HEPARAN SULFATE: FUNCTIONS, SYNTHESIS, RELATIONSHIP WITH DISEASES - BIOLOGY - 2025

The heparan sulfate is an extracellular matrix proteoglycan. In addition, it exists on the cell surface of various cells, including cutaneous fibroblasts and the wall of the aorta. Heparan sulfate can be found in free form or by creating a variety of heparan sulfate proteoglycans (HSPG).

Among the HSPGs that are known are those that are part of cell membranes (syndecanes), those that are anchored to the cell membrane (glypicans) and those that constitute the extracellular matrix (perlecan, agrin, and collagen XVIII).

Chemical structure of heparan sulfate: Source: Roland Mattern

Heparan sulfate, like heparin, is part of the glycosaminoglycan family. In fact, they are structurally very similar, but small differences make them have different functions.

It is composed of abundant D-glucuronic acid units with subunits of N-acetylglucosamine repeatedly and alternately. It also contains D-glucosamine residues that can be sulfated or acetylated.

Heparan sulfate is able to bind very specifically to certain proteins, these being called HSBP for its acronym in English (Heparan Sulfate-Binding Proteins).

HSBPs are a heterogeneous set of proteins, each one related to different physiological processes such as: the immune system, the structural proteins of the extracellular matrix, cell coupling, morphogenesis, lipid metabolism or cell repair, among others.

In this sense, some of the structures that bind to heparan sulfate can be mentioned: cytokines, chemokines, coagulation factors, growth factors, complement proteins, collagen fibers, vitronectin, fibronectin, transmembrane receptors (TLR4) or proteins. cell adhesion, among others.

Features

Heparan sulfate in the extracellular matrix is ​​capable of interacting with various molecules, such as proteins of the matrix itself and growth factors.

Heparan sulfate is said to act as 1) free 2) or attached to HSBPs in the extracellular matrix or on the surface of cell membranes, depending on circumstances and needs.

When it acts freely, it fragments adopting a soluble form. Heparan sulfate is useful in inflammation or in tissue damage processes, so that it contributes to tissue repair under physiological conditions.

At the dendritic cell level, it is capable of binding and activating TLR4 receptors. This triggers the dendritic cell to mature and perform its functions as an antigen-presenting cell.

Cardiac fibroblasts also possess these receptors and at this level their activation promotes the increase in interleukin -1ß (IL1- ß) and the expression of ICAM-1 and VCAM-1 receptors. This shows that it actively participates in the repair of cardiac tissue.

On the other hand, heparan sulfate protects the integrity of the vascular endothelium. Among the most prominent actions at this level are: it regulates the amount of lipids in the endothelium, stores growth factors and participates in the binding of the enzyme superoxide dismutase on the endothelium (antioxidant action).

All of these functions prevent protein extravasation into the extravascular space.

Synthesis

Heparan sulfate is synthesized by most cells, especially fibroblasts.

However, it is believed that the endothelial cells of the vascular wall play a fundamental role in the regulation of coagulation and thrombotic processes.

It has been seen that many of its actions have to do with the inhibition of platelet aggregation and activation and dissolution of the clot by the activation of plasminogen.

Therefore, it is believed that these cells synthesize at least 5 types of heparan sulfate and some of them bind to certain clotting factors. Among the enzymes involved in the synthesis of heparan sulfate are glycosyltransferases, sulfotransferases, and epimerase.

Heparan sulfate and cancer

Both heparan sulfate and heparan sulfate proteoglycans (HSPG) are involved in various mechanisms that promote some oncogenic pathologies.

In addition, it has been seen that there is an overexpression of HSPG in cells of breast, pancreas or colon cancer, among others.

Among the factors involved are, disorders in the biosynthesis of heparan sulfate and HSGP, structural changes of both molecules, intervention in the regulation of apoptosis, stimulation of the evasion of the immune system, increased synthesis of heparanases.

Biosynthesis disorders and structural changes

It is believed that a disorder in heparan sulfate biosynthesis or structural changes in HSPGs may influence the development and progression of certain types of neoplasms and solid tumors.

One of the mechanisms of oncogenic induction is the overstimulation of fibroblast growth factor receptors by modified HSPG; thus increasing the mitotic capacity and DNA synthesis of cancer cells (tumor angiogenesis).

Likewise, it acts on the stimulation of platelet-derived growth factor receptors, with similar consequences.

Regulation of apoptosis

Heparan sulfate and HSPGs have also been found to play a critical role in the regulation of cell apoptosis, as well as cell senescence (aging).

Evasion of the immune system

Another mechanism involved is the ability to suppress the cellular response, favoring tumor progression due to the evasion of the immune system.

Furthermore, heparan sulfate proteoglycans can serve as biomarkers of the presence of cancer and in turn can be used as a target for immunotherapy with specific antibodies or other drugs.

They also influence innate immunity, as it is known that NK cells are activated against cancer cells when they bind to HSGPs, through the recognition of ligand by the natural cytotoxic receptor (NCR).

However, cancer cells promote an increase in heparanase enzymes, resulting in decreased interaction of the NK killer cell receptors with HSGP (NCR-HSPG).

Increased cell differentiation

Finally, the structures of heparan sulfate and modified HSPG are related to the state of cellular differentiation. Cells that overexpress modified heparan sulfate molecules are known to decrease the ability to differentiate and increase the ability to proliferate.

Degradation of heparan sulfate

Increased synthesis of certain enzymes, such as heparanases, metalloproteinases, as well as the action of reactive oxygen species and leukocytes, act by degrading both heparan sulfate and HSPG.

Increased heparanas destroys the integrity of the endothelium and increases the likelihood of cancer metastasis.

Virus receptor

It is believed that heparan sulfate peptidoglycan may be involved in the binding of HPV virus to the cell surface. However, there are still many controversies about it.

In the case of herpesvirus, the picture is much clearer. Herpesvirus has surface proteins called VP7 and VP8 that bind to heparan sulfate residues on the cell surface. Subsequently, the fusion occurs.

On the other hand, in dengue infection, the binding of the virus to the cell is favored by the negative charges that heparan sulfate possesses, which attracts the virus.

This is used as a coreceptor, facilitating the approach of the virus to the cell surface, to later bind to a receptor that allows the virus to enter the cell (endocytosis).

A similar mechanism occurs in the case of respiratory syncytial virus, since the virus's surface G protein binds to heparan sulfate, and then binds to the chemokine receptor (CX3CR1). This is how the virus manages to enter the host cell.

Heparan sulfate and its relationship with Alzheimer's and Parkinson's disease

In the study of these diseases, researchers have found that there is an intracellular degradation or alteration of the fibrils of the Tau protein, when they bind to heparan sulfate peptidoglycans.

The mechanism appears to be similar to the degradation produced by prions. This causes neurodegenerative disorders called tauopathies and synucleopathies, such as Alzheimer's, Pick's disease, Parkinson's or Huntington's disease, among others.

References

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