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Frontiers in Endocrinology 2022Although traditionally considered a glucose metabolism-associated modification, the -linked β-N-Acetylglucosamine (GlcNAc) regulatory system interacts extensively with... (Review)
Review
Although traditionally considered a glucose metabolism-associated modification, the -linked β-N-Acetylglucosamine (GlcNAc) regulatory system interacts extensively with lipids and is required to maintain lipid homeostasis. The enzymes of GlcNAc cycling have molecular properties consistent with those expected of broad-spectrum environmental sensors. By direct protein-protein interactions and catalytic modification, -GlcNAc cycling enzymes may provide both acute and long-term adaptation to stress and other environmental stimuli such as nutrient availability. Depending on the cell type, hyperlipidemia potentiates or depresses GlcNAc levels, sometimes biphasically, through a diversity of unique mechanisms that target UDP-GlcNAc synthesis and the availability, activity and substrate selectivity of the glycosylation enzymes, -GlcNAc Transferase (OGT) and -GlcNAcase (OGA). At the same time, OGT activity in multiple tissues has been implicated in the homeostatic regulation of systemic lipid uptake, storage and release. Hyperlipidemic patterns of -GlcNAcylation in these cells are consistent with both transient physiological adaptation and feedback uninhibited obesogenic and metabolic dysregulation. In this review, we summarize the numerous interconnections between lipid and GlcNAc metabolism. These links provide insights into how the GlcNAc regulatory system may contribute to lipid-associated diseases including obesity and metabolic syndrome.
Topics: Acetylglucosamine; Glucose; Glycosylation; Lipids; Uridine Diphosphate
PubMed: 36111295
DOI: 10.3389/fendo.2022.943576 -
Journal of Enzyme Inhibition and... Dec 2019Allosamidins come from the secondary metabolites of species, and they have the pseudotrisaccharide structures. Allosamidins are chitinase inhibitors that can be used to... (Review)
Review
Allosamidins come from the secondary metabolites of species, and they have the pseudotrisaccharide structures. Allosamidins are chitinase inhibitors that can be used to study the physiological effects of chitinases in a variety of organisms. They have the novel antiasthmatic activity and insecticidal/antifungal activities. Herein, the synthesis and activities of allosamidins were summarized and analyzed.
Topics: Acetylglucosamine; Animals; Anti-Asthmatic Agents; Antifungal Agents; Asthma; Fungi; Humans; Insecticides; Molecular Conformation; Moths; Streptomyces; Trisaccharides
PubMed: 31307248
DOI: 10.1080/14756366.2019.1623208 -
International Journal of Molecular... May 2017In this review, the sugar portions of glycoproteins, glycolipids, and glycosaminoglycans constitute the glycome, and the genes involved in their biosynthesis,... (Review)
Review
In this review, the sugar portions of glycoproteins, glycolipids, and glycosaminoglycans constitute the glycome, and the genes involved in their biosynthesis, degradation, transport and recognition are referred to as "glycogenes". The extreme complexity of the glycome requires the regulatory layer to be provided by the epigenetic mechanisms. Almost all types of cancers present glycosylation aberrations, giving rise to phenotypic changes and to the expression of tumor markers. In this review, we discuss how cancer-associated alterations of promoter methylation, histone methylation/acetylation, and miRNAs determine glycomic changes associated with the malignant phenotype. Usually, increased promoter methylation and miRNA expression induce glycogene silencing. However, treatment with demethylating agents sometimes results in silencing, rather than in a reactivation of glycogenes, suggesting the involvement of distant methylation-dependent regulatory elements. From a therapeutic perspective aimed at the normalization of the malignant glycome, it appears that miRNA targeting of cancer-deranged glycogenes can be a more specific and promising approach than the use of drugs, which broad target methylation/acetylation. A very specific type of glycosylation, the addition of GlcNAc to serine or threonine (O-GlcNAc), is not only regulated by epigenetic mechanisms, but is an epigenetic modifier of histones and transcription factors. Thus, glycosylation is both under the control of epigenetic mechanisms and is an integral part of the epigenetic code.
Topics: Acetylglucosamine; Animals; Epigenesis, Genetic; Galectins; Glycosylation; Histones; Humans; Neoplasms; Protein Processing, Post-Translational
PubMed: 28481247
DOI: 10.3390/ijms18050998 -
ACS Chemical Biology Mar 2020O-Linked N-acetyl glucosamine (O-GlcNAc) is a protein modification found on thousands of nuclear, cytosolic, and mitochondrial proteins. Many O-GlcNAc sites occur in...
O-Linked N-acetyl glucosamine (O-GlcNAc) is a protein modification found on thousands of nuclear, cytosolic, and mitochondrial proteins. Many O-GlcNAc sites occur in proximity to protein sites that are likewise modified by phosphorylation. While several studies have uncovered crosstalk between these two signaling modifications on individual proteins and pathways, an understanding of the role of O-GlcNAc in regulating kinases, the enzymes that install the phosphate modification, is still emerging. Here we review recent methods to profile the O-GlcNAc modification on a global scale that have revealed more than 100 kinases are modified by O-GlcNAc and highlight existing studies about regulation of these kinases by O-GlcNAc. Continuing efforts to profile the O-GlcNAc proteome and understand the role of O-GlcNAc on kinases will reveal new mechanisms of regulation and potential avenues for manipulation of the signaling mechanisms at the intersection of O-GlcNAc and phosphorylation.
Topics: Acetylglucosamine; Amino Acid Sequence; Catalytic Domain; Glycosylation; Phosphorylation; Phosphotransferases; Protein Binding; Protein Conformation; Protein Engineering; Protein Processing, Post-Translational; Proteome; Signal Transduction; Structure-Activity Relationship
PubMed: 32155042
DOI: 10.1021/acschembio.9b01015 -
The Journal of Biological Chemistry Mar 2023The dynamic cycling of O-linked GlcNAc (O-GlcNAc) on and off Ser/Thr residues of intracellular proteins, termed O-GlcNAcylation, is mediated by the conserved enzymes...
The dynamic cycling of O-linked GlcNAc (O-GlcNAc) on and off Ser/Thr residues of intracellular proteins, termed O-GlcNAcylation, is mediated by the conserved enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase. O-GlcNAc cycling is important in homeostatic and stress responses, and its perturbation sensitizes the heart to ischemic and other injuries. Despite considerable progress, many molecular pathways impacted by O-GlcNAcylation in the heart remain unclear. The mitogen-activated protein kinase (MAPK) pathway is a central signaling cascade that coordinates developmental, physiological, and pathological responses in the heart. The developmental or adaptive arm of MAPK signaling is primarily mediated by Erk kinases, while the pathophysiologic arm is mediated by p38 and Jnk kinases. Here, we examine whether O-GlcNAcylation affects MAPK signaling in cardiac myocytes, focusing on Erk1/2 and p38 in basal and hypertrophic conditions induced by phenylephrine. Using metabolic labeling of glycans coupled with alkyne-azide "click" chemistry, we found that Erk1/2 and p38 are O-GlcNAcylated. Supporting the regulation of p38 by O-GlcNAcylation, the OGT inhibitor, OSMI-1, triggers the phosphorylation of p38, an event that involves the NOX2-Ask1-MKK3/6 signaling axis and also the noncanonical activator Tab1. Additionally, OGT inhibition blocks the phenylephrine-induced phosphorylation of Erk1/2. Consistent with perturbed MAPK signaling, OSMI-1-treated cardiomyocytes have a blunted hypertrophic response to phenylephrine, decreased expression of cTnT (key component of the contractile apparatus), and increased expression of maladaptive natriuretic factors Anp and Bnp. Collectively, these studies highlight new roles for O-GlcNAcylation in maintaining a balanced activity of Erk1/2 and p38 MAPKs during hypertrophic growth responses in cardiomyocytes.
Topics: Humans; Myocytes, Cardiac; Signal Transduction; Phosphorylation; Hypertrophy; Proteins; N-Acetylglucosaminyltransferases; Acetylglucosamine
PubMed: 36642184
DOI: 10.1016/j.jbc.2023.102907 -
Chemistry (Weinheim An Der Bergstrasse,... Sep 2020The O-linked β-N-acetylglucosamine (O-GlcNAc) modification, termed O-GlcNAcylation, is an essential and dynamic post-translational modification in cells. O-GlcNAc... (Review)
Review
The O-linked β-N-acetylglucosamine (O-GlcNAc) modification, termed O-GlcNAcylation, is an essential and dynamic post-translational modification in cells. O-GlcNAc transferase (OGT) installs this modification on serine and threonine residues, whereas O-GlcNAcase (OGA) hydrolyzes it. O-GlcNAc modifications are found on thousands of intracellular proteins involved in diverse biological processes. Dysregulation of O-GlcNAcylation and O-GlcNAc cycling enzymes has been detected in many diseases, including cancer, diabetes, cardiovascular and neurodegenerative diseases. Here, recent advances in the development of molecular tools to investigate OGT and OGA functions and substrate recognition are discussed. New chemical approaches to study O-GlcNAc dynamics and its potential roles in the immune system are also highlighted. It is hoped that this minireview will encourage more research in these areas to advance the understanding of O-GlcNAc in biology and diseases.
Topics: Acetylglucosamine; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational; Serine; Threonine; beta-N-Acetylhexosaminidases
PubMed: 32207184
DOI: 10.1002/chem.202000155 -
Nature Chemical Biology May 2024Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer's and Parkinson's disease, can form different fibril structures or strains with...
Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer's and Parkinson's disease, can form different fibril structures or strains with distinct toxic properties, seeding activities and pathology. Understanding the determinants contributing to the formation of different amyloid features could open new avenues for developing disease-specific diagnostics and therapies. Here we report that O-GlcNAc modification of α-synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by cryogenic electron microscopy, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson's disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc-modified fibrils remain unclear, our in vitro mechanistic studies indicate that heat shock proteins interactions with O-GlcNAc fibril inhibit their seeding activity, suggesting that the O-GlcNAc modification may alter the interactome of the α-synuclein fibrils in ways that lead to reduce seeding activity in vivo. Our results show that posttranslational modifications, such as O-GlcNAc modification, of α-synuclein are key determinants of α-synuclein amyloid strains and pathogenicity.
Topics: alpha-Synuclein; Amyloid; Humans; Animals; Mice; Parkinson Disease; Acetylglucosamine; Protein Processing, Post-Translational; Cryoelectron Microscopy; Neurons
PubMed: 38347213
DOI: 10.1038/s41589-024-01551-2 -
FEBS Letters Dec 2018O-GlcNAcylation is an essential post-translational modification important for integrating metabolism with cell physiology. Using diverse model systems, studies of this... (Review)
Review
O-GlcNAcylation is an essential post-translational modification important for integrating metabolism with cell physiology. Using diverse model systems, studies of this evolutionarily conserved intracellular glycosylation have highlighted its role in stem cell maintenance, lineage specification, and disease. Although discovered over 30 years ago, the study of O-GlcNAc continues to evolve and uncover surprising roles for O-GlcNAc and the enzymes of O-GlcNAc cycling: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). In this review, using the immune system as a model of stem cell biology and cell fate determination, we discuss how O-GlcNAc is at the nexus of metabolism, proliferation, and disease.
Topics: Acetylglucosamine; Cell Differentiation; Glycosylation; Humans; Immune System; Models, Biological; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational; Stem Cells; T-Lymphocytes
PubMed: 29904918
DOI: 10.1002/1873-3468.13159 -
Journal of Bioenergetics and... Jun 2018Elevated O-GlcNAcylation is emerging as a general characteristic of most cancers. Although O-GlcNAcylation can regulate many cell biological pathways, recent evidence... (Review)
Review
Elevated O-GlcNAcylation is emerging as a general characteristic of most cancers. Although O-GlcNAcylation can regulate many cell biological pathways, recent evidence suggests that it is a key regulator of metabolic pathways including glycolysis in cancer cells. This review summarizes our current understanding of how O-GlcNAcylation regulates glycolytic pathways and contributes to alterations in cancer cell metabolism.
Topics: Acetylglucosamine; Animals; Glycolysis; Glycosylation; Humans; Metabolic Networks and Pathways; Nervous System
PubMed: 29344764
DOI: 10.1007/s10863-018-9742-3 -
The Journal of Biological Chemistry Dec 2014O-GlcNAcylation is an abundant nutrient-driven modification linked to cellular signaling and regulation of gene expression. Utilizing precursors derived from metabolic... (Review)
Review
O-GlcNAcylation is an abundant nutrient-driven modification linked to cellular signaling and regulation of gene expression. Utilizing precursors derived from metabolic flux, O-GlcNAc functions as a homeostatic regulator. The enzymes of O-GlcNAc cycling, OGT and O-GlcNAcase, act in mitochondria, the cytoplasm, and the nucleus in association with epigenetic "writers" and "erasers" of the histone code. Both O-GlcNAc and O-phosphate modify repeats within the RNA polymerase II C-terminal domain (CTD). By communicating with the histone and CTD codes, O-GlcNAc cycling provides a link between cellular metabolic status and the epigenetic machinery. Thus, O-GlcNAcylation is poised to influence trans-generational epigenetic inheritance.
Topics: Acetylglucosamine; Animals; Epigenesis, Genetic; Histones; Humans; N-Acetylglucosaminyltransferases; RNA Polymerase II; beta-N-Acetylhexosaminidases
PubMed: 25336654
DOI: 10.1074/jbc.R114.595439