Review

Authors: Xuemeng Xu, Qiu Peng, Xianjie Jiang...

Glycosylation, a key mode of protein modification in living organisms, is critical in regulating various biological functions by influencing protein folding, transportation, and localization. Changes in glycosylation patterns are a significant feature of cancer, are associated with a range of pathological activities in cancer-related processes, and serve as critical biomarkers providing new targets for cancer diagnosis and treatment. Glycoproteins like human epidermal growth factor receptor 2 (HER2) for breast cancer, alpha-fetoprotein (AFP) for liver cancer, carcinoembryonic antigen (CEA) for colon cancer, and prostate-specific antigen (PSA) for prostate cancer are all tumor biomarkers approved for clinical use. Here, we introduce the diversity of glycosylation structures and newly discovered glycosylation substrate-glycosylated RNA (glycoRNA). This article focuses primarily on tumor metastasis, immune evasion, metabolic reprogramming, aberrant ferroptosis responses, and cellular senescence to illustrate the role of glycosylation in cancer. Additionally, we summarize the clinical applications of protein glycosylation in cancer diagnostics, treatment, and multidrug resistance. We envision a promising future for the clinical applications of protein glycosylation.

Topics: Humans; Glycosylation; Neoplasms; Biomarkers, Tumor; Animals

PubMed: 39305520
DOI: 10.1002/cac2.12610

Authors: Jerry Eichler

Eichler introduces the diversity of protein glycosylations and the roles of these modifications in regulating protein function.

Topics: Glycosylation; Proteins

PubMed: 30939300
DOI: 10.1016/j.cub.2019.01.003

Authors: Joseph Zaia, Sylvie Ricard-Blum

Topics: Glycosylation; Carbohydrates

PubMed: 36179500
DOI: 10.1016/j.sbi.2022.102468

Review

Authors: Sen-itiroh Hakomori Si

Physically distinguishable microdomains associated with various functional membrane proteins are one of the major current topics in cell biology. Glycosphingolipids present in such microdomains have been used as "markers;" however, the functional role of glycosyl epitopes in microdomains has received little attention. In this review, I have tried to summarize the evidence that glycosyl epitopes in microdomains mediate cell adhesion and signal transduction events that affect cellular phenotypes. Molecular assemblies that perform such functions are hereby termed "glycosynapse" in analogy to "immunological synapse," the membrane assembly of immunocyte adhesion and signaling. Three types of glycosynapses are so far distinguishable: (i) Glycosphingolipids organized with cytoplasmic signal transducers and proteolipid tetraspanin with or without growth factor receptors; (ii) transmembrane mucin-type glycoproteins with clustered O-linked glycoepitopes for cell adhesion and associated signal transducers at lipid domain; and (iii) N-glycosylated transmembrane adhesion receptors complexed with tetraspanin and gangliosides, as typically seen with the integrin-tetraspanin-ganglioside complex. The possibility is discussed that glycosynapses give rise to a high degree of diversity and complexity of phenotypes.

Topics: Animals; Cell Adhesion; Cell Line; Cell Membrane; Gangliosides; Glycosphingolipids; Glycosylation; Humans; Mice; Models, Biological; Neoplasms; Phenotype; Protein Structure, Tertiary; Signal Transduction; Synapses; Tumor Cells, Cultured

PubMed: 11773621
DOI: 10.1073/pnas.012540899

Review

Authors: László Hajba, Ákos Szekrényes, Beáta Borza...

The recent expiration of several protein therapeutics opened the door for biosimilar development. Biosimilars are biologic medical products that are similar but not identical copies of already-authorized protein therapeutics. Critical quality attributes (CQA), such as post-translational modifications of recombinant biotherapeutics, are important for the clinical efficacy and safety of both the innovative biologics and their biosimilar counterparts. Here, we summarize biosimilarity CQAs, considering the regulatory guidelines and the statistical aspects (e.g., biosimilarity index) and then discuss glycosylation as one of the important attributes of biosimilarity. Finally, we introduced the 'Glycosimilarity Index', which is based on the averaged biosimilarity criterion.

Topics: Animals; Biological Products; Biosimilar Pharmaceuticals; Glycosylation; Humans; Protein Processing, Post-Translational

PubMed: 29337201
DOI: 10.1016/j.drudis.2018.01.009

Authors: Daniel Madriz Sørensen, Christian Büll, Thomas D Madsen...

Small molecule inhibitors of glycosylation enzymes are valuable tools for dissecting glycan functions and potential drug candidates. Screening for inhibitors of glycosyltransferases are mainly performed by in vitro enzyme assays with difficulties moving candidates to cells and animals. Here, we circumvent this by employing a cell-based screening assay using glycoengineered cells expressing tailored reporter glycoproteins. We focused on GalNAc-type O-glycosylation and selected the GalNAc-T11 isoenzyme that selectively glycosylates endocytic low-density lipoprotein receptor (LDLR)-related proteins as targets. Our screen of a limited small molecule compound library did not identify selective inhibitors of GalNAc-T11, however, we identify two compounds that broadly inhibited Golgi-localized glycosylation processes. These compounds mediate the reversible fragmentation of the Golgi system without affecting secretion. We demonstrate how these inhibitors can be used to manipulate glycosylation in cells to induce expression of truncated O-glycans and augment binding of cancer-specific Tn-glycoprotein antibodies and to inhibit expression of heparan sulfate and binding and infection of SARS-CoV-2.

Topics: Animals; Glycosylation; SARS-CoV-2; COVID-19; Glycoproteins; Polysaccharides

PubMed: 36804936
DOI: 10.1038/s41467-023-36598-7

Review

Authors: Ewa Gruszewska, Agnieszka Grytczuk, Lech Chrostek...

BACKGROUND

The interaction between hepatitis viruses and host cells is regulated by glycans exposed on the surfaces of human and viruses cells. As the biosynthesis and degradation of human glycoproteins take place at the highest level in the liver, the changes in glycosylation of serum proteins may potentially be useful in the diagnosis of liver pathology. On the other hand, specific alterations in viruses envelope glycans could cause large changes in the entry process of hepatitis viruses into a host cells.

SCOPE OF REVIEW

Unique alterations in glycosylation of specific proteins can be detected in HBV and HCV infected patients especially with confirmed fibrosis/cirrhosis. On the other hand, viral envelope proteins that bind to host cells are glycosylated. These glycosylated proteins play a key role in recognition, binding and penetration of the host cells. In this review we summarized the knowledge about significance of glycosylation for viral and host factors.

MAJOR CONCLUSIONS

Glycosylation changes in single serum glycoproteins are noticed in the sera of patients with viral hepatitis. However, a more specific biomarker for the diagnosis of chronic hepatitis than that of a single glycosylated molecule is systemic investigation of complete set of glycan structures (N-glycome). Glycans play important roles in the viral biology cycle especially as a connecting element with host receptors.

GENERAL SIGNIFICANCE

The interaction between virus glycoproteins and cellular receptors, which are also glycoproteins, determines the possibility of virus penetration into host cells. Therefore these glycans can be the targets for the developing of novel treatment strategies of viral hepatitis.

Topics: Glycosylation; Hepatitis, Viral, Human; Humans

PubMed: 34474116
DOI: 10.1016/j.bbagen.2021.129997

Review

Authors: Christina Schäffer, Paul Messner

Glycosylation of proteins is one of the most prevalent post-translational modifications occurring in nature, with a wide repertoire of biological implications. Pathways for the main types of this modification, the N- and O-glycosylation, can be found in all three domains of life-the Eukarya, Bacteria and Archaea-thereby following common principles, which are valid also for lipopolysaccharides, lipooligosaccharides and glycopolymers. Thus, studies on any glycoconjugate can unravel novel facets of the still incompletely understood fundamentals of protein N- and O-glycosylation. While it is estimated that more than two-thirds of all eukaryotic proteins would be glycosylated, no such estimate is available for prokaryotic glycoproteins, whose understanding is lagging behind, mainly due to the enormous variability of their glycan structures and variations in the underlying glycosylation processes. Combining glycan structural information with bioinformatic, genetic, biochemical and enzymatic data has opened up an avenue for in-depth analyses of glycosylation processes as a basis for glycoengineering endeavours. Here, the common themes of glycosylation are conceptualised for the major classes of prokaryotic (i.e. bacterial and archaeal) glycoconjugates, with a special focus on glycosylated cell-surface proteins. We describe the current knowledge of biosynthesis and importance of these glycoconjugates in selected pathogenic and beneficial microbes.

Topics: Archaea; Bacteria; Glycoproteins; Glycosylation; Membrane Proteins; Polysaccharides

PubMed: 27566466
DOI: 10.1093/femsre/fuw036

Authors: Fei Yu, Jiayi Li, Paul M DeMent...

Carbohydrates are essential moieties of many bioactive molecules in nature. However, efforts to elucidate their modes of action are often impeded by limitations in synthetic access to well-defined oligosaccharides. Most of the current methods rely on the design of specialized coupling partners to control selectivity during the formation of glycosidic bonds. Reported herein is the use of a commercially available phenanthroline to catalyze stereoretentive glycosylation with glycosyl bromides. The method provides efficient access to α-1,2-cis glycosides. This protocol has been performed for the large-scale synthesis of an octasaccharide adjuvant. Density-functional theory calculations, together with kinetic studies, suggest that the reaction proceeds by a double S 2 mechanism.

Topics: Bromides; Catalysis; Glycosides; Glycosylation; Kinetics; Phenanthrolines; Stereoisomerism

PubMed: 30920099
DOI: 10.1002/anie.201901346

Review

Authors: Paul G Hitchen, Anne Dell

Glycosylated proteins are ubiquitous components of eukaryote cellular surfaces, where the glycan moieties are implicated in a wide range of cell-cell recognition events. Once thought to be restricted to eukaryotes, glycosylation is now being increasingly reported in prokaryotes. Many of these discoveries have grown from advances in analytical technologies and genome sequencing. This review highlights the capabilities of high-sensitivity mass spectrometry for carbohydrate structure determination of bacterial glycoproteins and the emergence of glycoproteomic strategies that have evolved from proteomics and genomics for the functional analysis of bacterial glycosylation.

Topics: Bacteria; Bacterial Proteins; Carbohydrate Sequence; Glycoproteins; Glycosylation; Mass Spectrometry; Proteomics

PubMed: 16735721
DOI: 10.1099/mic.0.28859-0