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Diagnosis and Pathobiology
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
The covalent linking of a carbohydrate to another molecule is known as glycation (nonenzymatic glycosylation, which is a process of joining glycans to proteins, lipids, or other organic molecules via catalysis) [368]. Over 50% of proteins undergo this type of PTM and influence multiple activities involving cellular adhesion, proliferation, inflammation, oncogenesis, immunological responses, and viral replication [368]. While histones can be O-GlcNAc-modified proteins, the joining of O-linked β-N-acetylglucosamine (O-GlcNAc) moieties to serine and threonine residues of nuclear, mitochondrial, and cytoplasmic proteins (histone and nonhistone) is termed ‘O-GlcNAcylation' [387, 419–423]. This is a noncanonical glycosylation and is linked to metabolic disorders because of its sensitivity to cellular stress (e.g., nutrient deprivation, heat shock, hypoxia) [421, 424–426]. O-GlcNAcylation is the hexosamine biosynthetic pathway (HBP) nutrient flux product [421]. HBP combines amino acid, glucose, nucleotide, and fatty acid metabolism to produce the O-GlcNAcylation donor substrate [421]. The transfer of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc: donor substrate), to the target protein is catalyzed by O-GlcNAc transferase (OGT) and the removal of the sugar is performed by β-N-acetylglucosaminidase (O-GlcNAcase or OGA) [387, 419, 421].
Postimplantation diabetic embryopathy
Published in Moshe Hod, Lois G. Jovanovic, Gian Carlo Di Renzo, Alberto de Leiva, Oded Langer, Textbook of Diabetes and Pregnancy, 2018
Ulf J. Eriksson, Parri Wentzel
It has been suggested that hexosamine stress may have a role in diabetic teratogenesis.46,213,282 Indeed, defect development has been demonstrated in preimplantation mouse embryos, treated with glucose (27 mM) or glucosamine (0.2 mM) that was added to embryo culture media. Both treatments disturbed embryo development, increased apoptosis, and decreased cell number in the resulting blastocysts.282 Addition of benzyl-2-acetamido-2-deoxy-a-d-galactopyranoside (BADGP), an inhibitor of O-linked beta-N-acetylglucosaminyltransferase (OGT), the enzyme that adds O-GlcNAc to proteins, rescued all these phenotypes in the hyperglycemia treatment group, although only mild improvement was seen in the glucosamine group.282 This may reflect the relative potencies of each hexose in their capacity to stimulate UDP-GlcNAc production.278 In another study, pregnant mice were injected with glucose to induce hyperglycemia, or glucosamine, to directly activate the hexosamine pathway. Both treatments increased the NTD rate in the embryos, decreased GSH levels, and increased oxidative stress, as indicated by increased 2,7-dichlorodihydrofluorescein fluorescence. Glucose and glucosamine also inhibited expression of Pax-3; however, all these effects were prevented by GSH ethyl ester administration.213
Introduction
Published in Emmanuel Opara, NUTRITION and DIABETES, 2005
Hyperglycemia also stimulates release of xanthine oxidase from liver cells into plasma, where this enzyme further contributes to worsening oxidative stress through generation of superoxide ion [48]. There is evidence to suggest that increased superoxide-anion production also activates the hexosamine pathway, which inhibits eNOS activation by O-acetylglucsoaminylation at the Protein Kinase B, a serine threonine protein kinase (Akt) site of the eNOS protein [47]. Shunting of excess glucose into the hexosamine pathway is also believed to result in increased activity of the enzyme O-GlcNAc-β-N-acetylglucosaminidase [49]. This activation likely results in O-acetylglucoaminylation of the transcription factor Sp1 and other glucose-responsive genes, thereby modulating both gene expression and protein function in the vascular wall to contribute to the pathogenesis of diabetic complications.
Relevance of glycans in the interaction between T lymphocyte and the antigen presenting cell
Published in International Reviews of Immunology, 2021
Wilton Gómez-Henao, Eda Patricia Tenorio, Francisco Raúl Chávez Sanchez, Miguel Cuéllar Mendoza, Ricardo Lascurain Ledezma, Edgar Zenteno
O-GlcNAcylation (O-GlcNAc) is a type of dynamic glycosylation found in cytosolic, nuclear, and mitochondrial proteins, involved in biological processes such as cell metabolism, cell differentiation, development of neurodegenerative diseases, among others [20, 122, 123]. O-GlcNAc consists of the addition of a GlcNAc molecule to a Ser/Thr residue, its synthesis is regulated by the substrate donor UDP-GlcNAc and by the O-GlcNAc transferase (OGT) and the O-GlcNAcase (OGA) enzymes that, respectively, add and remove glycans from the target protein [115]. O-GlcNAc along with phosphorylation regulates protein functions acting as a “switch” to activate and inhibit signals in cascades that lead to the development of cellular responses, maintaining the homeostasis of the communication systems of the cell with its environment [19, 124].
O-GlcNAc Signaling Augmentation Protects Human Corneal Endothelial Cells from Oxidative Stress via AKT Pathway Activation
Published in Current Eye Research, 2020
Chang Ki Yoon, Sam Young Yoon, Jin Sun Hwang, Young Joo Shin
O-linked β-N-acetylglucosamine (O-GlcNAc) is a post-translational modification on serine or threonine residues of nucleocytoplasmic and mitochondrial proteins.21 Interestingly, the novel post-translational sugar modification, O-GlcNAc has been shown in numerous studies and in different cell types to act as an inducible, cytoprotective stress response.21–23 PUGNAc ((phenylcarbamoyl)oxime analog of GlcNAc; Molecular Weight, 353.3) is a drug, which acts as an inhibitor of N-acetylglucosaminidase. PUGNAc inhibits O-GlcNAcase (OGA), a beta-exo-N-acetylhexosaminidase, which results in increasing O-GlcNAc levels in cells. The solubility of PUGNAc is approximately 1 mg/ml in PBS, pH 7.2 and 100 mM in DMSO. In this study, we investigated the effect of O-GlcNAc augmentation on CECs against oxidative stress.
Mass spectrometry for the identification and analysis of highly complex glycosylation of therapeutic or pathogenic proteins
Published in Expert Review of Proteomics, 2020
Yukako Ohyama, Kazuki Nakajima, Matthew B. Renfrow, Jan Novak, Kazuo Takahashi
O-glycosylation most often occurs on Ser and Thr residues, which are hydroxyl groups-containingamino acids. The most common sugars attached to Ser/Thr are GlcNAc and N-acetylgalactosamine (GalNAc) in humans. Attachment of O-GlcNAc occurs in proteins in the nucleus, mitochondria, and cytoplasm; these proteins play important roles in regulating cellular processes, such as epigenetics, gene expression, translation, protein degradation, signal transduction, mitochondrial bioenergetics, the cell cycle, and protein localization [7]. O-GlcNAc is dynamically added and removed from proteins by O-GlcNAc transferase and O-GlcNAcase, respectively. O-GlcNAc modification is reported to act in a reciprocal manner to O-phosphate modification, and their respective addition and removal can affect protein structure, activity, and function [8].