The product is a purified form of human iduronate-2-sulfatase(IDS), a lysosomal enzyme, expressed in a human cell line. The product is an enzyme that hydrolyzes the 2-sulfate esters of terminal iduronate sulfate residues from the glycosaminoglycans dermatan sulfate and heparan sulfate in the lysosomes of various cell types. The product is a 525-amino acid glycoprotein with a molecular weight of approximately 76 KDa. The enzyme contains eight asparagine-linked glycosylation sites occupied by complex oligosaccharide structures. The enzyme activity of the product is dependent on the post-translational modification of a specific cysteine to formylglycine.
<0.001 EU per 1 μg of the peptide by the LAL method
For the treatment of Hunter syndrome in adults and children ages 5 and older.
Examples of Clinical Use:
The product is a purified form of the lysosomal enzyme human iduronate-2-sulfatase of recombinant DNA origin. It is designed to replace the natural enzyme, increasing catabolism of certain accumulated glycosaminoglycans (GAG), which abnormally accumulate in multiple tissue types in patients with mucopolysaccharidosis II (MPS-II, or Hunter syndrome).
Mechanism of action:
Hunter's Syndrome is an X-linked recessive disease caused by insufficient levels of the lysosomal enzyme iduronate-2-sulfatase. This enzyme cleaves the terminal 2-O-sulfate moieties from the glycosaminoglycans (GAG) dermatan sulfate and heparan sulfate. Due to the missing or defective iduronate-2-sulfatase enzyme in patients with Hunter's Syndrome, GAG progressively accumulate in the lysosomes of a variety of cells, leading to cellular engorgement, organomegaly, tissue destruction and organ system dysfunction. Treatment of Hunter's Syndrome patients with idursulfase provides exogenous enzyme for uptake into cellular lysosomes. Targeting of idursulfase to the lysosome occurs by endocytosis from the cell surface. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow specific binding of the enzymes to the M6P receptors on the cell surface, leading to cellular internalization of the enzyme, targeting to intracellular lysosomes and subsequent catabolism of accumulated GAG.
1. A basic introduction to Human iduronate-2-sulfatase(IDS)
Human iduronate-2-sulfatase (IDS) is an enzyme that plays a crucial role in the breakdown of complex carbohydrates called glycosaminoglycans (GAGs). Specifically, IDS is involved in the degradation of two specific GAGs known as dermatan sulfate and heparan sulfate. Glycosaminoglycans are long chains of sugar molecules that are found in various tissues throughout the body. They are essential for maintaining the structural integrity of tissues and organs, as well as for regulating important cellular processes.
In individuals with a genetic disorder called mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, there is a deficiency or malfunction of the IDS enzyme. This deficiency leads to the accumulation of dermatan sulfate and heparan sulfate in various tissues, including the bones, joints, organs, and central nervous system. The buildup of GAGs in MPS II causes progressive damage to these tissues and organs, leading to a wide range of symptoms and clinical manifestations. These can include skeletal abnormalities, heart problems, respiratory difficulties, hearing loss, developmental delays, and cognitive impairment.
Correcting the deficiency or malfunction of IDS is a primary therapeutic target in the management of MPS II. Enzyme replacement therapy (ERT) involving the administration of exogenous IDS has been developed as a treatment option. This therapy aims to supplement the deficient or malfunctioning IDS enzyme in order to promote the breakdown of accumulated GAGs and reduce the severity of symptoms.
2. Composition and structure of Human iduronate 2-sulfatase(IDS)
Human iduronate-2-sulfatase (IDS) is a glycoprotein enzyme encoded by the IDS gene located on the X chromosome. The IDS protein consists of 550 amino acids and has a molecular weight of approximately 76 kDa. The primary structure of IDS is characterized by the sequence of amino acids that make up the protein. This sequence determines the specific function and properties of the enzyme. Mutations in the IDS gene can result in variations in the primary structure of the IDS protein, leading to enzyme dysfunction in individuals with MPS II.
The secondary structure of IDS refers to the folding patterns and arrangement of amino acid residues in localized regions of the protein. It includes alpha-helices, beta-sheets, and random coils. The secondary structure is critical for stabilizing the overall conformation of IDS and maintaining its enzymatic activity. The tertiary structure of IDS refers to the three-dimensional arrangement of the entire protein molecule. It is critical for enzyme function and involves the folding of secondary structures and the interactions between different regions of the protein. The active site of IDS, where it catalyzes the breakdown of GAGs, is located within the tertiary structure of the protein.
The quaternary structure of IDS refers to the arrangement of multiple protein subunits, if applicable. In the case of IDS, it exists as a monomer, meaning it consists of a single polypeptide chain. IDS is a lysosomal enzyme, meaning it is primarily located within the lysosomes of cells. The lysosomes are cellular compartments responsible for the breakdown of various molecules through the action of specific enzymes.
3. Medical application of Human iduronate-2-sulfatase(IDS)
The medical application of human iduronate-2-sulfatase (IDS) primarily lies in the treatment of a metabolic disorder known as mucopolysaccharidosis type II (MPS II), also called Hunter syndrome. MPS II is a rare genetic disorder caused by a deficiency or malfunction of IDS enzyme activity. Patients with MPS II exhibit a wide range of symptoms, including developmental delay, skeletal abnormalities, organomegaly (enlarged organs), cognitive impairment, and progressive neurodegeneration. These symptoms arise due to the accumulation of glycosaminoglycans (GAGs), specifically dermatan sulfate and heparan sulfate, in various tissues and organs.
To address the deficiency of IDS in MPS II patients, enzyme replacement therapy (ERT) has been developed as a treatment approach. ERT involves injecting a modified form of IDS into the patient's bloodstream, allowing it to be taken up by cells and delivered to the lysosomes. Once inside the lysosomes, IDS can then break down the accumulated GAGs, reducing their levels and alleviating the symptoms associated with MPS II. During ERT, recombinant IDS is produced through genetic engineering techniques, where the IDS gene is inserted into host cells, such as Chinese hamster ovary (CHO) cells, to produce the enzyme. The recombinant IDS is then purified and administered to MPS II patients through regular intravenous infusions.
Although ERT cannot reverse the existing damage caused by GAG accumulation, it has been shown to improve certain clinical features of MPS II, such as pulmonary function, walking ability, and reductions in liver and spleen size. ERT is generally well-tolerated, but it requires lifelong administration and may have limitations in crossing the blood-brain barrier, leading to incomplete reversal of neurological symptoms. Research is ongoing to further optimize the delivery and efficacy of IDS replacement therapy, develop novel treatment strategies, and explore potential combination therapies to address the full spectrum of symptoms associated with MPS II.
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