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Biochemistry Jan 2018O-Linked β-N-acetylglucosamine (O-GlcNAc) is a critical post-translational modification (PTM) of thousands of intracellular proteins. Reversible O-GlcNAcylation governs... (Review)
Review
O-Linked β-N-acetylglucosamine (O-GlcNAc) is a critical post-translational modification (PTM) of thousands of intracellular proteins. Reversible O-GlcNAcylation governs many aspects of cell physiology and is dysregulated in numerous human diseases. Despite this broad pathophysiological significance, major aspects of O-GlcNAc signaling remain poorly understood, including the biochemical mechanisms through which O-GlcNAc transduces information. Recent work from many laboratories, including our own, has revealed that O-GlcNAc, like other intracellular PTMs, can control its substrates' functions by inhibiting or inducing protein-protein interactions. This dynamic regulation of multiprotein complexes exerts diverse downstream signaling effects in a range of processes, cell types, and organisms. Here, we review the literature about O-GlcNAc-regulated protein-protein interactions and suggest important questions for future studies in the field.
Topics: Acetylglucosamine; Aminoacylation; Animals; Biochemistry; Humans; Models, Biological; Protein Interaction Domains and Motifs; Protein Multimerization; Protein Processing, Post-Translational; Signal Transduction
PubMed: 29099585
DOI: 10.1021/acs.biochem.7b00871 -
Current Opinion in Pharmacology Apr 2021The post-translational modification of serine and threonine residues of proteins by O-linked N-acetylglucosamine (O-GlcNAc) regulates diverse cellular processes in the... (Review)
Review
The post-translational modification of serine and threonine residues of proteins by O-linked N-acetylglucosamine (O-GlcNAc) regulates diverse cellular processes in the cardiovascular system. UDP-GlcNAc is a substrate for O-GlcNAc transferase, which catalyzes the attachment of O-GlcNAc to proteins. O-GlcNAcase catalyzes the removal of O-GlcNAc from proteins. UDP-GlcNAc is the end product of the hexosamine biosynthesis pathway, which is regulated primarily by glucose-6-phosphate-Glutamine:fructose-6-phosphate amidotransferase (GFAT). GFAT catalyzes the formation of glucosamine-6-phosphate from fructose-6-phosphate and glutamine. Whereas O-GlcNAc is essential for cell viability, sustained increases in O-GlcNAc levels have been implicated in the etiology of many chronic diseases and is associated with glucose toxicity and diabetic complications in various organs including the cardiovascular system. This review provides an overview of the regulation of protein O-GlcNAcylation followed by a discussion of potential mechanisms by which dysregulation in O-GlcNAc cycling contributes to the adverse effects of diabetes on the cardiovascular system.
Topics: Acetylglucosamine; Cardiovascular System; Diabetes Complications; Diabetes Mellitus; Hexosamines; Humans; Protein Processing, Post-Translational
PubMed: 32937226
DOI: 10.1016/j.coph.2020.08.005 -
Protein & Cell May 2023
Topics: Oxidative Phosphorylation; Acetylglucosamine; Uridine Diphosphate N-Acetylglucosamine
PubMed: 37155316
DOI: 10.1093/procel/pwac009 -
Circulation Research Jan 2020
Topics: Acetylglucosamine; Humans; Mitochondrial Proteins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Phenotype; Proteasome Endopeptidase Complex; Transferases; Ubiquitin
PubMed: 31895665
DOI: 10.1161/CIRCRESAHA.119.316281 -
The Journal of Biological Chemistry Dec 2023The post-translational modification of intracellular proteins by O-linked β-GlcNAc (O-GlcNAc) has emerged as a critical regulator of cardiac function. Enhanced... (Comparative Study)
Comparative Study
The post-translational modification of intracellular proteins by O-linked β-GlcNAc (O-GlcNAc) has emerged as a critical regulator of cardiac function. Enhanced O-GlcNAcylation activates cytoprotective pathways in cardiac models of ischemia-reperfusion (I/R) injury; however, the mechanisms underpinning O-GlcNAc cycling in response to I/R injury have not been comprehensively assessed. The cycling of O-GlcNAc is regulated by the collective efforts of two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which catalyze the addition and hydrolysis of O-GlcNAc, respectively. It has previously been shown that baseline heart physiology and pathophysiology are impacted by sex. Here, we hypothesized that sex differences in molecular signaling may target protein O-GlcNAcylation both basally and in ischemic hearts. To address this question, we subjected male and female WT murine hearts to ex vivo ischemia or I/R injury. We assessed hearts for protein O-GlcNAcylation, abundance of OGT, OGA, and glutamine:fructose-6-phosphate aminotransferase (GFAT2), activity of OGT and OGA, and UDP-GlcNAc levels. Our data demonstrate elevated O-GlcNAcylation in female hearts both basally and during ischemia. We show that OGT activity was enhanced in female hearts in all treatments, suggesting a mechanism for these observations. Furthermore, we found that ischemia led to reduced O-GlcNAcylation and OGT-specific activity. Our findings provide a foundation for understanding molecular mechanisms that regulate O-GlcNAcylation in the heart and highlight the importance of sex as a significant factor when assessing key regulatory events that control O-GlcNAc cycling. These data suggest the intriguing possibility that elevated O-GlcNAcylation in females contributes to reduced ischemic susceptibility.
Topics: Animals; Female; Male; Mice; Acetylglucosamine; Heart; Ischemia; Myocardium; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational; Sex Characteristics; Signal Transduction
PubMed: 37949223
DOI: 10.1016/j.jbc.2023.105447 -
The International Journal of... Oct 2022O-GlcNAcylation is a post-translational modification which affects approximately 5000 human proteins. Its involvement has been shown in many if not all biological... (Review)
Review
O-GlcNAcylation is a post-translational modification which affects approximately 5000 human proteins. Its involvement has been shown in many if not all biological processes. Variations in O-GlcNAcylation levels can be associated with the development of diseases. Deciphering the role of O-GlcNAcylation is an important issue to (i) understand its involvement in pathophysiological development and (ii) develop new therapeutic strategies to modulate O-GlcNAc levels. Over the past 30 years, despite the development of several approaches, knowledge of its role and regulation have remained limited. This review proposes an overview of the currently available tools to study O-GlcNAcylation and identify O-GlcNAcylated proteins. Briefly, we discuss pharmacological modulators, methods to study O-GlcNAcylation levels and approaches for O-GlcNAcylomic profiling. This review aims to contribute to a better understanding of the methods used to study O-GlcNAcylation and to promote efforts in the development of new strategies to explore this promising modification.
Topics: Acetylglucosamine; Glycosylation; Humans; Protein Processing, Post-Translational; Proteins
PubMed: 36031106
DOI: 10.1016/j.biocel.2022.106289 -
Frontiers in Cellular and Infection... 2017
Topics: Acetylglucosamine; Biofilms; Drug Resistance, Multiple, Bacterial; Humans; Pneumococcal Infections; Streptococcus pneumoniae
PubMed: 28744450
DOI: 10.3389/fcimb.2017.00310 -
Journal of Bioenergetics and... Jun 2018Hundreds of proteins in the nervous system are modified by the monosaccharide O-GlcNAc. A single protein is often O-GlcNAcylated on several amino acids and the... (Review)
Review
Hundreds of proteins in the nervous system are modified by the monosaccharide O-GlcNAc. A single protein is often O-GlcNAcylated on several amino acids and the modification of a single site can play a crucial role for the function of the protein. Despite its complexity, only two enzymes add and remove O-GlcNAc from proteins, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Global and local regulation of these enzymes make it possible for O-GlcNAc to coordinate multiple cellular functions at the same time as regulating specific pathways independently from each other. If O-GlcNAcylation is disrupted, metabolic disorder or intellectual disability may ensue, depending on what neurons are affected. O-GlcNAc's promise as a clinical target for developing drugs against neurodegenerative diseases has been recognized for many years. Recent literature puts O-GlcNAc in the forefront among mechanisms that can help us better understand how neuronal circuits integrate diverse incoming stimuli such as fluctuations in nutrient supply, metabolic hormones, neuronal activity and cellular stress. Here the functions of O-GlcNAc in the nervous system are reviewed.
Topics: Acetylglucosamine; Adult; Aged; Brain; Brain Chemistry; CD4-Positive T-Lymphocytes; Humans; Lymphocyte Activation; Metabolic Networks and Pathways; Protein Processing, Post-Translational
PubMed: 29790000
DOI: 10.1007/s10863-018-9760-1 -
Functional characterization of the phosphotransferase system in Parageobacillus thermoglucosidasius.Scientific Reports May 2023Parageobacillus thermoglucosidasius is a thermophilic bacterium characterized by rapid growth, low nutrient requirements, and amenability to genetic manipulation. These...
Parageobacillus thermoglucosidasius is a thermophilic bacterium characterized by rapid growth, low nutrient requirements, and amenability to genetic manipulation. These characteristics along with its ability to ferment a broad range of carbohydrates make P. thermoglucosidasius a potential workhorse in whole-cell biocatalysis. The phosphoenolpyruvate:carbohydrate phosphotransferase system (PTS) catalyzes the transport and phosphorylation of carbohydrates and sugar derivatives in bacteria, making it important for their physiological characterization. In this study, the role of PTS elements on the catabolism of PTS and non-PTS substrates was investigated for P. thermoglucosidasius DSM 2542. Knockout of the common enzyme I, part of all PTSs, showed that arbutin, cellobiose, fructose, glucose, glycerol, mannitol, mannose, N-acetylglucosamine, N-acetylmuramic acid, sorbitol, salicin, sucrose, and trehalose were PTS-dependent on translocation and coupled to phosphorylation. The role of each putative PTS was investigated and six PTS-deletion variants could not grow on arbutin, mannitol, N-acetylglucosamine, sorbitol, and trehalose as the main carbon source, or showed diminished growth on N-acetylmuramic acid. We concluded that PTS is a pivotal factor in the sugar metabolism of P. thermoglucosidasius and established six PTS variants important for the translocation of specific carbohydrates. This study lays the groundwork for engineering efforts with P. thermoglucosidasius towards efficient utilization of diverse carbon substrates for whole-cell biocatalysis.
Topics: Acetylglucosamine; Arbutin; Trehalose; Phosphotransferases; Carbohydrates; Bacteria; Mannitol; Sorbitol; Phosphoenolpyruvate Sugar Phosphotransferase System; Bacterial Proteins
PubMed: 37130962
DOI: 10.1038/s41598-023-33918-1 -
Frontiers in Immunology 2022The addition of N-acetyl glucosamine (GlcNAc) on the hydroxy group of serine/threonine residues is known as -GlcNAcylation (OGN). The dynamic cycling of this... (Review)
Review
The addition of N-acetyl glucosamine (GlcNAc) on the hydroxy group of serine/threonine residues is known as -GlcNAcylation (OGN). The dynamic cycling of this monosaccharide on and off substrates occurs -linked β-N-acetylglucosamine transferase (OGT) and -linked β-N-acetylglucosaminase (OGA) respectively. These enzymes are found ubiquitously in eukaryotes and genetic knock outs of the gene has been found to be lethal in embryonic mice. The substrate scope of these enzymes is vast, over 15,000 proteins across 43 species have been identified with -GlcNAc. OGN has been known to play a key role in several cellular processes such as: transcription, translation, cell signaling, nutrient sensing, immune cell development and various steps of the cell cycle. However, its dysregulation is present in various diseases: cancer, neurodegenerative diseases, diabetes. -GlcNAc is heavily involved in cross talk with other post-translational modifications (PTM), such as phosphorylation, acetylation, and ubiquitination, by regulating each other's cycling enzymes or directly competing addition on the same substrate. This crosstalk between PTMs can affect gene expression, protein localization, and protein stability; therefore, regulating a multitude of cell signaling pathways. In this review the roles of OGN will be discussed. The effect -GlcNAc exerts over protein-protein interactions, the various forms of crosstalk with other PTMs, and its role as a nutrient sensor will be highlighted. A summary of how these -GlcNAc driven processes effect the immune system will also be included.
Topics: Acetylglucosamine; Animals; Humans; Immune System; Lymphocyte Activation; N-Acetylglucosaminyltransferases; Phosphorylation; Protein Processing, Post-Translational; Signal Transduction; Ubiquitination
PubMed: 35173739
DOI: 10.3389/fimmu.2022.828648