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NCBI Bookshelf. Jarett Casale ; Jonathan S. Authors Jarett Casale 1 ; Jonathan S. Crane 2. Glycosaminoglycans GAGsalso known as mucopolysaccharides, are negatively-charged polysaccharide compounds. They are composed of repeating disaccharide units that are present in every mammalian tissue. Historically, the function of GAGs was thought to be limited to cell hydration and structural scaffolding.
However, evidence now suggests that GAGs play a key role in cell aling, which serves to modulate a vast amount of biochemical processes. The cellular organelles involved in the synthesis and modification of GAGs to their final, bioactive structure are numerous and differ based on the unique GAG synthesized. This section will provide an overview of the cellular mechanisms involved in GAG biosynthesis. It is important to note that unlike proteins and nucleic acids, GAG biosynthesis is a non-template driven process that occurs through the combined action of several tissue-specific enzymes.
The process of GAG biosynthesis begins in the cellular cytoplasm with the synthesis of five uridine diphosphate UDP derived activated sugars. Instead of undergoing modification and sulfation in the Golgi apparatus, the HA precursor sugars UDP-glucuronic acid and UDP- N -acetylglucosamine are transported from the cytoplasm to the plasma membrane for further processing without sulfation, which le to the production of HA.
The sulfated GAGs synthesized in the Golgi apparatus undergo covalent linkage to anchor proteins known as proteoglycans PGs. Keratan sulfate is the only sulfated GAG that is not linked to a PG protein core by this mechanism and is instead linked by various other compounds depending on the subtype of keratan sulfate, described in further detail below. Modification by epimerization of the resulting polysaccharide structures by enzymatic different types of gags is responsible for the production of the various molecular structures of GAGs and their resulting properties.
The molecular structures of individual Different types of gags are in the following section. The molecular structure of each of the major appears below. Instead, the structure consists of sequentially bound glucuronic acid and N -acetylglucosamine residues. Heparan sulfate HS and heparin Hep contain repeating disaccharide units of N -acetylglucosamine and hexuronic acid residues.
The hexuronic acid residue glucuronic acid is seen in heparan sulfate, while iduronic acid is present in heparin. Their disaccharide repeat consists of N -acetylgalactosamine and hexuronic acids — iduronic acid in CS and glucuronic acid in DS. They are tethered to a PG protein core via the same serine residue and tetrasaccharide linker as HS.
CS polysaccharide chains linked to carrier proteins range in their of repeat units from 10 to and are found both on cell surfaces and in the extracellular matrix. Keratan sulfate KS contains the disaccharide repeat consisting of galactose and N -acetylglucosamine. Sulfation patterns may be present on either unit of the disaccharide repeat of KS with increased frequency on the N -acetylglucosamine residue.
As ly mentioned, KS is the only sulfated GAG that is not connected to the PG protein core by a tetrasaccharide linker compound. KS type II chains are predominantly found in cartilage and utilize an N -acetylgalactosamine link via a serine or threonine residue.
KS type III are most frequency noted in brain tissue and use a mannose linker to the protein core via serine or threonine residues. Pathophysiological processes related to GAGs are very broad in range due to the ubiquitous nature of GAGs in the body. This section will describe how GAGs are involved in the pathophysiology of various infectious processes as well as a group of rare genetic diseases known as Mucopolysaccharidoses MPS related to the metabolism of GAGs. GAGs are very important to the infectious processes of various viral, bacterial, fungal, and parasitic pathogens.
The mechanisms by which these pathogens utilize GAGs to promote virulence varies based on the unique GAGs expressed in each organ system. When this outer layer of skin is compromised, pathogens can then invade and proliferate to cause infection using GAGs.
Due to the abundance of HA already present in the dermis and epidermis, the HA capsule of GAS prevents recognition and subsequent phagocytosis by host leukocytes. Mucopolysaccharidoses comprise a group of rare genetic diseases characterized by a deficiency of lysosomal enzymes required for the metabolism of GAGs.
Mucopolysaccharidoses manifest with variable symptoms depending on the dysfunctional enzyme and associated expression of affected GAG metabolism in different types of gags systems. Initial diagnostic steps of mucopolysaccharidoses following clinical suspicion include urinary GAG and enzyme assays. Confirmatory testing for mucopolysaccharidosis is via molecular diagnosis. ly, treatment for mucopolysaccharidoses had their basis around symptom management. However, both enzyme replacement therapy and hematopoietic stem cell transplantation have been successfully used to treat certain subgroups of mucopolysaccharidosis.
As ly mentioned, GAGs play an essential role in many physiological processes present throughout the body. The clinical ificance of each class of GAG will be summarized below. Note that the information provided is concise and is not intended to represent all physiological processes that involve GAGs. HA is ubiquitous in body tissues and is best-known for its capability of attracting water molecules. The highly polar structure of HA makes it capable of binding times its own weight in water. Due to this characteristic, it plays a key role in lubrication of synovial ts and wound healing processes.
Heparan sulfate is one of the most well-studied GAGs due to its many roles and potential use as a pharmacological target for cancer treatment. Noteworthy functions of heparan sulfate include extracellular matrix ECM organization and modulation of cellular growth factor aling by acting as a bridge between receptors and ligands.
In the extracellular matrix, heparan sulfate interacts with many compounds including collagen, different types of gags, and fibronectin to promote cell to cell and cell to extracellular matrix adhesion. In the setting of malignancy such as melanoma, degradation of heparan sulfate in the extracellular matrix by the action of the enzyme heparanase le to migration of malignant cells and metastasis.
This mechanism makes heparanase and heparan sulfate viable pharmacological targets for prevention of cancer metastasis. Heparan sulfate also plays a key role in cellular growth factor aling. One example of this role involves the interaction of heparan sulfate with fibroblast growth factor FGF and fibroblast growth factor receptor FGFR. Heparan sulfate facilitates the formation of FGF-FGFR complexes, resulting in a aling cascade that le to cellular proliferation. The degree of sulfation of heparan sulfate influences the formation of these complexes.
For example, the proliferation of melanoma cells gets stimulated by the action of highly sulfated heparan sulfate on FGF. Heparin represents the earliest recognized biological role of GAGs for its use as an anticoagulant. Differing molecular weights of heparin have been studied to exhibit various clinical anticoagulation intensity . Chondroitin sulfate is historically known for its clinical use as a disease-modifying osteoarthritis drug DMOAD.
Clinical trials have documented its potential for symptomatic pain relief as well as the structure-modifying effect in osteoarthritis OA based on radiographic t findings. The pain-relieving properties of chondroitin sulfate in OA relate to its anti-inflammatory properties that cause attenuation of the nuclear factor-kappa-B NF-kappa-B pathway that is overactive in OA.
One of the leading pathophysiological causes of OA relates to loss of chondroitin sulfate from articular cartilage in ts, leading to inflammation and catabolism of cartilage and subchondral bone.
The structure-modifying role of chondroitin sulfate in OA is due to its role in stimulating type II collagen and PG production in both articular cartilage and the synovial membrane. This anabolic effect of chondroitin sulfate prevents further tissue damage and remodeling of synovial tissues.
Keratan sulfate has been well-studied for its functional role in both the cornea and the nervous system.
The cornea comprises the richest known source of keratan sulfate in the body, followed by brain tissue. As with other GAGs, the degree of sulfation of keratan sulfate determines its functional status. Abnormal sulfation patterns of keratan sulfate due to specific genetic mutations result in increased opacity of the cornea and resulting visual disturbances. Keratan sulfate has also been shown to play an important regulatory role in the development of neural tissue. Various subgroups of keratan sulfate in the brain have key roles for stimulating the growth of microglial cells and the promotion of axonal repair following injury.
Abakan is an example of a type of keratan sulfate seen in brain different types of gags that serves to block neural attachment, which marks boundaries of neural growth in the developing brain. In conclusion, glycosaminoglycans GAGshave widespread functions within the body. They play a crucial role in the cell aling process, including regulation of cell growth, proliferation, promotion of cell adhesion, anticoagulation, and wound repair. This book is distributed under the terms of the Creative Commons Attribution 4.
Turn recording back on. National Center for Biotechnology InformationU. StatPearls [Internet]. Search term. Introduction Glycosaminoglycans GAGsalso known as mucopolysaccharides, are negatively-charged polysaccharide compounds. Cellular The cellular organelles involved in the synthesis and modification of GAGs to their final, bioactive structure are numerous and differ based on the unique GAG synthesized.
Infection GAGs are very important to the infectious processes of various viral, bacterial, fungal, and parasitic pathogens.
Clinical ificance As ly mentioned, GAGs play an essential role in many physiological processes present throughout the body. Hyaluronic Acid HA is ubiquitous in body tissues and is best-known for its capability of attracting water molecules. Comment on this article. Biochemistry, Glycosaminoglycans. In: StatPearls [Internet]. In this. Similar articles in PubMed. Review Bench-to-bedside review: the role of glycosaminoglycans in respiratory disease.
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