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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
The Development of Improved Therapeutics through a Glycan- “Designer” Approach
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Knowing that the benefit of glycosylation serves tailored immunogenicity and activity of antimicrobial peptides, there is need for a fast, cheap, and reliable technique to attach glycan at the precise location. For this purpose, many techniques have been developed, including recombinant Protein–glycan coupling technology (PGCT) and recently published similar technique for O-linked glycan attachment, so-called site-directed glycosylation. The site-directed glycosylation similarly to PGCT uses E. coli as a host. However, it consists of two steps: Introduction of O-linked N-Acetylglucosamine (O-Glc-NAc) priming monosaccharide on the target protein/peptide followed by a ligation of eukaryotic N-glycan onto the O-GlcNAc (Wu et al., 2016). The first step requires catalyzing enzyme oligosaccharyltransferase (OGT) that transfers O-linked GlcNAc onto the accessible Serine/Threonine residue of a protein through β-linkage. In the method of site directed glycosylation both protein and the OGTase are expressed on separate plasmids in vivo E. coli. In the second step of transferring the N-glycan onto the primed protein researchers used an optimized enzyme endo-β-N-acetylglucosaminidase (Endo MN175Q) (Wu et al., 2016; Umekawa et al., 2010), which showed to have promiscuous substrate tolerance for GlcNAc-O-linked peptides/proteins in addition to its GlcNAc-N -linked natural preference. The efficiency of the O-linked substrate transfer was much lower (21%) then the N-linked one (73%) nonetheless with future improvements and optimizations this technique could be viable for tailoring glycans of interest to a monosaccharide primed protein.
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].
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].
Upregulated protein O-GlcNAcylation promoted functional and structural recovery of the contused spinal cord injury in rats by Thiamet-G treatment
Published in Neurological Research, 2019
Hongsheng Liang, Lin Xu, Aili Gao, Yongxiang Shao, Shanshan Yang, Zhenfeng Jiang, Wei Ma, Shiyi Zhu, Tie Lin, Xiangtong Zhang
Glucose can be converted to uridine diphosphate (UDP)-GlcNAc in the cell through the hexosamine biosynthetic pathway (HBP) [30], while UDP-GlcNAc serves as a direct donor for modification of proteins with O-GlcNAc [31]. In response to multiple forms of stress, cells rapidly increase glucose uptake [5]. Stress-induced hyperglycemia helps to produce further elevation of protein O-GlcNAcylation through the HBP after SCI [29]. The activity of O-linked β-N-acetylglucosamine transferase (OGT, which catalyzes the addition of O-GlcNAc to proteins) has also been observed to dramatically increase in accordance with increasing concentrations of UDP-GlcNAc [32]. All these factors could explain the elevated O-GlcNAcylation protein after injury. On the other hand, Thiamet-G is a promising selective OGA inhibitor, which can prohibit the O-GlcNAc from the dissociation of the protein, and promote the protein O-GlcNAcylation elevation.