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

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.

Download Full-text

Design and synthesis of structurally defined heparan sulfate (HS)-FK506 conjugates as an exogenous approach to investigate biological functions of nucleus HS

Bioorganic Chemistry ◽

10.1016/j.bioorg.2018.08.015 ◽

2018 ◽

Vol 81 ◽

pp. 203-210

Author(s):

MaoLin Li ◽

SiSi. Yuan ◽

Jian Chen ◽

Li Lv ◽

ShiYin Guo ◽

...

Keyword(s):

Heparan Sulfate ◽

Biological Functions ◽

Design And Synthesis

Download Full-text

VEGF: an Essential Mediator of Both Angiogenesis and Endochondral Ossification

Journal of Dental Research ◽

10.1177/154405910708601006 ◽

2007 ◽

Vol 86 (10) ◽

pp. 937-950 ◽

Cited By ~ 229

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

Download Full-text

Chemoenzymatic synthesis of heparan sulfate and heparin

Natural Product Reports ◽

10.1039/c4np00076e ◽

2014 ◽

Vol 31 (12) ◽

pp. 1676-1685 ◽

Cited By ~ 112

Author(s):

Jian Liu ◽

Robert J. Linhardt

Keyword(s):

Heparan Sulfate ◽

High Efficiency ◽

Chemoenzymatic Synthesis ◽

Biological Functions ◽

Wide Range

Heparin and heparan sulfate are sulfated carbohydrates that display a wide range of biological functions. A chemoenzymatic method is becoming a promising approach to synthesize heparin-like oligosaccharides with high efficiency.

Download Full-text

Heparan Sulfate Proteoglycans Biosynthesis and Post Synthesis Mechanisms Combine Few Enzymes and Few Core Proteins to Generate Extensive Structural and Functional Diversity

Molecules ◽

10.3390/molecules25184215 ◽

2020 ◽

Vol 25 (18) ◽

pp. 4215

Author(s):

Thibault Annaval ◽

Rebekka Wild ◽

Yoann Crétinon ◽

Rabia Sadir ◽

Romain R. Vivès ◽

...

Keyword(s):

Heparan Sulfate ◽

Structural Complexity ◽

Heparan Sulfate Proteoglycans ◽

Biological Functions ◽

Concerted Action ◽

Post Translational Modification ◽

Structural Variety ◽

Core Proteins ◽

Post Synthesis ◽

Ubiquitous Presence

Glycosylation is a common and widespread post-translational modification that affects a large majority of proteins. Of these, a small minority, about 20, are specifically modified by the addition of heparan sulfate, a linear polysaccharide from the glycosaminoglycan family. The resulting molecules, heparan sulfate proteoglycans, nevertheless play a fundamental role in most biological functions by interacting with a myriad of proteins. This large functional repertoire stems from the ubiquitous presence of these molecules within the tissue and a tremendous structural variety of the heparan sulfate chains, generated through both biosynthesis and post synthesis mechanisms. The present review focusses on how proteoglycans are “gagosylated” and acquire structural complexity through the concerted action of Golgi-localized biosynthesis enzymes and extracellular modifying enzymes. It examines, in particular, the possibility that these enzymes form complexes of different modes of organization, leading to the synthesis of various oligosaccharide sequences.

Download Full-text

Sulfation Code and Conformational Plasticity of l-Iduronic Acid Homo-Oligosaccharides Mimic the Biological Functions of Heparan Sulfate

ACS Chemical Biology ◽

10.1021/acschembio.1c00582 ◽

2021 ◽

Author(s):

Chethan D. Shanthamurthy ◽

Ana Gimeno ◽

Shani Leviatan Ben-Arye ◽

Nanjundaswamy Vijendra Kumar ◽

Prashant Jain ◽

...

Keyword(s):

Heparan Sulfate ◽

Biological Functions ◽

Iduronic Acid ◽

Conformational Plasticity

Download Full-text

Antiresorptive activity of osteoprotegerin requires an intact heparan sulfate-binding site

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2005859117 ◽

2020 ◽

Vol 117 (29) ◽

pp. 17187-17194 ◽

Cited By ~ 1

Author(s):

Miaomiao Li ◽

Ding Xu

Keyword(s):

Heparan Sulfate ◽

Biological Significance ◽

Bone Homeostasis ◽

Biological Functions ◽

Factor B ◽

Normal Bone ◽

Receptor Activator ◽

Bind Cell Surface ◽

Terminal Domains

Osteoprotegerin (OPG), a secreted decoy receptor for receptor activator of nuclear factor B ligand (RANKL), plays an essential role in regulating bone resorption. While much is known about the function of the N-terminal domains of OPG, which is responsible for binding to RANKL, the exact biological functions of the three C-terminal domains of OPG remain uncertain. We have previously shown that one likely function of the C-terminal domains of OPG is to bind cell surface heparan sulfate (HS), but the in vivo evidence was lacking. To investigate the biological significance of OPG–HS interaction in bone remodeling, we created OPG knock-in mice (opgAAA). The mutated OPG is incapable of binding to HS but binds RANKL normally. Surprisingly,opgAAA/AAAmice displayed a severe osteoporotic phenotype that is very similar toopg-null mice, suggesting that the antiresorption activity of OPG requires HS. Mechanistically, we propose that the HS immobilizes secreted OPG at the surface of osteoblasts lineage cells, which facilitates binding of OPG to membrane-anchored RANKL. To further support this model, we altered the structure of osteoblast HS genetically to make it incapable of binding to OPG. Interestingly,osteocalcin-Cre;Hs2stf/fmice also displayed osteoporotic phenotype with similar severity toopgAAA/AAAmice. Combined, our data provide strong genetic evidence that OPG–HS interaction is indispensable for normal bone homeostasis.

Download Full-text