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Nonimmune Hydrops Fetalis
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Chelsea DeBolt, Katherine Connolly, Mary E. Norton, Joanne Stone
Congenital disorders of glycosylation (CDG) are another category of IEM that have been shown to cause NIH. CDG are a large family of rare genetic diseases resulting from defects in the glycosylation of proteins or lipids. Glycosylation defects may show a highly diverse clinical presentation, as there are more than 130 identified genetic disorders across several glycosylation pathways. In a recent review, patients with CDG and NIH, had poor outcomes, among live births, 71% of infants died and among those who survived beyond the neonatal period, 80% reported developmental delay [40].
The Acute Phase Response: An Overview
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Irving Kushner, Andrzej Mackiewicz
Most of the APP except CRP, SAA, and albumin are glycoproteins. They almost exclusively bear N-glucosidically linked complex-type glycans which may contain two to four N-acetyllactosamine residues — branches (biantennary, triantennary, and tetraantennary structures) arising from the 1,3- and 1,6-α-linked mannose (Man) residues of the pentasaccharide inner core structure [Manα1,3(Manα1,6)Manβ1,4GlcNAcβ1,4GlcNAc]. N-acetyllactosamine residues can in turn bear sialic acid, fucose, or other sugars in a number of different configuratons. Moreover, in these antennary structures, a bisecting GlcNAc in a 1,4 linkage on the β-linked core Man may be present. Variations in the glycan structure present at a given glycosylation site have been referred to as microheterogeneity. Two types of microheterogeneity have been distinguished: major microheterogeneity, which reflects differences in the number of branches on the antennary structures, and minor microheterogeneity, referring to variations in sialic acid or fucose content.92
PMM2-CDG (Congenital disorders of glycosylation, type Ia)
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Glycosylation comprises all processes in which carbohydrates are added to proteins and lipids, thereby modifying their properties. It involves a huge variety of enzymes involved in the synthesis and processing of nucleotide-activated sugars, vesicular transport and glycosylation of biomolecules directing a tremendous heterogeneity of physiologic functions. Following PMM2-CDG, related disorders of glycosylation have been discovered. By now, more than 60 entities comprise a still growing group of monogenetic diseases of glycoprotein biosynthesis termed congenital disorders of glycosylation (CDG). The oligosaccharide moieties determine critical biologic processes like protein quality control, directed protein transport, enzymatic activity, and protein stability. Deficiencies lead to multiorgan diseases with neurologic symptoms often dominating. The identification of a considerable number of “new” CDG-types afforded the improvement of nomenclature which now connects the abbreviation of defective proteins with the term CDG (e.g. deficiency of the enzyme phosphomannomutase 2 (PMM2), formerly known as CDG-Ia, changed to PMM2-CDG.
Assessing developability early in the discovery process for novel biologics
Published in mAbs, 2023
Monica L. Fernández-Quintero, Anne Ljungars, Franz Waibl, Victor Greiff, Jan Terje Andersen, Torleif T. Gjølberg, Timothy P. Jenkins, Bjørn Gunnar Voldborg, Lise Marie Grav, Sandeep Kumar, Guy Georges, Hubert Kettenberger, Klaus R. Liedl, Peter M. Tessier, John McCafferty, Andreas H. Laustsen
As biologics are often complex molecules to manufacture, it is of high importance that expression systems and purification methods are optimized to enable repeated, reproducible production of high-quality material. This involves optimization of yields, folding, post-translational modifications, such as glycosylation, and reduction of host cell proteins. Here, it is expected that glycoengineering will continue to play an important role, and we foresee that the consideration of glycosylation patterns (and other post-translational modifications) early in the discovery process might improve success rates for many protein-based biologics. In this area, however, much remains unknown, and it will be important to better establish knowledge and guidelines for how not only to engineer biologics to have human-like post-translational modifications, but also to have modifications that are even better than the corresponding human ones.
A versatile design platform for glycoengineering therapeutic antibodies
Published in mAbs, 2022
Seth D. Ludwig, Zachary J. Bernstein, Christian Agatemor, Kris Dammen-Brower, Jeffrey Ruffolo, Jonah M. Rosas, Jeremy D. Post, Robert N. Cole, Kevin J. Yarema, Jamie B. Spangler
A common glycoengineering approach designed to improve efficacy is the introduction of new glycosylation sites into a therapeutic protein. This approach was used in the design of darbepoetin, a marketed form of erythropoietin (EPO). Two N-glycan sites were installed into native EPO to yield darbepoetin, which has a serum half-life that is approximately three-fold longer than that of EPO.8 Other examples of therapeutic proteins that have been glycoengineered to incorporate “built-in” N-glycans include an insulin with improved PK properties;9 human immunodeficiency virus (HIV) neutralizing antibodies with improved potency;10 and a therapeutic enzyme ectonucleotide pyrophosphatase phospodiesterase-1 (ENPP-1) with improved bioavailability and PK properties.11
Inhibition of O-glycosylation aggravates GalN/LPS-induced liver injury through activation of ER stress
Published in Immunopharmacology and Immunotoxicology, 2021
Dongkui Xu, Zhenguo Zhao, Yixian Li, Chao Shang, Lijie Liu, Jiaxu Yan, Ying Zheng, Zongmei Wen, Tao Gu
Glycosylation is the enzymatic addition of carbohydrate chains to proteins, which is the most common post-translational modification on many membrane-associated and secreted proteins [1,2]. Glycosylation can significantly affect a variety of fundamental biological processes [3]. According to sugar-amino acid linkages, glycosylation can be divided into two major types: N-glycosylation (Asn-linked) and O-glycosylation (Ser/Thr-linked) [4]. N-glycosylation is well-studied and predictable, whereas O-glycosylation is more complex and less elucidated [5]. O-glycosylation is essential for protein function, including protein structure, folding, stability, localization, and recognition, etc., and can also modulate enzyme activity and cell-to-cell and cell-to-extracellular matrix (ECM) interactions [6,7]. Many carcinomas exhibit aberrant O-glycosylation and produce truncated O-glycans, such as Tn/STn antigen [8,9]. Pathological exposure of Tn antigen on the cell surface or secreted proteins may promote cancer progression and metastasis [9–11]. In addition, aberrant O-glycosylation may play a role in systemic inflammation, ranging from leukocyte trafficking to initiation of innate immunity, which manifests as pro- or anti-inflammatory effects under certain conditions [12–14]. So far the specific functions of O-glycosylation during inflammation remain to be determined. Understanding the molecular mechanisms of O-glycosylation in the regulation of inflammation may lead to a greater appreciation of the related diseases involving altered O-glycosylation.