scholarly journals Investigation of the biological functions of heparan sulfate using a chemoenzymatic synthetic approach

2021 ◽  
Author(s):  
Zhangjie Wang ◽  
Katelyn Arnold ◽  
Vijay Manohar Dhurandhare ◽  
Yongmei Xu ◽  
Jian Liu
Keyword(s):  
Heparan Sulfate ◽  
Sulfated Polysaccharide ◽  
Synthetic Approach ◽  
Biological Functions ◽  
Animal Kingdom

Heparan sulfate (HS) is a highly sulfated polysaccharide playing essential physiological and pathophysiological roles in the animal kingdom.

scholarly journals The 3-O-sulfation of heparan sulfate modulates protein binding and lyase degradation

2021 ◽  
Vol 118 (3) ◽  
pp. e2012935118
Author(s):  
Pradeep Chopra ◽  
Apoorva Joshi ◽  
Jiandong Wu ◽  
Weigang Lu ◽  
Tejabhiram Yadavalli ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Binding Proteins ◽  
Factor Xa ◽  
Tissue Expression ◽  
Cell Entry ◽  
Synthetic Approach ◽  
Array Technology ◽  
Wide Range ◽  
Simplex Virus

Humans express seven heparan sulfate (HS) 3-O-sulfotransferases that differ in substrate specificity and tissue expression. Although genetic studies have indicated that 3-O-sulfated HS modulates many biological processes, ligand requirements for proteins engaging with HS modified by 3-O-sulfate (3-OS) have been difficult to determine. In particular, the context in which the 3-OS group needs to be presented for binding is largely unknown. We describe herein a modular synthetic approach that can provide structurally diverse HS oligosaccharides with and without 3-OS. The methodology was employed to prepare 27 hexasaccharides that were printed as a glycan microarray to examine ligand requirements of a wide range of HS-binding proteins. The binding selectivity of antithrombin-III (AT-III) compared well with anti-Factor Xa activity supporting robustness of the array technology. Many of the other examined HS-binding proteins required an IdoA2S-GlcNS3S6S sequon for binding but exhibited variable dependence for the 2-OS and 6-OS moieties, and a GlcA or IdoA2S residue neighboring the central GlcNS3S. The HS oligosaccharides were also examined as inhibitors of cell entry by herpes simplex virus type 1, which, surprisingly, showed a lack of dependence of 3-OS, indicating that, instead of glycoprotein D (gD), they competitively bind to gB and gC. The compounds were also used to examine substrate specificities of heparin lyases, which are enzymes used for depolymerization of HS/heparin for sequence determination and production of therapeutic heparins. It was found that cleavage by lyase II is influenced by 3-OS, while digestion by lyase I is only affected by 2-OS. Lyase III exhibited sensitivity to both 3-OS and 2-OS.

scholarly journals Chemical synthesis of human syndecan-4 glycopeptide bearing O-, N-sulfation and multiple aspartic acids for probing impacts of the glycan chain and the core peptide on biological functions

2020 ◽  
Vol 11 (25) ◽  
pp. 6393-6404 ◽  
Author(s):  
Weizhun Yang ◽  
Yigitcan Eken ◽  
Jicheng Zhang ◽  
Logan Emerson Cole ◽  
Sherif Ramadan ◽  
...  
Keyword(s):  
Chemical Synthesis ◽  
Heparan Sulfate ◽  
Biological Functions ◽  
Peptide Backbone ◽  
The Core ◽  
Glycan Chain ◽  
Core Peptide

Attaching heparan sulfate glycan on a peptide backbone can modulate biological functions of the glycan.

Synthetic heparin and heparan sulfate: probes in defining biological functions

2017 ◽  
Vol 40 ◽  
pp. 152-159 ◽  
Author(s):  
Ching-Ting Tsai ◽  
Medel Manuel L Zulueta ◽  
Shang-Cheng Hung
Keyword(s):  
Heparan Sulfate ◽  
Biological Functions

Heparanase: Structure, Biological Functions, and Inhibition by Heparin-Derived Mimetics of Heparan Sulfate

2007 ◽  
Vol 13 (20) ◽  
pp. 2057-2073 ◽  
Author(s):  
Israel Vlodavsky ◽  
Neta Ilan ◽  
Annamaria Naggi ◽  
Benito Casu
Keyword(s):  
Heparan Sulfate ◽  
Biological Functions

scholarly journals The Dominating Role of N-Deacetylase/N-Sulfotransferase 1 in Forming Domain Structures in Heparan Sulfate

2011 ◽  
Vol 286 (22) ◽  
pp. 19768-19776 ◽  
Author(s):  
Juzheng Sheng ◽  
Renpeng Liu ◽  
Yongmei Xu ◽  
Jian Liu
Keyword(s):  
Cell Growth ◽  
Substrate Specificity ◽  
Heparan Sulfate ◽  
Blood Coagulation ◽  
Sulfated Polysaccharide ◽  
Physiological Functions ◽  
Domain Structures

Heparan sulfate (HS) is a highly sulfated polysaccharide participated in essential physiological functions from regulating cell growth to blood coagulation. HS contains sulfated domains known as N-S domains and low sulfate domains known as N-Ac domains. The distribution of the domain structures is likely governed by the action of glucosaminyl N-deacetylase/N-sulfotransferase (NDST). Here, we sought to determine the substrate specificity of NDST using model substrates and recombinant NDST protein. We discovered that NDST-1 carries out the modification in a highly ordered fashion. The enzyme sulfates the substrate from the nonreducing end toward the reducing end consecutively, leading to the product with a cluster of N-sulfo glucosamine residues. Furthermore, a preexisting N-sulfo glucosamine residue prevents the action of NDST-1 at the residues immediately located at the nonreducing end, allowing the formation of an N-Ac domain. Our results provide the long sought evidence for understanding the formation of sulfated versus nonsulfated domains in the HS isolated from cells and tissues. The study demonstrates the regulating role of NDST-1 in mapping the sulfation patterns of HS.

scholarly journals Biochemical and ultrastructural studies of proteoheparan sulfates synthesized by PYS-2, a basement membrane-producing cell line.

1982 ◽  
Vol 92 (2) ◽  
pp. 357-367 ◽  
Author(s):  
A Oohira ◽  
T N Wight ◽  
J McPherson ◽  
P Bornstein
Keyword(s):  
Basement Membrane ◽  
Heparan Sulfate ◽  
Cell Line ◽  
Molecular Size ◽  
Sulfated Polysaccharide ◽  
Ruthenium Red ◽  
Basement Membranes ◽  
Gel Chromatography ◽  
Ultrastructural Studies ◽  
Type Iv

The mouse teratocarcinoma-derived cell line, PYS-2, has been shown to produce laminin, a basement membrane-specific glycoprotein. In these studies we demonstrate that PYS-2 cells synthesize and secrete into the culture medium a proteoglycan which contains only heparan sulfate as its sulfated polysaccharide side chains, as well as type IV procollagen and laminin. The apparent molecular weights of the proteoglycan and its heparan sulfate side chain were estimated to be 400,000 and 25,000, respectively, by gel chromatography. A proteoheparan sulfate with properties closely similar, if not identical, to those of the proteoglycan in the medium, together with two heparan sulfate single chains of different molecular size, were extracted from the cell layer with 2% SDS in the presence of protease inhibitors. Ultrastructurally, a fine fibrillar intercellular matrix was recognized which contained discrete 100-200 A diameter ruthenium red-positive granules interspersed throughout the filamentous meshwork. The PYS-2 cultures were shown by immunofluorescence to react with antibodies against the heparan sulfate-containing proteoglycan isolated from the mouse EHS sarcoma (Hassell, J. R., P. G. Robey, H. J. Barrach, J. Wilczek, S. I. Rennard, and G. R. Martin. 1980. Proc. Natl. Acad. Sci. U. S. A. 77:4494-4498). Immunoelectron microscopic examination, using the same antibodies, revealed that the proteoheparan sulfate was located not only at the edges but also within the interstices of the matrix. These findings indicate that PYS-2 cells synthesize and secrete a proteoglycan with properties similar to those of basement membrane proteoglycan. These cells may therefore serve as a useful model system for the study of the biosynthesis and structure of basement membranes.

Heparan sulfate glycomics: towards systems biology strategies

2010 ◽  
Vol 38 (5) ◽  
pp. 1356-1360 ◽  
Author(s):  
Jeremy E. Turnbull
Keyword(s):  
Systems Biology ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Biological Functions ◽  
Combined Application ◽  
Cellular Events ◽  
Structure Activity ◽  
Future Potential ◽  
Heparan Sulfates ◽  
Molecular Code

HSs (heparan sulfates) are a complex family of cell-surface and matrix polysaccharides that have diverse biological functions, underpinned by structurally diverse patterns of backbone chain modification, especially by sulfate groups. These variant structures represent a molecular code, the ‘heparanome’, that confers the ability to interact selectively with a wide interactome of proteins, the ‘heparactome’, and thereby influence a network of cellular events. It is becoming increasingly apparent that understanding the structure–activity relationships of these enigmatic molecules requires the development of a holistic systems biology view of their structure and interactions. In the present paper, I describe some of the new tools available to realize this strategy, and discuss the future potential for the combined application of glycomics and other ‘-omics’ approaches to define the molecular code of the heparanome.

scholarly journals VEGF: an Essential Mediator of Both Angiogenesis and Endochondral Ossification

2007 ◽  
Vol 86 (10) ◽  
pp. 937-950 ◽  
Author(s):  
J. Dai ◽  
A.B.M. Rabie
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Heparan Sulfate ◽  
Endochondral Ossification ◽  
Transforming Growth Factor ◽  
Heparan Sulfate Proteoglycans ◽  
Vascular Endothelial ◽  
Biological Functions ◽  
Placenta Growth Factor ◽  
Endothelial Growth Factor

During bone growth, development, and remodeling, angiogenesis as well as osteogenesis are closely associated processes, sharing some essential mediators. Vascular endothelial growth factor (VEGF) was initially recognized as the best-characterized endothelial-specific growth factor, which increased vascular permeability and angiogenesis, and it is now apparent that this cytokine regulates multiple biological functions in the endochondral ossification of mandibular condylar growth, as well as long bone formation. The complexity of VEGF biology is paralleled by the emerging complexity of interactions between VEGF ligands and their receptors. This narrative review summarizes the family of VEGF-related molecules, including 7 mammalian members, namely, VEGF, placenta growth factor (PLGF), and VEGF-B, -C, -D, -E, and -F. The biological functions of VEGF are mediated by at least 3 corresponding receptors: VEGFR-1/Flt-1, VEGFR-2/Flk-1, VEGFR-3/Flt-4 and 2 co-receptors of neuropilin (NRP) and heparan sulfate proteoglycans (HSPGs). Current findings on endochondral ossification are also discussed, with emphasis on VEGF-A action in osteoblasts, chondroblasts, and chondroclasts/osteoclasts and regulatory mechanisms involving oxygen tension, and some growth factors and hormones. Furthermore, the therapeutic implications of recombinant VEGF-A protein therapy and VEGF-A gene therapy are evaluated. Abbreviations used: VEGF, Vascular endothelial growth factor; PLGF, placenta growth factor; NRP, neuropilin; HSPGs, heparan sulfate proteoglycans; FGF, fibroblast growth factor; TGF, transforming growth factor; HGF, hepatocyte growth factor; TNF, tumor necrosis factor; ECM, extracellular matrix; RTKs, receptor tyrosine kinases; ERK, extracellular signal kinases; HIF, hypoxia-inducible factor

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