-
Organic & Biomolecular Chemistry Jul 2017Heparin and heparan sulfate glycosaminoglycans are long, linear polysaccharides that are made up of alternating dissacharide sequences of sulfated uronic acid and amino... (Review)
Review
Heparin and heparan sulfate glycosaminoglycans are long, linear polysaccharides that are made up of alternating dissacharide sequences of sulfated uronic acid and amino sugars. Unlike heparin, which is only found in mast cells, heparan sulfate is ubiquitously expressed on the cell surface and in the extracellular matrix of all animal cells. These negatively-charged glycans play essential roles in important cellular functions such as cell growth, adhesion, angiogenesis, and blood coagulation. These biomolecules are also involved in pathophysiological conditions such as pathogen infection and human disease. This review discusses past and current methods for targeting these complex biomolecules as a novel therapeutic strategy to treating disorders such as cancer, neurodegenerative diseases, and infection.
Topics: Animals; Glycosaminoglycans; Heparin; Heparitin Sulfate; Humans; Infections; Neoplasms; Neurodegenerative Diseases; Small Molecule Libraries
PubMed: 28653068
DOI: 10.1039/c7ob01058c -
The Journal of Histochemistry and... Jan 2021The biosynthesis of heparan sulfate (HS) proteoglycans occurs in the Golgi compartment of cells and will determine the sulfation pattern of HS chains, which in turn will... (Review)
Review
The biosynthesis of heparan sulfate (HS) proteoglycans occurs in the Golgi compartment of cells and will determine the sulfation pattern of HS chains, which in turn will have a large impact on the biological activity of the proteoglycans. Earlier studies in mice have demonstrated the importance of HS for embryonic development. In this review, the enzymes participating in zebrafish HS biosynthesis, along with a description of enzyme mutants available for functional studies, are presented. The consequences of the zebrafish genome duplication and maternal transcript contribution are briefly discussed as are the possibilities of CRISPR/Cas9 methodologies to use the zebrafish model system for studies of biosynthesis as well as proteoglycan biology.
Topics: Animals; Biosynthetic Pathways; CRISPR-Cas Systems; Glycosyltransferases; Heparitin Sulfate; Mutation; Sulfotransferases; Zebrafish; Zebrafish Proteins
PubMed: 33216642
DOI: 10.1369/0022155420973980 -
International Journal of Molecular... Oct 2022β-cells in the islets of Langerhans of the pancreas secrete insulin in response to the glucose concentration in the blood. When these pancreatic β-cells are damaged,... (Review)
Review
β-cells in the islets of Langerhans of the pancreas secrete insulin in response to the glucose concentration in the blood. When these pancreatic β-cells are damaged, diabetes develops through glucose intolerance caused by insufficient insulin secretion. High molecular weight polysaccharides, such as heparin and heparan sulfate (HS) proteoglycans, and HS-degrading enzymes, such as heparinase, participate in the protection, maintenance, and enhancement of the functions of pancreatic islets and β-cells, and the demand for studies on glycobiology within the field of diabetes research has increased. This review introduces the roles of complex glycoconjugates containing high molecular weight polysaccharides and their degrading enzymes in pancreatic islets and β-cells, including those obtained in studies conducted by us earlier. In addition, from the perspective of glycobiology, this study proposes the possibility of application to diabetes medicine.
Topics: Heparan Sulfate Proteoglycans; Heparin Lyase; Heparitin Sulfate; Islets of Langerhans; Insulin; Heparin; Glucose
PubMed: 36292936
DOI: 10.3390/ijms232012082 -
Journal of the Royal Society, Interface Sep 2015Heparan sulfate (HS) polysaccharides are ubiquitous components of the cell surface and extracellular matrix of all multicellular animals, whereas heparin is present... (Review)
Review
Heparan sulfate (HS) polysaccharides are ubiquitous components of the cell surface and extracellular matrix of all multicellular animals, whereas heparin is present within mast cells and can be viewed as a more sulfated, tissue-specific, HS variant. HS and heparin regulate biological processes through interactions with a large repertoire of proteins. Owing to these interactions and diverse effects observed during in vitro, ex vivo and in vivo experiments, manifold biological/pharmacological activities have been attributed to them. The properties that have been thought to bestow protein binding and biological activity upon HS and heparin vary from high levels of sequence specificity to a dependence on charge. In contrast to these opposing opinions, we will argue that the evidence supports both a level of redundancy and a degree of selectivity in the structure-activity relationship. The relationship between this apparent redundancy, the multi-dentate nature of heparin and HS polysaccharide chains, their involvement in protein networks and the multiple binding sites on proteins, each possessing different properties, will also be considered. Finally, the role of cations in modulating HS/heparin activity will be reviewed and some of the implications for structure-activity relationships and regulation will be discussed.
Topics: Animals; Binding Sites; Heparin; Heparitin Sulfate; Humans; Mast Cells; Proteins; Structure-Activity Relationship
PubMed: 26289657
DOI: 10.1098/rsif.2015.0589 -
American Journal of Physiology. Cell... Jun 2022Heparan sulfate is a widely expressed polysaccharide in the extracellular matrix and on the cell surface. 3--sulfated heparan sulfate represents only a small percentage... (Review)
Review
Heparan sulfate is a widely expressed polysaccharide in the extracellular matrix and on the cell surface. 3--sulfated heparan sulfate represents only a small percentage of heparan sulfate from biological sources. However, this subpopulation is closely associated with biological functions of heparan sulfate. The 3--sulfated heparan sulfate is biosynthesized by heparan sulfate 3--sulfotransferase, which exists in seven different isoforms. This review article summarizes the recent progress in the substrate specificity studies of different 3--sulfotransferase isoforms involving the use of homogeneous oligosaccharide substrates and crystal structural analysis. The article also reviews a newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method to analyze the level of 3--sulfated heparan sulfate with high sensitivity and quantitative capability. This newly emerged technology will provide new tools to study the structure and function relationship of heparan sulfate.
Topics: Chromatography, Liquid; Heparitin Sulfate; Protein Isoforms; Sulfates; Sulfotransferases; Tandem Mass Spectrometry
PubMed: 35417268
DOI: 10.1152/ajpcell.00110.2022 -
Seminars in Thrombosis and Hemostasis Apr 2021Cell surface proteoglycans are important constituents of the glycocalyx and participate in cell-cell and cell-extracellular matrix (ECM) interactions, enzyme activation... (Review)
Review
Cell surface proteoglycans are important constituents of the glycocalyx and participate in cell-cell and cell-extracellular matrix (ECM) interactions, enzyme activation and inhibition, and multiple signaling routes, thereby regulating cell proliferation, survival, adhesion, migration, and differentiation. Heparanase, the sole mammalian heparan sulfate degrading endoglycosidase, acts as an "activator" of HS proteoglycans, thus regulating tissue hemostasis. Heparanase is a multifaceted enzyme that together with heparan sulfate, primarily syndecan-1, drives signal transduction, immune cell activation, exosome formation, autophagy, and gene transcription via enzymatic and nonenzymatic activities. An important feature is the ability of heparanase to stimulate syndecan-1 shedding, thereby impacting cell behavior both locally and distally from its cell of origin. Heparanase releases a myriad of HS-bound growth factors, cytokines, and chemokines that are sequestered by heparan sulfate in the glycocalyx and ECM. Collectively, the heparan sulfate-heparanase axis plays pivotal roles in creating a permissive environment for cell proliferation, differentiation, and function, often resulting in the pathogenesis of diseases such as cancer, inflammation, endotheliitis, kidney dysfunction, tissue fibrosis, and viral infection.
Topics: Disease; Glucuronidase; Heparitin Sulfate; Humans
PubMed: 33794549
DOI: 10.1055/s-0041-1725066 -
Advanced Drug Delivery Reviews Feb 2016Heparin and heparan sulfates are closely related linear anionic polysaccharides, called glycosaminoglycans, which exhibit a number of important biological and... (Review)
Review
Heparin and heparan sulfates are closely related linear anionic polysaccharides, called glycosaminoglycans, which exhibit a number of important biological and pharmacological activities. These polysaccharides, having complex structures and polydispersity, are biosynthesized in the Golgi of animal cells. While heparan sulfate is a widely distributed membrane and extracellular glycosaminoglycan, heparin is found primarily intracellularly in the granules of mast cells. While heparin has historically received most of the scientific attention for its anticoagulant activity, interest has steadily grown in the multi-faceted role heparan sulfate plays in normal and pathophysiology. The chemical synthesis of these glycosaminoglycans is largely precluded by their structural complexity. Today, we depend on livestock animal tissues for the isolation and the annual commercial production of hundred ton quantities of heparin used in the manufacture of anticoagulant drugs and medical device coatings. The variability of animal-sourced heparin and heparan sulfates, their inherent impurities, the limited availability of source tissues, the poor control of these source materials and their manufacturing processes, suggest a need for new approaches for their production. Over the past decade there have been major efforts in the biotechnological production of these glycosaminoglycans, driven by both therapeutic applications and as probes to study their natural functions. This review focuses on the complex biology of these glycosaminoglycans in human health and disease, and the use of recombinant technology in the chemoenzymatic synthesis and metabolic engineering of heparin and heparan sulfates.
Topics: Animals; Biomedical Engineering; Heparin; Heparitin Sulfate; Humans
PubMed: 26555370
DOI: 10.1016/j.addr.2015.11.002 -
Cells Oct 2022Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, and its management places a huge burden on healthcare systems through... (Review)
Review
Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, and its management places a huge burden on healthcare systems through hospitalisation and treatment. Atherosclerosis is a chronic inflammatory disease of the arterial wall resulting in the formation of lipid-rich, fibrotic plaques under the subendothelium and is a key contributor to the development of CVD. As such, a detailed understanding of the mechanisms involved in the development of atherosclerosis is urgently required for more effective disease treatment and prevention strategies. Heparanase is the only mammalian enzyme known to cleave heparan sulfate of heparan sulfate proteoglycans, which is a key component of the extracellular matrix and basement membrane. By cleaving heparan sulfate, heparanase contributes to the regulation of numerous physiological and pathological processes such as wound healing, inflammation, tumour angiogenesis, and cell migration. Recent evidence suggests a multifactorial role for heparanase in atherosclerosis by promoting underlying inflammatory processes giving rise to plaque formation, as well as regulating lesion stability. This review provides an up-to-date overview of the role of heparanase in physiological and pathological processes with a focus on the emerging role of the enzyme in atherosclerosis.
Topics: Animals; Humans; Heparan Sulfate Proteoglycans; Glucuronidase; Heparitin Sulfate; Atherosclerosis; Plaque, Atherosclerotic; Lipids; Mammals
PubMed: 36291066
DOI: 10.3390/cells11203198 -
Romanian Journal of Ophthalmology 2017The extracellular matrix (ECM) is responsible for many of the cell behavior processes, including cell proliferation and growth, survival, change in cell shape,... (Review)
Review
The extracellular matrix (ECM) is responsible for many of the cell behavior processes, including cell proliferation and growth, survival, change in cell shape, migration, and differentiation. The most important component of the ECM is heparan sulfate (HS), because it insures the storage of many cell communication proteins, necessary for the continuous and identical renewal of cells and thus for tissue regeneration. Regenerating agents (RGTA®) are bioengineered structural analogues of heparan sulfate glycosaminoglycans that replace the degraded endogenous HS of the ECM. In the ophthalmological field, RGTA® represents an innovative approach for the improvement of the ocular surface wound healing and matrix remodeling and plays a role in controlling and regulating the wound healing process in various ocular diseases.
Topics: Biomimetic Materials; Cell- and Tissue-Based Therapy; Corneal Diseases; Extracellular Matrix; Guided Tissue Regeneration; Heparitin Sulfate; Humans; Regenerative Medicine; Tissue Engineering; Wound Healing
PubMed: 29450364
DOI: 10.22336/rjo.2017.2 -
Matrix Biology : Journal of the... Apr 2014Heparan sulfate proteoglycans (HSPG) are present on the cell surface, within the extracellular matrix, and as soluble molecules in tissues and blood. HSPGs are known to... (Review)
Review
Heparan sulfate proteoglycans (HSPG) are present on the cell surface, within the extracellular matrix, and as soluble molecules in tissues and blood. HSPGs are known to regulate a wide range of cellular functions predominantly by serving as co-receptors for growth factors, chemokines, and other regulatory proteins that control inflammation, wound healing and tumorigenesis. Several studies have demonstrated the presence of heparan sulfate (HS) or HSPGs in the cell nucleus, but little attention has been focused on their role there. However, evidence is mounting that nuclear HS and HSPGs have important regulatory functions that impact the cell cycle, proliferation, transcription and transport of cargo to the nucleus. The discovery of proteoglycans in the nucleus extends the list of "non-traditional nuclear proteins" that includes, for example, cytoskeletal proteins such as actin and tubulin, and growth factors and their receptors. In this review we discuss the discovery and fascinating roles of HS and HSPGs in the nucleus and propose a number of key questions that remain to be addressed.
Topics: Active Transport, Cell Nucleus; Animals; Cell Cycle; Cell Nucleus; Cell Physiological Phenomena; Cell Proliferation; Chromatin Assembly and Disassembly; Extracellular Matrix; Gene Expression Regulation; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans
PubMed: 24309018
DOI: 10.1016/j.matbio.2013.10.009