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Protein & Cell Oct 2017Dynamic changes of the post-translational O-GlcNAc modification (O-GlcNAcylation) are controlled by O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) and the... (Review)
Review
Dynamic changes of the post-translational O-GlcNAc modification (O-GlcNAcylation) are controlled by O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) and the glycoside hydrolase O-GlcNAcase (OGA) in cells. O-GlcNAcylation often occurs on serine (Ser) and threonine (Thr) residues of the specific substrate proteins via the addition of O-GlcNAc group by OGT. It has been known that O-GlcNAcylation is not only involved in many fundamental cellular processes, but also plays an important role in cancer development through various mechanisms. Recently, accumulating data reveal that O-GlcNAcylation at histones or non-histone proteins can lead to the start of the subsequent biological processes, suggesting that O-GlcNAcylation as 'protein code' or 'histone code' may provide recognition platforms or executive instructions for subsequent recruitment of proteins to carry out the specific functions. In this review, we summarize the interaction of O-GlcNAcylation and epigenetic changes, introduce recent research findings that link crosstalk between O-GlcNAcylation and epigenetic changes, and speculate on the potential coordination role of O-GlcNAcylation with epigenetic changes in intracellular biological processes.
Topics: Acetylglucosamine; Animals; Epigenesis, Genetic; Glycoside Hydrolases; Humans; N-Acetylglucosaminyltransferases; Neoplasms; Protein Processing, Post-Translational
PubMed: 28488246
DOI: 10.1007/s13238-017-0416-4 -
The Biochemical Journal Jul 2021Neurodegenerative diseases such as Alzheimer's and Parkinson's remain highly prevalent and incurable disorders. A major challenge in fully understanding and combating... (Review)
Review
Neurodegenerative diseases such as Alzheimer's and Parkinson's remain highly prevalent and incurable disorders. A major challenge in fully understanding and combating the progression of these diseases is the complexity of the network of processes that lead to progressive neuronal dysfunction and death. An ideal therapeutic avenue is conceivably one that could address many if not all of these multiple misregulated mechanisms. Over the years, chemical intervention for the up-regulation of the endogenous posttranslational modification (PTM) O-GlcNAc has been proposed as a potential strategy to slow down the progression of neurodegeneration. Through the development and application of tools that allow dissection of the mechanistic roles of this PTM, there is now a growing body of evidence that O-GlcNAc influences a variety of important neurodegeneration-pertinent mechanisms, with an overall protective effect. As a PTM that is appended onto numerous proteins that participate in protein quality control and homeostasis, metabolism, bioenergetics, neuronal communication, inflammation, and programmed death, O-GlcNAc has demonstrated beneficence in animal models of neurodegenerative diseases, and its up-regulation is now being pursued in multiple clinical studies.
Topics: Acetylglucosamine; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Glycosylation; Humans; N-Acetylglucosaminyltransferases; Parkinson Disease; Protein Processing, Post-Translational; alpha-Synuclein; tau Proteins
PubMed: 34297044
DOI: 10.1042/BCJ20200609 -
Frontiers in Endocrinology 2021The dynamic cycling of -acetylglucosamine, termed as O-GlcNAcylation, is a post-translational modification of proteins and is involved in the regulation of fundamental... (Review)
Review
The dynamic cycling of -acetylglucosamine, termed as O-GlcNAcylation, is a post-translational modification of proteins and is involved in the regulation of fundamental cellular processes. It is controlled by two essential enzymes, O-GlcNAc transferase and O-GlcNAcase. O-GlcNAcylation serves as a modulator in placental tissue; furthermore, increased levels of protein O-GlcNAcylation have been observed in women with hyperglycemia during pregnancy, which may affect the short-and long-term development of offspring. In this review, we focus on the impact of O-GlcNAcylation on placental functions in hyperglycemia-associated pregnancies. We discuss the following topics: effect of O-GlcNAcylation on placental development and its association with hyperglycemia; maternal-fetal nutrition transport, particularly glucose transport, the mammalian target of rapamycin and AMP-activated protein kinase pathways; and the two-sided regulatory effect of O-GlcNAcylation on inflammation. As O-GlcNAcylation in the placental tissues of pregnant women with hyperglycemia influences near- and long-term development of offspring, research in this field has significant therapeutic relevance.
Topics: Acetylglucosamine; Female; Humans; Hyperglycemia; N-Acetylglucosaminyltransferases; Placenta; Pregnancy; Pregnancy Complications; Proteins; beta-N-Acetylhexosaminidases
PubMed: 34140929
DOI: 10.3389/fendo.2021.659733 -
Journal of the American Chemical Society Apr 2024Protein O-linked β--acetylglucosamine modification (O-GlcNAcylation) plays a crucial role in regulating essential cellular processes. The disruption of the homeostasis...
Protein O-linked β--acetylglucosamine modification (O-GlcNAcylation) plays a crucial role in regulating essential cellular processes. The disruption of the homeostasis of O-GlcNAcylation has been linked to various human diseases, including cancer, diabetes, and neurodegeneration. However, there are limited chemical tools for protein- and site-specific O-GlcNAc modification, rendering the precise study of the O-GlcNAcylation challenging. To address this, we have developed heterobifunctional small molecules, named O-GlcNAcylation TArgeting Chimeras (OGTACs), which enable protein-specific O-GlcNAcylation in living cells. OGTACs promote O-GlcNAcylation of proteins such as BRD4, CK2α, and EZH2 by recruiting FKBP12-fused O-GlcNAc transferase (OGT), with temporal, magnitude, and reversible control. Overall, the OGTACs represent a promising approach for inducing protein-specific O-GlcNAcylation, thus enabling functional dissection and offering new directions for O-GlcNAc-targeting therapeutic development.
Topics: Humans; Nuclear Proteins; Transcription Factors; Protein Processing, Post-Translational; Neoplasms; N-Acetylglucosaminyltransferases; Acetylglucosamine; Bromodomain Containing Proteins; Cell Cycle Proteins
PubMed: 38561350
DOI: 10.1021/jacs.3c14380 -
The FEBS Journal Jun 2022O-linked modification of nuclear and cytosolic proteins with monosaccharides is essential in all eukaryotes. While many aspects of this post-translational modification...
O-linked modification of nuclear and cytosolic proteins with monosaccharides is essential in all eukaryotes. While many aspects of this post-translational modification are highly conserved, there are striking differences between plants and the animal kingdom. In animals, dynamic cycling of O-GlcNAc is established by two essential single copy enzymes, the O-GlcNAc transferase OGT and O-GlcNAc hydrolase OGA. In contrast, plants balance O-GlcNAc with O-fucose modifications, catalyzed by the OGT SECRET AGENT (SEC) and the protein O-fucosyltransferase (POFUT) SPINDLY (SPY). However, specific glycoside hydrolases for either of the two modifications have not yet been identified. Nucleocytoplasmic O-glycosylation is still not very well understood in plants, even though a high number of proteins were found to be affected. One important open question is how specificity is established in a system where only two enzymes modify hundreds of proteins. Here, we discuss the possibility that O-GlcNAc- and O-fucose-binding proteins could introduce an additional flexible layer of regulation in O-glycosylation-mediated signaling pathways, with the potential of integrating internal or external signals.
Topics: Acetylglucosamine; Animals; Cell Nucleus; Fucose; Glycosylation; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational; Signal Transduction
PubMed: 34051053
DOI: 10.1111/febs.16038 -
Nature Aging Mar 2022Impaired T cell immunity with aging increases mortality from infectious disease. The branching of Asparagine-linked glycans is a critical negative regulator of T cell...
Impaired T cell immunity with aging increases mortality from infectious disease. The branching of Asparagine-linked glycans is a critical negative regulator of T cell immunity. Here we show that branching increases with age in females more than males, in naïve more than memory T cells, and in CD4 more than CD8 T cells. Female sex hormones and thymic output of naïve T cells (T) decrease with age, however neither thymectomy nor ovariectomy altered branching. Interleukin-7 (IL-7) signaling was increased in old female more than male mouse T cells, and triggered increased branching. N-acetylglucosamine, a rate-limiting metabolite for branching, increased with age in humans and synergized with IL-7 to raise branching. Reversing elevated branching rejuvenated T cell function and reduced severity of infection in old female mice. These data suggest sex-dimorphic antagonistic pleiotropy, where IL-7 initially benefits immunity through T maintenance but inhibits T function by raising branching synergistically with age-dependent increases in N-acetylglucosamine.
Topics: Humans; Male; Female; Animals; Mice; CD8-Positive T-Lymphocytes; Acetylglucosamine; Interleukin-7; Aging; Polysaccharides
PubMed: 35528547
DOI: 10.1038/s43587-022-00187-y -
Journal of Bacteriology Oct 2021The ability of Enterococcus faecalis to use a variety of carbon sources enables colonization at various anatomic sites within a mammalian host. -Acetylglucosamine...
The ability of Enterococcus faecalis to use a variety of carbon sources enables colonization at various anatomic sites within a mammalian host. -Acetylglucosamine (GlcNAc) is one of the most abundant natural sugars and provides bacteria with a source of carbon and nitrogen when metabolized. -Acetylglucosamine is also a component of bacterial peptidoglycan, further highlighting the significance of -acetylglucosamine utilization. In this study, we show that CcpA-regulated enzymes are required for growth on the poly-β1,4-linked GlcNAc substrate, chitopentaose (β1,4-linked GlcNAc). We also show that EF0114 (EndoE) is required for growth on chitobiose (β1,4-linked GlcNAc) and that the GH20 domain of EndoE is required for the conversion of GlcNAc to -acetylglucosamine. GlcNAc is transported into the cell via two separate phosphotransferase system (PTS) complexes, either the PTS IICBA encoded by () or the Mpt glucose/mannose permease complex (MptBACD). The Mpt PTS is also the primary glucosamine transporter. In order for -acetylglucosamine to be utilized as a carbon source, phosphorylated -acetylglucosamine (GlcNAc-6-P) must be deacetylated, and here, we show that this activity is mediated by EF1317 (an -acetylglucosamine-6-phosphate deacetylase; NagA homolog), as a deletion of is unable to grow on GlcNAc as the carbon source. Deamination of glucosamine to fructose-6-phosphate is required for entry into glycolysis, and we show that growth on glucosamine is dependent on EF0466 (a glucosamine-6-phosphate deaminase; NagB homolog). Collectively, our data highlight the chitinolytic machinery required for breaking down exogenous chitinous substrates, as well as the uptake and cytosolic enzymes needed for metabolizing -acetylglucosamine. Enterococcus faecalis causes life-threatening health care-associated infections in part due to its intrinsic and acquired antibiotic resistance, its ability to form biofilms, and its nutrient versatility. Alternative nutrient acquisition systems are key factors that contribute to enterococcal colonization at biologically unique host anatomic sites. Although E. faecalis can metabolize an array of carbon sources, little is known of how this bacterium acquires these secondary nutrient sources in mammalian hosts. Our research identifies the glycosidase machinery required for degrading exogenous chitinous substrates into -acetylglucosamine monomers for transport and metabolism of one of the most abundant naturally occurring sugars, -acetylglucosamine. Disrupting the function of this -acetylglucosamine acquisition pathway may lead to new treatments against multidrug-resistant enterococcal infections.
Topics: Acetylglucosamine; Aldose-Ketose Isomerases; Amidohydrolases; Bacterial Proteins; Biological Transport; Enterococcus faecalis; Gene Deletion; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; Glucosamine; Glycoside Hydrolases
PubMed: 34424034
DOI: 10.1128/JB.00371-21 -
Critical Reviews in Biochemistry and... 2014Posttranslational modifications (PTM) including glycosylation, phosphorylation, acetylation, methylation and ubiquitination dynamically alter the proteome. The... (Review)
Review
Posttranslational modifications (PTM) including glycosylation, phosphorylation, acetylation, methylation and ubiquitination dynamically alter the proteome. The evolutionarily conserved enzymes O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase are responsible for the addition and removal, respectively, of the nutrient-sensitive PTM of protein serine and threonine residues with O-GlcNAc. Indeed, the O-GlcNAc modification acts at every step in the "central dogma" of molecular biology and alters signaling pathways leading to amplified or blunted biological responses. The cellular roles of OGT and the dynamic PTM O-GlcNAc have been clarified with recently developed chemical tools including high-throughput assays, structural and mechanistic studies and potent enzyme inhibitors. These evolving chemical tools complement genetic and biochemical approaches for exposing the underlying biological information conferred by O-GlcNAc cycling.
Topics: Acetylglucosamine; Animals; Enzyme Assays; Enzyme Inhibitors; Humans; N-Acetylglucosaminyltransferases; Protein Isoforms; Protein Processing, Post-Translational
PubMed: 25039763
DOI: 10.3109/10409238.2014.931338 -
Molecular & Cellular Proteomics : MCP 2021O-GlcNAcylation, the addition of a single N-acetylglucosamine residue to serine and threonine residues of cytoplasmic, nuclear, or mitochondrial proteins, is a... (Review)
Review
O-GlcNAcylation, the addition of a single N-acetylglucosamine residue to serine and threonine residues of cytoplasmic, nuclear, or mitochondrial proteins, is a widespread regulatory posttranslational modification. It is involved in the response to nutritional status and stress, and its dysregulation is associated with diseases ranging from Alzheimer's to diabetes. Although the modification was first detected over 35 years ago, research into the function of O-GlcNAcylation has accelerated dramatically in the last 10 years owing to the development of new enrichment and mass spectrometry techniques that facilitate its analysis. This article summarizes methods for O-GlcNAc enrichment, key mass spectrometry instrumentation advancements, particularly those that allow modification site localization, and software tools that allow analysis of data from O-GlcNAc-modified peptides.
Topics: Acetylglucosamine; Animals; Humans; Immunoprecipitation; Lectins; Mass Spectrometry; Protein Processing, Post-Translational; Software
PubMed: 32938750
DOI: 10.1074/mcp.R120.002206 -
Glycobiology Aug 2018In metazoans, thousands of intracellular proteins are modified with O-linked β-N-acetylglucosamine (O-GlcNAc) in response to a wide range of stimuli and stresses. In... (Review)
Review
In metazoans, thousands of intracellular proteins are modified with O-linked β-N-acetylglucosamine (O-GlcNAc) in response to a wide range of stimuli and stresses. In particular, a complex and evolutionarily conserved interplay between O-GlcNAcylation and oxidative stress has emerged in recent years. Here, we review the current literature on the connections between O-GlcNAc and oxidative stress, with a particular emphasis on major signaling pathways, such as KEAP1/NRF2, FOXO, NFκB, p53 and cell metabolism. Taken together, this work sheds important light on the signaling functions of protein glycosylation and the mechanisms of stress responses alike and illuminates how the two are integrated in animal cell physiology.
Topics: Acetylglucosamine; Animals; Humans; Oxidative Stress; Signal Transduction
PubMed: 29548027
DOI: 10.1093/glycob/cwy027