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ACS Chemical Biology Feb 2017O-GlcNAcylation is the modification of serine and threonine residues with β-N-acetylglucosamine (O-GlcNAc) on intracellular proteins. This dynamic modification is... (Review)
Review
O-GlcNAcylation is the modification of serine and threonine residues with β-N-acetylglucosamine (O-GlcNAc) on intracellular proteins. This dynamic modification is attached by O-GlcNAc transferase (OGT) and removed by O-GlcNAcase (OGA) and is a critical regulator of various cellular processes. Furthermore, O-GlcNAcylation is dysregulated in many diseases, such as diabetes, cancer, and Alzheimer's disease. However, the precise role of this modification and its cycling enzymes (OGT and OGA) in normal and disease states remains elusive. This is partially due to the difficulty in studying O-GlcNAcylation with traditional genetic and biochemical techniques. In this review, we will summarize recent progress in chemical approaches to overcome these obstacles. We will cover new inhibitors of OGT and OGA, advances in metabolic labeling and cellular imaging, synthetic approaches to access homogeneous O-GlcNAcylated proteins, and cross-linking methods to identify O-GlcNAc-protein interactions. We will also discuss remaining gaps in our toolbox for studying O-GlcNAcylation and questions of high interest that are yet to be answered.
Topics: Acetylglucosamine; Glycosyltransferases; Mass Spectrometry; Microscopy, Fluorescence; Molecular Probes; Proteins
PubMed: 28055183
DOI: 10.1021/acschembio.6b01065 -
Current Opinion in Structural Biology Jun 2021O-GlcNAcylation is an enzymatic post-translational modification occurring in hundreds of protein substrates. This modification occurs through the addition of the... (Review)
Review
O-GlcNAcylation is an enzymatic post-translational modification occurring in hundreds of protein substrates. This modification occurs through the addition of the monosaccharide N-acetylglucosamine to serine and threonine residues on intracellular proteins in the cytosol, nucleus, and mitochondria. As a highly dynamic form of modification, changes in O-GlcNAc levels coincide with alterations in metabolic state, the presence of stressors, and cellular health. At the protein level, the consequences of the sugar modification can vary, thus necessitating biochemical investigations on protein-specific and site-specific effects. To this end, enzymatic and chemical methods to 'encode' the modification have been developed and the utilization of these synthetic glycopeptides and glycoproteins has since been instrumental in the discovery of the mechanisms by which O-GlcNAcylation can affect a diverse array of biological processes.
Topics: Acetylglucosamine; Glycoproteins; Peptides; Protein Processing, Post-Translational
PubMed: 33434850
DOI: 10.1016/j.sbi.2020.12.005 -
Journal of Molecular Cell Biology Feb 2023O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a highly dynamic and widespread post-translational modification (PTM) that regulates the activity, subcellular... (Review)
Review
O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a highly dynamic and widespread post-translational modification (PTM) that regulates the activity, subcellular localization, and stability of target proteins. O-GlcNAcylation is a reversible PTM controlled by two cycling enzymes: O-linked N-acetylglucosamine transferase and O-GlcNAcase. Emerging evidence indicates that O-GlcNAcylation plays critical roles in innate immunity, inflammatory signaling, and cancer development. O-GlcNAcylation usually occurs on serine/threonine residues, where it interacts with other PTMs, such as phosphorylation. Thus, it likely has a broad regulatory scope. This review discusses the recent research advances regarding the regulatory roles of O-GlcNAcylation in innate immunity and inflammation. A more comprehensive understanding of O-GlcNAcylation could help to optimize therapeutic strategies regarding inflammatory diseases and cancer.
Topics: Humans; Protein Processing, Post-Translational; Phosphorylation; Neoplasms; Immunity, Innate; Inflammation; Acetylglucosamine
PubMed: 36473120
DOI: 10.1093/jmcb/mjac065 -
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 -
Pharmacological Research Mar 2018Post-translational modifications (PTMs) covalently modify proteins and diversify protein functions. Along with protein phosphorylation, another common PTM is the... (Review)
Review
Post-translational modifications (PTMs) covalently modify proteins and diversify protein functions. Along with protein phosphorylation, another common PTM is the addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to serine and/or threonine residues. O-GlcNAc modification is similar to phosphorylation in that it occurs to serine and threonine residues and cycles on and off with a similar time scale. However, a striking difference is that the addition and removal of the O-GlcNAc moiety on all substrates are mediated by the two enzymes regardless of proteins, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. O-GlcNAcylation can interact or potentially compete with phosphorylation on serine and threonine residues, and thus serves as an important molecular mechanism to modulate protein functions and activation. However, it has been challenging to address the role of O-GlcNAc modification in regulating protein functions at the molecular level due to the lack of convenient tools to determine the sites and degrees of O-GlcNAcylation. Studies in this field have only begun to expand significantly thanks to the recent advances in detection and manipulation methods such as quantitative proteomics and highly selective small-molecule inhibitors for OGT and OGA. Interestingly, multiple brain regions, especially hippocampus, express high levels of both OGT and OGA, and a number of neuron-specific proteins have been reported to undergo O-GlcNAcylation. This review aims to discuss the recent updates concerning the impacts of O-GlcNAc modification on neuronal functions at multiple levels ranging from intrinsic neuronal properties to synaptic plasticity and animal behaviors.
Topics: Acetylglucosamine; Acylation; Animals; Humans; N-Acetylglucosaminyltransferases; Neurons; Phosphorylation; beta-N-Acetylhexosaminidases
PubMed: 29223644
DOI: 10.1016/j.phrs.2017.12.006 -
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 -
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 -
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 -
Journal of Enzyme Inhibition and... Dec 2015The pseudo-trisaccharide allosamidin 1 is a potent inhibitor of all family-18 chitinases, and it is confirmed to have insecticidal and antifungal activities. But the... (Review)
Review
The pseudo-trisaccharide allosamidin 1 is a potent inhibitor of all family-18 chitinases, and it is confirmed to have insecticidal and antifungal activities. But the synthesis of allosamidins is very difficult, and it is a challengeable subject. Allosamidins were synthesized in solid-liquid phase, total solid-phase and total liquid-phase, respectively. Solid-liquid phase method realizes the partial solid-phase synthesis of allosamidins. Total solid-phase method greatly simplifies the purification process. Total liquid-phase method shortens the synthetic steps of allosamidins. The insecticidal and antifungal activities of allosamidins were also reported herein.
Topics: Acetylglucosamine; Animals; Antifungal Agents; Bombyx; Carbohydrate Conformation; Chitinases; Enzyme Inhibitors; Fungi; Insecticides; Spodoptera; Trisaccharides
PubMed: 25486024
DOI: 10.3109/14756366.2014.987137 -
Nature Mar 2017Plants encounter a myriad of microorganisms, particularly at the root-soil interface, that can invade with detrimental or beneficial outcomes. Prevalent beneficial... (Review)
Review
Plants encounter a myriad of microorganisms, particularly at the root-soil interface, that can invade with detrimental or beneficial outcomes. Prevalent beneficial associations between plants and microorganisms include those that promote plant growth by facilitating the acquisition of limiting nutrients such as nitrogen and phosphorus. But while promoting such symbiotic relationships, plants must restrict the formation of pathogenic associations. Achieving this balance requires the perception of potential invading microorganisms through the signals that they produce, followed by the activation of either symbiotic responses that promote microbial colonization or immune responses that limit it.
Topics: Acetylglucosamine; Nitrogen; Phosphorus; Plant Immunity; Plants; Signal Transduction; Symbiosis
PubMed: 28300100
DOI: 10.1038/nature22009