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Iduronate 2-sulfatase

Iduronate 2-sulfatase (IDS), also referred to as Alpha-L-iduronate sulfate sulfatase or Idursulfase, is a lysosomal enzyme involved in the degradation pathway of dermatan sulfate and heparan sulfate.[1]

Function

Iduronate 2-sulfatase is located in the lysosome.[1] It is involved in the lysosomal degradation pathway of dermatan sulfate and heparan sulfate.[1] IDS hydrolyzes the 2-sulfate groups of the L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate and heparin.[1] Dermatan sulfate and heparan sulfate are complex glycosaminoglycans, which are essentially large sugar molecules.[2] They play important roles in cell adhesion, growth, proliferation and repair, and their degradation and recycling in the lysosome are essential for cellular maintenance.[2] IDS is expressed in the tissues of the liver, kidney, lung, and placenta.[1]

Disease

Mutations in Iduronate 2-sulfatase on the Xq28 chromosome can lead to Mucopolysaccharidosis 2 (MPS2), more commonly known as Hunter syndrome.[1] MPS2 is an X-linked lysosomal storage disease.[1] Due to the loss of IDS activity, the disease is characterized by the intracellular accumulation of the glycosaminoglycans heparan sulfate and dermatan sulfate, which are then excreted in urine.[1] Scientists have identified over 500 mutations on the Xq28 chromosome that include rearrangements, insertions/deletions, splicing defects and nonsense point mutations.[2] It is rare to find adults with severe Hunter syndrome as the average life expectancy for those with MPS2 is 15 years of age.[1] Most children diagnosed with MPS2 have somatic abnormalities including skeletal deformities, hepatosplenomegaly, and progressive cardiopulmonary deterioration.[1] Neurological damage is also prevalent beginning with what seems to be a developmental delay and hyperactivity, but progresses to mental retardation and dementia.[1] Death from MPS2 is typically due to obstructive airway disease or cardiac failure.[1] A treatment for patients with mild Hunter syndrome is enzyme replacement therapy, which involves the recombinant human IDS.[2]

Structural highlights

References

1. UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. Iduronate 2-sulfatase https://www.uniprot.org/uniprot/P22304#pathology_and_biotech (accessed Apr 28, 2021). 2. Demydchuk M, Hill CH, Zhou A, Bunkóczi G, Stein PE, Marchesan D, Deane JE, Read RJ. Insights into Hunter syndrome from the structure of iduronate-2-sulfatase. Nat Commun. 2017 Jun 8;8:15786. doi: 10.1038/ncomms15786. PMID: 28593992; PMCID: PMC5472762.

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-==Structure of Brain Trypsin (human trypsin IV) ==
+==Iduronate 2-sulfatase==
-<StructureSection load='1H4W' size='340' side='right' caption='Triose phosphate isomerase' scene=''>
+<StructureSection load='5FQL' size='340' side='right' caption='Iduronate 2-sulfatase protein' scene=''>
-'''Human Trypsin IV''' is a 224 residue proteinase found in the brains of Alzheimer's patients (1). Trypsins are mainly found in the pancreas and aid in food digestion; however, there are other trypsins that are present in the human brain and are homologous to those found in other animals such as cows and mice (1). A lot of research is being conducted in this particular protein because of its association with neurodegenerative diseases.
+Iduronate 2-sulfatase (IDS), also referred to as Alpha-L-iduronate sulfate sulfatase or Idursulfase, is a lysosomal enzyme involved in the degradation pathway of dermatan sulfate and heparan sulfate.[1]
 == Function ==
+Iduronate 2-sulfatase is located in the lysosome.[1] It is involved in the lysosomal degradation pathway of dermatan sulfate and heparan sulfate.[1] IDS hydrolyzes the 2-sulfate groups of the L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate and heparin.[1] Dermatan sulfate and heparan sulfate are complex glycosaminoglycans, which are essentially large sugar molecules.[2] They play important roles in cell adhesion, growth, proliferation and repair, and their degradation and recycling in the lysosome are essential for cellular maintenance.[2] IDS is expressed in the tissues of the liver, kidney, lung, and placenta.[1]
-It is mostly associated with disease and abnormal function in the brain. It is unclear if there is a normal function of this protein, but there is research suggesting it plays a role in neural development (1).It is associated with neurodegenerative diseases such as Alzheimer's, and possibly dementia (2). Trypsin IV is found in glial cells and astrocytes (2). It breaks down proteins in the brain and forms aggregates called amyloids (2). These sticky structures harden and form plaque (2).
-Progressive accumulation of plaque in the brain is what causes Alzheimer's. There are inhibitors of this protein present in the brain, but it is able to defend against them because it is too big to fit into the active site of the inhibitor (2). This protein is highly conserved, but in humans, there is a change in one of its residues, which is responsible for the immunity to its inhibitor. Gly193 has become Arginine in humans, and it can cause disease.
 == Disease ==
-The disease it is most often associated with is Alzheimer's. The change from Gly193 to Arg193 disrupts normal brain activity. Arginine is much larger than Glycine, which causes steric hinderance in the active site of its inhibitor, APP (Amyloid Precursor Protein) trypsin inhibitor. Arginine is also positively charged which also interferes with the inhibitor. When APP Trypsin inhibitor cannot do its job, brain trypsin will start degrading other proteins in the brain and form amyloid (plaque). The plaque blocks nerve impulses. It starts in the hyppocampus, but will spread to other parts of the brain.
+Mutations in Iduronate 2-sulfatase on the Xq28 chromosome can lead to Mucopolysaccharidosis 2 (MPS2), more commonly known as Hunter syndrome.[1] MPS2 is an X-linked lysosomal storage disease.[1] Due to the loss of IDS activity, the disease is characterized by the intracellular accumulation of the glycosaminoglycans heparan sulfate and dermatan sulfate, which are then excreted in urine.[1] Scientists have identified over 500 mutations on the Xq28 chromosome that include rearrangements, insertions/deletions, splicing defects and nonsense point mutations.[2] It is rare to find adults with severe Hunter syndrome as the average life expectancy for those with MPS2 is 15 years of age.[1] Most children diagnosed with MPS2 have somatic abnormalities including skeletal deformities, hepatosplenomegaly, and progressive cardiopulmonary deterioration.[1] Neurological damage is also prevalent beginning with what seems to be a developmental delay and hyperactivity, but progresses to mental retardation and dementia.[1] Death from MPS2 is typically due to obstructive airway disease or cardiac failure.[1] A treatment for patients with mild Hunter syndrome is enzyme replacement therapy, which involves the recombinant human IDS.[2]
+[[Image:Signs-and-symptoms-of-hunter-syndrome.jpg]]
+== Structural highlights ==
+<scene name='75/752270/Ide_mutations/1'>Scene 1: Location of mutations</scene>
-== Relevance ==
+<scene name='75/752270/Ide_atp_binding-active_sites/1'>Scene 2: ATP binding active sites</scene>
-This protein shows that trypsins are not limited to the pancreas, but its main relevance today is the fact that it is a primary cause of Alzheimer's. Research involving human trypsin IV is vital to the search for the disease which affects millions.
-== Structural highlights ==
+<scene name='75/752270/Ide_n_and_c_terminals/1'>Scene 3: N and C terminals</scene>
+<scene name='75/752270/Active_site_on_chain_a/1'>Scene 4: Active sites</scene>
 </StructureSection>
-This portion of the protein contains <scene name='75/752270/Ggc7/5'>Arg193</scene> which provides resistance to the inhibitor due to its large size and positive charge (2).
-Another significant feature of this protein is <scene name='75/752270/Ggc7/7'>Tyr150</scene> , which has an aromatic ring that interferes with the mobility of Arg193 and helps stabilize it (2). This protein is similar to human trypsin I, but has a few notable differences such as a Threonine in position 21 instead of Asparagine.
 == References ==
-<references/>
+. UniProt ConsortiumEuropean Bioinformatics InstituteProtein Information ResourceSIB Swiss Institute of Bioinformatics. Iduronate 2-sulfatase https://www.uniprot.org/uniprot/P22304#pathology_and_biotech (accessed Apr 28,  2021).
+. Demydchuk M, Hill CH, Zhou A, Bunkóczi G, Stein PE, Marchesan D, Deane JE, Read RJ. Insights into Hunter syndrome from the structure of iduronate-2-sulfatase. Nat Commun. 2017 Jun 8;8:15786. doi: 10.1038/ncomms15786. PMID: 28593992; PMCID: PMC5472762.

Sandbox GGC7

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Iduronate 2-sulfatase

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