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Physiological Reviews Apr 2021In the mid-1980s, the identification of serine and threonine residues on nuclear and cytoplasmic proteins modified by a -acetylglucosamine moiety (-GlcNAc) via an... (Review)
Review
In the mid-1980s, the identification of serine and threonine residues on nuclear and cytoplasmic proteins modified by a -acetylglucosamine moiety (-GlcNAc) via an -linkage overturned the widely held assumption that glycosylation only occurred in the endoplasmic reticulum, Golgi apparatus, and secretory pathways. In contrast to traditional glycosylation, the -GlcNAc modification does not lead to complex, branched glycan structures and is rapidly cycled on and off proteins by -GlcNAc transferase (OGT) and -GlcNAcase (OGA), respectively. Since its discovery, -GlcNAcylation has been shown to contribute to numerous cellular functions, including signaling, protein localization and stability, transcription, chromatin remodeling, mitochondrial function, and cell survival. Dysregulation in -GlcNAc cycling has been implicated in the progression of a wide range of diseases, such as diabetes, diabetic complications, cancer, cardiovascular, and neurodegenerative diseases. This review will outline our current understanding of the processes involved in regulating -GlcNAc turnover, the role of -GlcNAcylation in regulating cellular physiology, and how dysregulation in -GlcNAc cycling contributes to pathophysiological processes.
Topics: Acetylglucosamine; Animals; Cell Physiological Phenomena; Glycosylation; Humans; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational
PubMed: 32730113
DOI: 10.1152/physrev.00043.2019 -
Frontiers in Endocrinology 2020The centrosome apparatus is vital for spindle assembly and chromosome segregation during mitotic divisions. Its replication, disjunction and separation have to be... (Review)
Review
The centrosome apparatus is vital for spindle assembly and chromosome segregation during mitotic divisions. Its replication, disjunction and separation have to be fine-tuned in space and time. A multitude of post-translational modifications (PTMs) have been implicated in centrosome modulation, including phosphorylation, ubiquitination and acetylation. Among them is the emerging O-linked N-acetylglucosamine (O-GlcNAc) modification. This quintessential PTM has a sole writer, O-GlcNAc transferase (OGT), and the only eraser, O-GlcNAcase (OGA). O-GlcNAc couples glucose metabolism with signal transduction and forms a yin-yang relationship with phosphorylation. Evidence from proteomic studies as well as single protein investigations has pinpointed a role of O-GlcNAc in centrosome number and separation, centriole number and distribution, as well as the cilia machinery emanating from the centrosomes. Herein we review our current understanding of the sweet modification embedded in centrosome dynamics and speculate that more molecular details will be unveiled in the future.
Topics: Acetylglucosamine; Animals; Centrosome; Cilia; Humans; N-Acetylglucosaminyltransferases
PubMed: 33597927
DOI: 10.3389/fendo.2020.621888 -
Marine Drugs Sep 2010N-Acetylglucosamine (GlcNAc) is a monosaccharide that usually polymerizes linearly through (1,4)-β-linkages. GlcNAc is the monomeric unit of the polymer chitin, the... (Review)
Review
N-Acetylglucosamine (GlcNAc) is a monosaccharide that usually polymerizes linearly through (1,4)-β-linkages. GlcNAc is the monomeric unit of the polymer chitin, the second most abundant carbohydrate after cellulose. In addition to serving as a component of this homogeneous polysaccharide, GlcNAc is also a basic component of hyaluronic acid and keratin sulfate on the cell surface. In this review, we discuss the industrial production of GlcNAc, using chitin as a substrate, by chemical, enzymatic and biotransformation methods. Also, newly developed methods to obtain GlcNAc using glucose as a substrate in genetically modified microorganisms are introduced. Moreover, GlcNAc has generated interest not only as an underutilized resource but also as a new functional material with high potential in various fields. Here we also take a closer look at the current applications of GlcNAc, and several new and cutting edge approaches in this fascinating area are thoroughly discussed.
Topics: Acetylglucosamine; Chitin; Chitinases; Cosmetics; Glucose; Humans; Hydrolysis; N-Acetylneuraminic Acid; Polysaccharides
PubMed: 20948902
DOI: 10.3390/md8092493 -
The Journal of Biological Chemistry Nov 2023Recent advances in the understanding of the molecular mechanisms underlying cancer progression have led to the development of novel therapeutic targeting strategies.... (Review)
Review
Recent advances in the understanding of the molecular mechanisms underlying cancer progression have led to the development of novel therapeutic targeting strategies. Aberrant glycosylation patterns and their implication in cancer have gained increasing attention as potential targets due to the critical role of glycosylation in regulating tumor-specific pathways that contribute to cancer cell survival, proliferation, and progression. A special type of glycosylation that has been gaining momentum in cancer research is the modification of nuclear, cytoplasmic, and mitochondrial proteins, termed O-GlcNAcylation. This protein modification is catalyzed by an enzyme called O-GlcNAc transferase (OGT), which uses the final product of the Hexosamine Biosynthetic Pathway (HBP) to connect altered nutrient availability to changes in cellular signaling that contribute to multiple aspects of tumor progression. Both O-GlcNAc and its enzyme OGT are highly elevated in cancer and fulfill the crucial role in regulating many hallmarks of cancer. In this review, we present and discuss the latest findings elucidating the involvement of OGT and O-GlcNAc in cancer.
Topics: Humans; Acetylglucosamine; Biosynthetic Pathways; Glycosylation; N-Acetylglucosaminyltransferases; Neoplasms; Protein Processing, Post-Translational
PubMed: 37838167
DOI: 10.1016/j.jbc.2023.105344 -
Cells Nov 2022The modification of nuclear, mitochondrial, and cytosolic proteins by O-linked βN-acetylglucosamine (O-GlcNAc) has emerged as a dynamic and essential post-translational... (Review)
Review
The modification of nuclear, mitochondrial, and cytosolic proteins by O-linked βN-acetylglucosamine (O-GlcNAc) has emerged as a dynamic and essential post-translational modification of mammalian proteins. O-GlcNAc is cycled on and off over 5000 proteins in response to diverse stimuli impacting protein function and, in turn, epigenetics and transcription, translation and proteostasis, metabolism, cell structure, and signal transduction. Environmental and physiological injury lead to complex changes in O-GlcNAcylation that impact cell and tissue survival in models of heat shock, osmotic stress, oxidative stress, and hypoxia/reoxygenation injury, as well as ischemic reperfusion injury. Numerous mechanisms that appear to underpin O-GlcNAc-mediated survival include changes in chaperone levels, impacts on the unfolded protein response and integrated stress response, improvements in mitochondrial function, and reduced protein aggregation. Here, we discuss the points at which O-GlcNAc is integrated into the cellular stress response, focusing on the roles it plays in the cardiovascular system and in neurodegeneration.
Topics: Animals; Acetylglucosamine; Protein Processing, Post-Translational; Glycosylation; Oxidative Stress; Signal Transduction; Proteins; Mammals
PubMed: 36359905
DOI: 10.3390/cells11213509 -
Current Opinion in Structural Biology Jun 2019Glycosylation, or the addition of sugars to proteins, is a highly conserved protein modification defined by both the monosaccharide initially added as well as the amino... (Review)
Review
Glycosylation, or the addition of sugars to proteins, is a highly conserved protein modification defined by both the monosaccharide initially added as well as the amino acid to which it is attached. O-Linked glycosylation represents a diverse group of protein modifications occurring on the hydroxyl groups of serine and/or threonine residues. O-Glycosylation can have wide-ranging effects on protein stability and function, which translate into crucial consequences at the organismal level. This review will summarize structural and biological insights into the major O-glycans formed within the secretory apparatus (O-GalNAc, O-Man, O-Fuc, O-Glc and extracellular O-GlcNAc) from studies in the fruit fly Drosophila melanogaster. Drosophila has many advantages for investigating these complex modifications, boasting reduced functional redundancy within gene families, reduced length/complexity of glycan chains and sophisticated genetic tools. Gaining an understanding of the normal cellular and developmental roles of these conserved modifications in Drosophila will provide insight into how changes in O-glycans are involved in human disease and disease susceptibilities.
Topics: Acetylglucosamine; Animals; Drosophila melanogaster; Extracellular Space; Glycosylation; Humans; Oxygen
PubMed: 30852302
DOI: 10.1016/j.sbi.2019.01.014 -
Biochemical Society Transactions Apr 2017The post-translational modification of serine and threonine residues of proteins found in numerous subcellular locations by -linked -acetylglucosamine (-GlcNAc) is... (Review)
Review
The post-translational modification of serine and threonine residues of proteins found in numerous subcellular locations by -linked -acetylglucosamine (-GlcNAc) is emerging as a key mediator of many cardiovascular pathophysiological processes. Early studies implicated increased protein O-GlcNAcylation as contributing to the cardiovascular complications associated with diabetes, whereas subsequent studies demonstrated that acute increases in -GlcNAc levels were protective against ischemia/reperfusion injury. There is now a growing understanding that -GlcNAc modification of proteins influences numerous cellular functions, including transcription, protein turnover, calcium handling, and bioenergetics. As a result, a more nuanced view of the role of protein O-GlcNAcylation in the cardiovascular system is emerging along with the recognition that it is required for normal cellular function and homeostasis. Consequently, the impact of changes in -GlcNAc cycling due to stress or disease on the heart is complex and highly dependent on the specific context of these events. The goal of this review is to provide an overview of some of the more recent advances in our understanding of the role O-GlcNAcylation plays in mediating cardiovascular function and disease.
Topics: Acetylglucosamine; Animals; Cardiovascular Diseases; Diabetes Mellitus; Gene Expression Regulation; Glycosylation; Humans; Protein Processing, Post-Translational; Proteins; Signal Transduction
PubMed: 28408494
DOI: 10.1042/BST20160164 -
Journal of Bioenergetics and... Jun 2018The rapidly expanding field of immunometabolism focuses on how metabolism controls the function of immune cells. CD4 T cells are essential for the adaptive immune... (Review)
Review
The rapidly expanding field of immunometabolism focuses on how metabolism controls the function of immune cells. CD4 T cells are essential for the adaptive immune response leading to the eradication of specific pathogens. However, when T cells are inappropriately over-active, they can drive autoimmunity, allergic disease, and chronic inflammation. The mechanisms by which metabolic changes influence function in CD4 T cells are not fully understood. The post-translational protein modification, O-GlcNAc (O-linked β-N-acetylglucosamine), dynamically cycles on and off of intracellular proteins as cells respond to their environment and flux through metabolic pathways changes. As the rate of O-GlcNAc cycling fluctuates, protein function, stability, and/or localization can be affected. Thus, O-GlcNAc is critically poised at the nexus of cellular metabolism and function. This review highlights the intra- and extracellular metabolic factors that influence CD4 T cell activation and differentiation and how O-GlcNAc regulates these processes. We also propose areas of future research that may illuminate O-GlcNAc's role in the plasticity and pathogenicity of CD4 T cells and uncover new potential therapeutic targets.
Topics: Acetylglucosamine; Animals; CD4-Positive T-Lymphocytes; Humans; Lymphocyte Activation; Protein Processing, Post-Translational
PubMed: 29404877
DOI: 10.1007/s10863-018-9744-1 -
Biochemical Society Transactions Apr 2017Cell division (mitosis) and gamete production (meiosis) are fundamental requirements for normal organismal development. The mammalian cell cycle is tightly regulated by... (Review)
Review
Cell division (mitosis) and gamete production (meiosis) are fundamental requirements for normal organismal development. The mammalian cell cycle is tightly regulated by different checkpoints ensuring complete and precise chromosomal segregation and duplication. In recent years, researchers have become increasingly interested in understanding how -GlcNAc regulates the cell cycle. The -GlcNAc post-translation modification is an -glycosidic bond of a single β--acetylglucosamine sugar to serine/threonine residues of intracellular proteins. This modification is sensitive toward changes in nutrient levels in the cellular environment making -GlcNAc a nutrient sensor capable of influencing cell growth and proliferation. Numerous studies have established that O-GlcNAcylation is essential in regulating mitosis and meiosis, while loss of O-GlcNAcylation is lethal in growing cells. Moreover, aberrant O-GlcNAcylation is linked with cancer and chromosomal segregation errors. In this review, we will discuss how -GlcNAc controls different aspects of the cell cycle with a particular emphasis on mitosis and meiosis.
Topics: Acetylglucosamine; Acylation; Animals; Cell Proliferation; Humans; Meiosis; Mitosis; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational; Proteins
PubMed: 28408472
DOI: 10.1042/BST20160145 -
Cellular Signalling Feb 2022O-GlcNAcylation is a post-translational modification occurring on serine/threonine residues of nuclear and cytoplasmic proteins, mediated by the enzymes OGT and OGA... (Review)
Review
O-GlcNAcylation is a post-translational modification occurring on serine/threonine residues of nuclear and cytoplasmic proteins, mediated by the enzymes OGT and OGA which catalyze the addition or removal of the UDP-GlcNAc moieties, respectively. Structural changes brought by this modification lead to alternations of protein stability, protein-protein interactions, and phosphorylation. Importantly, O-GlcNAcylation is a nutrient sensor by coupling nutrient sensing with cellular signaling. Elevated levels of OGT and O-GlcNAc have been reported in a variety of cancers and has been linked to regulation of multiple cancer signaling pathways. In this review, we discuss the most recent findings on the role of O-GlcNAcylation as a metabolic sensor in signaling pathways and immune response in cancer.
Topics: Acetylglucosamine; Humans; N-Acetylglucosaminyltransferases; Neoplasms; Phosphorylation; Protein Processing, Post-Translational
PubMed: 34800629
DOI: 10.1016/j.cellsig.2021.110201