB Immunology AUR A KIN INH Cancer ABEMACICLIB HR+/HER2+MBC … Here we show, using a range of methods in neuroblastoma N2a cells, in primary rat neurons, and in mouse brain, that selective OGA inhibitors stimulate autophagy through an mTOR-independent pathway without obvious toxicity. The Glucose Metabolic Pathway as A Potential Target for Therapeutics: Crucial Role of Glycosylation in Alzheimer's Disease. These data have stimulated interest in the possibility of using OGA-selective inhibitors as pharmaceuticals to alter the progression of AD. Yu Y, Zhang L, Li X, Run X, Liang Z, Li Y, Liu Y, Lee MH, Grundke-Iqbal I, Iqbal K, Vocadlo DJ, Liu F, Gong CX. Please enable it to take advantage of the complete set of features! In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding … Our study supports OGA inhibition being a feasible therapeutic strategy for hindering the progression of AD and other neurodegenerative diseases. Additionally, OGA inhibition significantly decreased the levels of toxic protein species associated with AD pathogenesis in the JNPL3 tauopathy mouse model as well as the 3×Tg-AD mouse model. Wani WY, Chatham JC, Darley-Usmar V, McMahon LL, Zhang J. This effect correlates with increased nucleocytoplasmic levels of O ‐linked N ‐acetylglucosamine ( O ‐GlcNAc)‐modified proteins, and genetic knockdown of OGA expression closely phenocopies both these effects. Pharmacological inhibition of O-GlcNAcase (OGA), the sole enzyme that removes O-GlcNAc, reproducibly slows neurodegeneration in various Alzheimer's disease (AD) mouse models manifesting either tau or amyloid pathology. Epub 2019 Sep 10. Chem Biol 17: 937–948. Animal studies suggest that one strategy for treating Alzheimer disease and related tauopathies may be inhibition of O -GlcNAcase (OGA), which may subsequently decrease pathologic tau phosphorylation. General description The β-N-acetylglucosaminidase (OGA) gene encodes two alternatively spliced isoforms that are widely expressed in mammalian tissues.OGA (also known as O-GlcNAcase, MGEA5, NCOAT) belongs to the family of 84 glycoside hydrolases.The longer OGA form is a bifunctional nuclear/cytoplasmic enzyme that contains two distinct domains, an O-GlcNAcase domain at the N … European Journal of Pharmaceutical Sciences. ( 2 ):155-166. doi: 10.1039/c4cs00038b mechanism and substrate are engineered by the extension of the cell cycle )! The Glucose Metabolic pathway as a potential Target for Therapeutics: Crucial role of O-GlcNAc and... 7 ; 43 ( 19 ):6839-58. doi: 10.1038/s41598-019-43017-9 biochemical mechanisms and potential outcomes probing! 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