Posts Tagged ‘mucopolysaccharidoses’

Glycosaminoglycans, Mucopolysaccharides, L-iduronidase, Enzyme Therapy

Author and Curator: Larry H. Bernstein, MD, FCAP 


This is a portion of the discussion on carbohydrate metabolism that addresses complex carbohydrates, except for the cytoskeleton, but does involve the lysosomal function and storage diseases.

L-Iduronic acid is the major uronic acid component of the glycosaminoglycans dermatan sulfate, and heparin. It is also present in heparan sulfate although here in a minor amount relative to its carbon-5 epimer glucuronic acid.

Complex sugar structures

Carbohydrates form complex structures from glucose, galactose, and other sugars.  An amino sugar substitutes an amino group for one of the hydroxyls. An example is glucosamine. The amino group may be acetylated.  N-acetylneuraminate, (N-acetylneuraminic acid, also called sialic acid) is often found as a terminal residue of oligosaccharide chains of glycoproteins. Sialic acid imparts a negative charge to glycoproteins because its carboxyl group tends to dissociate a proton at physiological pH.

Glycosidic bonds: The anomeric hydroxyl group and a hydroxyl group of another sugar or some other compound can join together, splitting out water to form a glycosidic bond.

R-OH + HO-R’   –> R-O-R’ + H2O

For example, methanol reacts with the anomeric hydroxyl on glucose to form methyl glucoside (methyl-glucopyranose).

Plants store glucose as amylose or amylopectin, glucose polymers collectively called starch. Glucose storage in polymeric form minimizes osmotic effects. The end of the polysaccharide with an anomeric carbon (C1) that is not involved in a glycosidic bond is called the reducing end.

Glycogen, the glucose storage polymer in animals, is similar in structure to amylopectin. But glycogen has more α(1,6) branches. The highly branched structure permits rapid release of glucose from glycogen stores, e.g., in muscle cells during exercise. The ability to rapidly mobilize glucose is more essential to animals than to plants.

Glycosaminoglycans (mucopolysaccharides) are linear polymers of repeating disaccharides (diagrams p. 368-369). The constituent monosaccharides tend to be modified, with acidic groups, amino groups, sulfated hydroxyl and amino groups, etc. Glycosaminoglycans tend to be negatively charged, because of the prevalence of acidic groups.

Hyaluronate (hyaluronan) is a glycosaminoglycan with a repeating disaccharide consisting of two glucose derivatives, glucuronate (glucuronic acid) and N-acetylglucosamine. The glycosidic linkages are β(1,3) and β(1,4). Proteoglycans are glycosaminoglycans that are covalently linked to serine residues of specific core proteins. The glycosaminoglycan chain is synthesized by sequential addition of sugar residues to the core protein.

Some proteoglycans of the extracellular matrix bind non-covalently to hyaluronate via protein domains called link modules. For example:

  •     Multiple copies of the aggrecan proteoglycan associate with hyaluronate in cartilage to form large complexes.
  •     Versican, another proteoglycan, binds hyaluronate in the extracellular matrix of loose connective tissues.

Heparan sulfate is initially synthesized on a membrane-embedded core protein as a polymer of alternating glucuronate and N-acetylglucosamine residues. Later, in segments of the polymer, glucuronate residues may be converted to the sulfated sugar iduronic acid, while N-acetylglucosamine residues may be deacetylated and/or sulfated. Some cell surface heparan sulfate glycosaminoglycans remain covalently linked to core proteins associated with the plasma membrane.



Heparin, a soluble glycosaminoglycan found in granules of mast cells, has a structure similar to that of heparan sulfates, but is relatively highly sulfated. When released into the blood, it inhibits clot formation by interacting with the protein antithrombin. Heparin has an extended helical conformation. Charge repulsion by the many negatively charged groups may contribute to this conformation.

Proteins involved in signaling and adhesion at the cell surface recognize and bind heparan sulfate chains. For example, binding of some growth factors (small proteins) to cell surface receptors is enhanced by their binding also to heparan sulfates.

Regulated cell surface Sulf enzymes may remove sulfate groups at particular locations on heparan sulfate chains to alter affinity for signal proteins such as growth factors.

Oligosaccharides that are covalently attached to proteins or to membrane lipids may be linear or branched chains. They often include modified sugars, e.g., acetylglucosamine, etc. O-linked oligosaccharide chains of glycoproteins vary in complexity. They link to a protein via a glycosidic bond between a sugar residue and a serine or threonine hydroxyl. They have roles in recognition, interaction. N-acetylglucosamine (abbreviated GlcNAc) is a common O-linked glycosylation of protein serine or threonine residues. Many cellular proteins, including enzymes and transcription factors, are regulated by reversible attachment of GlcNAc. Often attachment of GlcNAc to a protein hydroxyl group alternates with phosphorylation, with these two modifications having opposite regulatory effects (stimulation or inhibition).

Many proteins secreted by cells have attached N-linked oligosaccharide chains. Genetic diseases have been attributed to deficiency of particular enzymes involved in synthesizing or modifying oligosaccharide chains of these glycoproteins. Such diseases, and gene knockout studies in mice, have been used to define pathways of modification of oligosaccharide chains of glycoproteins and glycolipids.

The C-type lectin-like domain is a Ca++-binding carbohydrate recognition domain present in many animal lectins. Recognition and binding of carbohydrate moieties of glycoproteins, glycolipids, and proteoglycans by animal lectins is a factor in cell-cell recognition, adhesion of cells to the extracellular matrix, interaction of cells with chemokines and growth factors, recognition of disease-causing microorganisms, and initiation and control of inflammation.

Synthesis of conformationally locked L-iduronic acid derivatives: direct evidence for a critical role of the skew-boat 2S0 conformer in the activation of antithrombin by heparin.

Das SK1, Mallet JM, Esnault J, Driguez PA, Duchaussoy P, Sizun P, Herault JP, Herbert JM, Petitou M, Sinaÿ P.    Chemistry. 2001 Nov 19;7(22):4821-34.

We have used organic synthesis to understand the role of L-iduronic acid conformational flexibility in the activation of antithrombin by heparin. Among known synthetic analogues of the genuine pentasaccharidic sequence representing the antithrombin binding site of heparin, we have selected as a reference compound the methylated anti-factor Xa pentasaccharide 1. We have synthesized three analogues of 1, in which the L-iduronic acid unit is locked in one of three fixed conformations. A covalent two atom bridge between carbon atoms two and five of L-iduronic acid was first introduced to lock the pseudorotational itinerary of the pyranoid ring around the 2S0 form. The locked pentasaccharide 23 showed about the same activity as the reference compound 1 in an antithrombin-mediated anti-Xa assay. These results clearly establish the critical importance of the 2S0 conformation of L-iduronic acid in the activation of antithrombin by heparin. http://www.ncbi.nlm.nih.gov/pubmed/11763451

L-Iduronic acid (IdoA) is the major uronic acid component of the glycosaminoglycans (GAGs) dermatan sulfate, and heparin. It is also present in heparan sulfate although here in a minor amount relative to its carbon-5 epimer glucuronic acid.  In 2000, LK Hallak described the importance of this sugar in respiratory syncytial virus infection. Dermatan sulfate and heparan sulfate were the only GAGs containing IdoA, and they were the only ones that inhibited RSV infection in cell culture.

The lysosomal hydrolase a-L-iduronidase (IDUA) is one of the enzymes in the metabolic pathway responsible for the degradation of the glycosaminoglycans heparin sulfate and dermatan sulfate. A genomic subclone and a cDNA clone encoding human IDUA were used to localize IDUA to chromosome 4p16.3.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1683689/pdf/ajhg00095-0040.pdf

catalytic pathway for IDUA

catalytic pathway for IDUA



Mucopolysaccharidoses (MPS (I-VI)

Mucopolysaccharidoses (MPSs) are a group of lysosomal storage diseases, each of which is produced by an inherited deficiency of an enzyme involved in the degradation of acid mucopolysaccharides, now called glycosaminoglycans (GAGs). These diseases are autosomal recessive, except for mucopolysaccharidosis type II, which is X-linked. People with a mucopolysaccharidosis either do not produce enough of one of
the 11 enzymes required to break down these sugar chains into simpler molecules, or they produce enzymes that do not work properly. Over time, these glycosaminoglycans collect in the cells, blood and connective tissues. In these diseases large amounts of complex sugar molecules accumulate in harmful amounts in the body’s cells.

The mucopolysaccharidoses (MPSs) are a group of rare, inherited lysosomal storage disorders that are clinically characterized by abnormalities in multiple organ systems and reduced life expectancy. The MPSs are heterogeneous, progressive disorders. Patients typically appear normal at birth, but during early childhood they experience the onset of clinical disease, including skeletal, joint, airway and cardiac involvement, hearing and vision impairment, and mental retardation in the severe forms of MPS I, MPS II and MPS VII and all subtypes of MPS III. There are two treatment options for patients with MPS that are directed at the underlying pathophysiology: haematopoietic stem cell transplantation, which is useful for selected patients, and recombinant i.v. enzyme replacement therapy, which is available for MPS I, II and VI. Early diagnosis and treatment can improve patient outcomes and may reduce the disease burden on patients and caregivers. As skeletal and joint abnormalities are characteristic of many patients with MPS, rheumatologists are positioned to recognize the features of the disease and to facilitate early diagnosis and referral.
Overview of the mucopolysaccharidoses. Joseph Muenzer.
Rheumatology 2011; 50 (suppl 5): v4-v12. http://dx.doi,org:/10.1093/rheumatology/ker394
Research funded by the NINDS has shown that viral-delivered gene therapy in animal models of the mucopolysaccharidoses can stop the buildup of storage materials in brain cells and improve learning and memory. Enzyme replacement therapy has proven useful in reducing non-neurological symptoms and pain. In 2006, the FDA approved the drug idursulfase (Elaprase) for the treatment of MPS II (Hunter syndrome).  This is the first drug shown to have any benefit for one of the mucopolysaccharidoses.

Another lysosomal storage disease often confused with the mucopolysaccharidoses is mucolipidosis. In this disorder, excessive amounts of fatty materials known as lipids (another principal component of living cells) are stored, in addition to sugars. Persons with mucolipidosis may share some of the clinical features associated with the mucopolysaccharidoses (certain facial features, bony structure abnormalities, and damage to the brain), and increased amounts of the enzymes needed to break down the lipids are found in the blood.

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