Glycotopics


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Mucin Decomposition Mechanisms in Gut Bacteria

Toshihiko Katoh / Takane Katayama

last updated 2024/2/01 (Glycoforum. 2023 Vol.27 (1), A3)  
DOI: https://doi.org/10.32285/glycoforum.27A3

Certain gut bacteria produce mucin-degrading enzymes as part of their strategy to adapt themselves to the human intestine. Recent advances in the analysis of these enzymes have identified a wide variety of enzymatic repertoires corresponding to the complex structures of mucins. In addition, information about such enzymes has been compiled in various databases, making it easier to provide a comprehensive understanding of mucin decomposition and related metabolic pathways in the human intestine. This paper discusses mucin decomposition pathways derived from the characteristics of mucin-decomposition-associated enzymes that have so far been identified in gut bacteria. ...and more

Analysis of expression and function of O-glycans in castration-resistant and hypoxic prostate cancer cells

Daiki Yamamoto / Toshinori Sato

last updated 2023/12/01 (Glycoforum. 2023 Vol.26 (6), A24)  
DOI: https://doi.org/10.32285/glycoforum.26A24

Prostate cancer (PCa) is the most common malignant tumor in men. As the number of patients increases, the number of patients with a highly malignant treatment-resistant form of prostate cancer is increasing, which is a problem. Therefore, there is a need to develop diagnostic and therapeutic methods for malignant prostate cancer. Prostate-specific antigen tests are currently used to diagnose PCa, but they have a high rate of false positives that often require the use of invasive diagnostic interventions. Therefore, more accurate diagnostic methods are needed. The authors elucidated the expression and function of O-glycans in PCa cells that have become malignant under hormone deprivation and hypoxic conditions. In order to understand the glycan structures expressed in cells, detection with antibodies and lectins, enzymatic and chemical excision, and analysis using mass spectrometry are being used. In addition, the saccharide primer method has been developed to analyze glycans expressed in cultured cells. In this article, we will introduce the results of O-glycan analysis using the saccharide primer method in prostate cancer cells that became malignant after hormone removal or in a hypoxic environment, as well as functional analysis of these glycans. ...and more

The property of the extracellular matrix formed by hyaluronan in the brain depends on the molecular weight of hyaluronan

Diana Egorova / Shinji Miyata

last updated 2023/12/01 (Glycoforum. 2023 Vol.26 (6), A23)  
DOI: https://doi.org/10.32285/glycoforum.26A23

Hyaluronan (HA) is a central component of the extracellular matrix (ECM) in the central nervous system. Brain HA exists in two distinct forms of ECM: the diffuse ECM, which is soluble in saline and detergents, and the condensed ECM, which forms aggregates, such as perineuronal nets. Although the physiological functions of HA significantly differ depending on its size, size differences in HA have not yet been examined in the two ECM types. Recently, we established a simple method to simultaneously assess the molecular weight (MW) of HA in multiple crude biological samples. HA was purified through single-step precipitation from tissue extracts using biotinylated HA-binding protein and streptavidin-coupled magnetic beads, followed by separation on gel electrophoresis. By applying this method to HA in the mouse brain, we revealed that the condensed ECM contained higher MW HA than the diffuse ECM. Higher MW HA and lower MW HA exhibited different spatial distributions: the former was confined to perineuronal nets, while the latter was widely present throughout the brain. Furthermore, the limited degradation of HA showed that higher MW HA was required to form an insoluble HA-aggrecan complex. The present study demonstrated that the MW of HA in the brain strongly correlates with the localization and solubility of the ECM it forms. ...and more

Collapse of the Glycocalyx in Dry Eye

Yuichi Uchino

last updated 2023/08/01 (Glycoforum. 2023 Vol.26 (4), A15)  
DOI: https://doi.org/10.32285/glycoforum.26A15

In Japan, dry eye is a very common disease, affecting approximately 20% of the Japanese population and approximately 65% of office workers who use computers for a long time. While Japan has its own definition and diagnostic criteria for dry eye, other Asian countries use the same definition and diagnostic criteria as that of Japan as a result of the exchange of opinions through the Asia Dry Eye Society. It can be said that tear film instability on the ocular surface is of paramount importance in understanding the pathophysiology of dry eye. Tear film instability is involved in the collapse of the glycocalyx on the ocular surface; the roles of galectin 3, a glycocalyx constituent protein, has been increasingly attracting attention. In this article, we briefly review the latest clinical and basic research on tear film behavior, explore the differences in the action of galectin 3 on the ocular surface between the normal and dry eye conditions, and also mention the pathophysiology of the tear film instability. ...and more

Podoplanin, a glycoprotein, as a therapeutic target of brain tumors

Atsushi Natsume

last updated 2023/06/01 (Glycoforum. 2023 Vol.26 (3), A11)  
DOI: https://doi.org/10.32285/glycoforum.26A11

We have focused on a molecule named podoplanin (PDPN) as a therapeutic target of malignant brain tumors. PDPN is a type I transmembrane mucin-like glycoprotein that is abundant in several solid tumors including squamous cell carcinoma, malignant mesothelioma, Kaposi sarcoma, angiosarcoma, testicular seminoma, and brain tumors. The expression level of PDPN is reported to increase as tumor malignancy increases. The side effects of currently available treatments can be avoided or mitigated if new measures are developed that only kill PDPN-expressing tumor cells. ...and more

Glycosidation of sialic acid

Hiromune Ando

last updated 2023/06/01 (Glycoforum. 2023 Vol.26 (3), A10)  
DOI: https://doi.org/10.32285/glycoforum.26A10

Sialic acid is a “uronic acid”, sugar with a carboxyl group as an acidic functional group. While many monosaccharides in glycans in the body are pentoses and hexoses, sialic acid is a nonose and plays various and important physiological roles. In the author’s opinion, sialic acid must be a distinguished from other sugars. Regarding the chemical synthesis of glycans, the presence of sialic acid in a glycan dramatically increases the difficulty of its synthesis. Because of its unique structure, sialic acid markedly decreases the success rate of glycosidation. A fundamental solution to this problem has been sought for more than half a century. Recently, our group successfully developed one approach to solving this problem. In this article, I will outline this approach. ...and more

Chondroitin sulfate proteoglycan as a novel molecular target for the treatment of dementia

Shozo Jinno

last updated 2023/04/03 (Glycoforum. 2023 Vol.26 (2), A7)  
DOI: https://doi.org/10.32285/glycoforum.26A7

The extracellular matrix (ECM) plays a central role in brain homeostasis. Earlier studies have shown that the ECM is involved in the control of neuronal and glial functions through regulation of growth factors, neurotrophic factors, and neurotransmitters. It has also been shown that ECM is involved in embryonic neurogenesis and axonal outgrowth during brain development. Interestingly, recent studies have suggested that the ECM constitutes a microenvironment called the “neurogenic niche” in the dentate gyrus of the adult hippocampus, where the ECM may be involved in the proliferation and differentiation of neural stem cells (NSCs) and neuronal progenitor cells (NPCs) into newborn granule cells (NGCs) . We have reported that chondroitin sulfate proteoglycan (CSPG), one of the major molecules of the brain ECM, may improve cognitive function via promotion of adult neurogenesis in the hippocampus. This perspective outlines that CSPG may work as a molecular target for dementia treatment. ...and more

Attachment of viral particles to the cell surface mediated by heparan sulfate

Yoshitaka Sato

last updated 2023/02/01 (Glycoforum. 2023 Vol.26 (1), A3)  
DOI: https://doi.org/10.32285/glycoforum.26A3

Many viral pathogens utilize heparan sulfate as attachment factors, which facilitates the initial interaction with host cells. We recently identified 3'-Phosphoadenosine 5'-Phosphosulfate Synthase 1(PAPSS1)as a host factor for herpes simplex virus type 1 (HSV-1) infection by a genome-wide loss-of function CRISPR screen1. The Knockout (KO) of PAPSS1 reduced heparan sulfate expression. Here, I would like to introduce and discuss the role of heparan sulfate on viral infection. ...and more

Ribitol phosphate and therapeutic strategy of muscular dystrophy

Motoi Kanagawa

last updated 2022/10/03 (Glycoforum. 2022 Vol.25 (5), A14)  
DOI: https://doi.org/10.32285/glycoforum.25A14

Ribitol phosphate is a sugar alcohol phosphate, which is known as a component of teichoic acid in bacterial cell walls. In 2016, ribitol phosphate was found in vertebrate cells as a sugar chain component of dystroglycan. At the same time, a group of enzymes involved in the biosynthesis of ribitol phosphate was also identified, and mutations in the genes encoding these enzymes are responsible for several types of muscular dystrophy. As the mechanism of ribitol phosphate modification is revealed, the development of therapies for ribitol phosphate-defective muscular dystrophy is heating up. This article describes the history of ribitol phosphate discovery and the therapeutic strategies currently proposed. ...and more

Anti-inflammatory activity of galactosylated, nonfucosylated intravenous immunoglobulin

Yusuke Mimura

last updated 2022/08/01 (Glycoforum. 2022 Vol.25 (4), A11)  
DOI: https://doi.org/10.32285/glycoforum.25A11

IgG activates FcγRs and the complement system while intravenous immunoglobulin (IVIG) consisting of plasma IgG exerts anti-inflammatory effects in the treatment of autoimmune diseases. Although IVIG has been used for >40 years as a treatment option for certain autoimmune disorders, its mechanism of action (MOA) remains unsolved. Recently developed chemo-enzymatic glycoengineering approach allows for remodeling of the Fc glycans of polyclonal IgG. We prepared fucosylated or nonfucosylated plasma IgG glycoforms having 2 sialic acids, 2 galactose, or 0 galactose at the nonreducing ends of the Fc glycans to investigate their anti-inflammatory activity. We have demonstrated that the galactosylated, nonfucosylated [(G2)2] glycoform has the highest affinity for FcγRIIIa and potency to inhibit antibody-dependent cellular cytotoxicity (ADCC) activity of immune cells. As the (G2)2 glycoform is a component of IVIG, glycoengineered IVIG consisting of the (G2)2 glycoform alone may be a potential next-generation antibody drug. This review outlines our current understanding of the role of IgG-Fc glycan in MOA of IVIG. ...and more

Electrochemical Glycosylation

Toshiki Nokami

last updated 2022/6/1 (Glycoforum. 2022 Vol.25 (3), A8)  
DOI: https://doi.org/10.32285/glycoforum.25A8

Enzymatic methods and chemical methods are two major methodologies for the synthesis of oligosaccharides. The enzymatic method using glycosyl transferase and/or glycosidase is useful for synthesizing oligosaccharides without introduction of protecting groups of hydroxyl groups. By contrast, the chemical method is based on techniques of synthetic organic chemistry. Thus, it is necessary to protect and deprotect reactive functional groups; however, both natural and unnatural oligosaccharides can be prepared. To synthesize these oligosaccharides, a number of building blocks have been developed and a variety of activation methods have also been reported for each of the building blocks. In this article, the electrochemical glycosylation of thioglycosides, which are widely used for chemical synthesis of oligosaccharides, is introduced. Although thioglycosides are stable and easy to handle, they can be selectively activated under electrochemical conditions. ...and more

Medical Applications of SKM9-2, an Antibody That Recognizes Glycopeptides

Shoutaro Tsuji

last updated 2022/04/01 (Glycoforum. 2022 Vol.25 (2), A5)  
DOI: https://doi.org/10.32285/glycoforum.25A5

The use of antibody drugs has been spreading rapidly because of their excellent pharmacological effects and the recent advances in antibody humanization technology and biologic production technology. Currently, a large number of antibody drugs are being marketed as block busters; as such, antibody drugs may be described as occupying an established position in the pharmaceutical industry. On the other hand, suitable targets for disease-specific treatments are increasingly being depleted; a key step in antibody drug development is the discovery of new-generation target antigens.
We are working on discovering specific cancer antigens for malignant mesothelioma, an intractable cancer. Mesothelioma has long been an “indistinct” cancer as it lacks good cancer markers and hence is quite difficult to diagnose pathologically. Recognizing a new protein antigen encompassing a “glycopeptide region with mesothelioma-specific glycosylation,” our anti-mesothelioma antibody is highly promising as a new antibody drug seed expected to contribute to the diagnosis and treatment of mesothelioma, and as a drug discovery seed for targeting glycans. This article provides a historical overview of the research and development, and future prospects for clinical application of this antibody. ...and more

Chemical Insertion of Glycan Extends the Scope of Homogeneous Glycoprotein Synthesis

Kota Nomura

last updated 2022/02/01 (Glycoforum. 2022 Vol.25 (1), A2)  
DOI: https://doi.org/10.32285/glycoforum.25A2

To understand the biological processes mediated by various glycoforms of glycoproteins, the preparation of homogeneous glycoproteins is essential for performing extensive biological experiments. Recently we found that diacyl disulfide coupling (DDC) between glycosyl asparagine and peptide yielded glycopeptides chemoselectively. DDC enabled us to develop a new glycoprotein synthesis method, “the chemical glycan insertion strategy,” which can insert glycosyl asparagine between the N- and C- termini of two unprotected peptides. In our design concept, fewer steps are needed to generate glycoproteins. Herein, I will introduce the latest strategy of glycoproteins synthesis by chemical insertion. ...and more

Is the 3-O-sulfated structure of heparan sulfate key to elucidating the structure-function relationship?

Hideo Mochizuki

last updated 2021/12/01 (Glycoforum. 2021 Vol.24 (6), A17)  
DOI: https://doi.org/10.32285/glycoforum.24A17

Heparan sulfate (HS) is present as a component of proteoglycans on cell surfaces and in the extracellular matrix in most animal species including Hydra, Caenorhabditis, Drosophila, and humans. HS chains are structurally heterogeneous, being composed of densely sulfated regions, or sulfated domains, connected by mostly nonsulfated and N-acetyl-rich regions. HS regulates various physiological processes by the interaction with numerous proteins such as growth factors, morphogens, cytokines, enzymes, and extracellular matrix proteins. The binding specificity of HS for each functional protein is thought to be dependent on the structure of the sulfated domain. ...and more

Mechanisms of atherosclerosis onset and progression mediated by vascular wall chondroitin sulfate chain elongation

Noriaki Emoto

last updated 2021/10/01 (Glycoforum. 2021 Vol.24 (5), A15)  
DOI: https://doi.org/10.32285/glycoforum.24A15

Cardiovascular and cerebrovascular diseases such as myocardial and cerebral infarction are caused by atherosclerotic disease1. Atherosclerotic diseases are the cause of approximately 25% of deaths in Japan, and constitute a major threat to the Japanese population, so there is a very high societal demand for these diseases to be defeated.
Treatment of atherosclerosis has previously focused on controlling the risk factors for cardiovascular disease development, represented by hypertension, diabetes, dyslipidemia, etc. Various risk factors are in fact increasingly controllable with renin-angiotensin system inhibitors, statins, etc. However, taking into consideration the continuing increase in the prevalence of cardiovascular diseases, there is an urgent need to establish new treatment strategies.
The response-to-retention hypothesis has been put forward for the mechanisms of onset and progression of atherosclerosis, and has been given considerable attention2,3. Accumulation of low-density lipoprotein (LDL) cholesterol and other lipids in vascular walls is considered to be a starting point for onset of early-stage arteriosclerosis, and it has recently been suggested that the structures of chondroitin sulfate chains in the tunica intima are connected to that accumulation, with the length of the chains being particularly closely connected4.
The present authors have put forward the following hypothesis: “Accumulation of lipids can be reduced by modifying the lengths of chondroitin sulfate chains, enabling prevention of or recovery from atherosclerosis”. Studies have since been performed to test this hypothesis, and the results are summarized here. ...and more

Glycan Dynamics of SARS-CoV-2 Spike Protein Revealed by Molecular Simulations

Takaharu Mori / Yuji Sugita

last updated 2021/08/01 (Glycoforum. 2021 Vol.24 (4), A12)  
DOI: https://doi.org/10.32285/glycoforum.24A12

The recent COVID-19 pandemic is caused by a new coronavirus, SARS-CoV-2, whose spike protein on its surface binds to human cells via angiotensin-converting enzyme 2 (ACE2) receptors in the initial stage of infection. In that process, the structure of the spike protein changes from a “down-form” to an “up-form”, as demonstrated by cryo-electron microscopy. Biochemical experiments have shown that the surface of the spike protein is modified by many glycans. Glycans have been considered to play a role in protection against antibodies, i.e., immune evasion; however, how they contribute to the structural changes of the spike protein remains unclear. In this paper, we describe the role of glycans as elucidated by molecular dynamics simulation of the spike protein. ...and more

Development of a Highly Functionalized Lactoferrin That Controls Nerve Function: Fusion of Glycan-Binding Ability and Neuroprotective Function

Masao Nakamura

last updated 2021/06/01 (Glycoforum. 2021 Vol.24 (3), A8)  
DOI: https://doi.org/10.32285/glycoforum.24A8

Lactoferrin (LF) is a glycosaminoglycan-binding protein that functions in innate immunity, and it is expected to be useful as a biopharmaceutical product due to its effects on the body. We aim to develop novel therapeutic agents that can promote effective recovery from spinal cord injuries. Through our recent research, we discovered that LF binds to chondroitin sulfate E (CS-E), inhibiting nerve axon outgrowth and neutralizing its toxicity. We have also developed a highly functionalized neuroprotective molecule consisting of granulocyte colony-stimulating factor (G-CSF) linked to LF. This paper introduces this highly functionalized LF and discusses its glycan-binding and neuroprotective properties. ...and more

The branched structure and properties of starch - determined from studies on branching enzymes

Ryuichiro Suzuki / Eiji Suzuki

last updated 2021/06/01 (Glycoforum. 2021 Vol.24 (3), A7)  
DOI: https://doi.org/10.32285/glycoforum.24A7

Starch, a polysaccharide composed of glucose molecules, is formed during photosynthesis by Archaeplastida and is found in staple food crops such as cereals, tubers, and beans. Starch is utilized not just for food and food additive purposes but also for industrial purposes, e.g., in the manufacture of glues and bioplastics. Starch consists of amylose and amylopectin. The primary constituent amylopectin has an orderly branched structure and its structure has an effect on the taste and physicochemical properties of starch. Starch synthase, branching enzyme, and debranching enzyme are involved in amylopectin biosynthesis, but the mechanism controlling the assembly of highly ordered structures remains to be elucidated. Understanding the mechanisms controlling amylopectin’s structure opens up the possibility of designing an amylopectin with a favorable structure and properties. The authors have clarified the mechanism controlling the length of branched chains formed by branching enzymes. In this article, we describe the problems that need to be solved in order to control the structure and properties of amylopectin and recent progress in studies on branching enzymes. The production of structure-controlled amylopectins contributes to the development of our nation by raising the level of its food self-sufficiency and helping it reach the goal of a decarbonized society. ...and more

Glycan-hydrolyzing enzymes link plants

Ken-ichi Kurotani / Michitaka Notaguchi

last updated 2021/02/01 (Glycoforum. 2021 Vol.24 (1), A2)  
DOI: https://doi.org/10.32285/glycoforum.24A2

Grafting is a technique for cultivating plants that combines the advantages of two different plant species, and it has been used as an agricultural technique since ancient times. The cell wall surrounding the plant cell is an extracellular matrix composed of multiple polysaccharides, the composition of which depends on the plant species. Grafting is thought to occur when the cell walls of two grafted plants are reconstituted at their boundaries, resulting in cell or tissue adhesion. In this article, we will introduce the mechanism of artificial plant grafting and the similarity between grafting in nature and grafting in plants, focusing on the function of digestive enzymes of cellulose, the main component of cell walls. ...and more

Frontal affinity chromatography: A champion method to study informational glycans(Glycoforum. 2020 Vol.23 (2), A7)
Kenichi Kasai
A saccharide primer method as a novel tool for glycomics(Glycoforum. 2020 Vol.23 (1), A3)
Toshinori Sato
Functional regulation of glucose assimilation by N-glycan-binding activities of pancreatic α-amylase(2019 Vol.22 (4), A11)
Kimie Date
Insights into the key roles of chondroitin sulfate proteoglycans in cancer biology(2019 Vol.22 (3), A8)
Satomi Nadanaka / Hiroshi Kitagawa
Synthetic development of keratan sulfate-related ligand of C-type lectin Langerin, and its anti-inflammatory effects(2019 Vol.22 (1), A3)
Yasuhiko Kizuka / Naoyuki Taniguchi
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