| Structural highlights
6i6x is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , , |
| Related: | 6i6r |
| Activity: | L-iduronidase, with EC number 3.2.1.76 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[IDUA_HUMAN] Hurler-Scheie syndrome;Hurler syndrome;Scheie syndrome. Defects in IDUA are the cause of mucopolysaccharidosis type 1H (MPS1H) [MIM:607014]; also known as Hurler syndrome. MPS1H is a severe form of mucopolysaccharidosis type 1, a rare lysosomal storage disease characterized by progressive physical deterioration with urinary excretion of dermatan sulfate and heparan sulfate. Patients with MPS1H usually present, within the first year of life, a combination of hepatosplenomegaly, skeletal deformities, corneal clouding and severe mental retardation. Obstructive airways disease, respiratory infection and cardiac complications usually result in death before 10 years of age.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Defects in IDUA are the cause of mucopolysaccharidosis type 1H/S (MPS1H/S) [MIM:607015]; also known as Hurler-Scheie syndrome. MPS1H/S is a form of mucopolysaccharidosis type 1, a rare lysosomal storage disease characterized by progressive physical deterioration with urinary excretion of dermatan sulfate and heparan sulfate. MPS1H/S represents an intermediate phenotype of the MPS1 clinical spectrum. It is characterized by relatively little neurological involvement, but most of the somatic symptoms described for severe MPS1 develop in the early to mid-teens, causing considerable loss of mobility. Defects in IDUA are the cause of mucopolysaccharidosis type 1S (MPS1S) [MIM:607016]; also known as Scheie syndrome. MPS1S is a mild form of mucopolysaccharidosis type 1, a rare lysosomal storage disease characterized by progressive physical deterioration with urinary excretion of dermatan sulfate and heparan sulfate. Patients with MPS1S may have little or no neurological involvement, normal stature and life span, but present development of joints stiffness, mild hepatosplenomegaly, aortic valve disease and corneal clouding.
Publication Abstract from PubMed
Cyclophellitol aziridines are potent irreversible inhibitors of retaining glycosidases and versatile intermediates in the synthesis of activity-based glycosidase probes (ABPs). Direct 3-amino-2-(trifluoromethyl)quinazolin-4(3H)-one-mediated aziridination of l-ido-configured cyclohexene has enabled the synthesis of new covalent inhibitors and ABPs of alpha-l-iduronidase, deficiency of which underlies the lysosomal storage disorder mucopolysaccharidosis type I (MPS I). The iduronidase ABPs react covalently and irreversibly in an activity-based manner with human recombinant alpha-l-iduronidase (rIDUA, Aldurazyme((R)) ). The structures of IDUA when complexed with the inhibitors in a non-covalent transition state mimicking form and a covalent enzyme-bound form provide insights into its conformational itinerary. Inhibitors 1-3 adopt a half-chair conformation in solution ((4) H3 and (3) H4 ), as predicted by DFT calculations, which is different from the conformation of the Michaelis complex observed by crystallographic studies. Consequently, 1-3 may need to overcome an energy barrier in order to switch from the (4) H3 conformation to the transition state ((2, 5) B) binding conformation before reacting and adopting a covalent (5) S1 conformation. rIDUA can be labeled with fluorescent Cy5 ABP 2, which allows monitoring of the delivery of therapeutic recombinant enzyme to lysosomes, as is intended in enzyme replacement therapy for the treatment of MPS I patients.
New Irreversible alpha-l-Iduronidase Inhibitors and Activity-Based Probes.,Artola M, Kuo CL, McMahon SA, Oehler V, Hansen T, van der Lienden M, He X, van den Elst H, Florea BI, Kermode AR, van der Marel GA, Gloster TM, Codee JDC, Overkleeft HS, Aerts JMFG Chemistry. 2018 Oct 11. doi: 10.1002/chem.201804662. PMID:30307091[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Clarke LA, Nelson PV, Warrington CL, Morris CP, Hopwood JJ, Scott HS. Mutation analysis of 19 North American mucopolysaccharidosis type I patients: identification of two additional frequent mutations. Hum Mutat. 1994;3(3):275-82. PMID:8019563 doi:http://dx.doi.org/10.1002/humu.1380030316
- ↑ Clarke LA, Scott HS. Two novel mutations causing mucopolysaccharidosis type I detected by single strand conformational analysis of the alpha-L-iduronidase gene. Hum Mol Genet. 1993 Aug;2(8):1311-2. PMID:8401515
- ↑ Bach G, Moskowitz SM, Tieu PT, Matynia A, Neufeld EF. Molecular analysis of Hurler syndrome in Druze and Muslim Arab patients in Israel: multiple allelic mutations of the IDUA gene in a small geographic area. Am J Hum Genet. 1993 Aug;53(2):330-8. PMID:8328452
- ↑ Scott HS, Litjens T, Nelson PV, Brooks DA, Hopwood JJ, Morris CP. alpha-L-iduronidase mutations (Q70X and P533R) associate with a severe Hurler phenotype. Hum Mutat. 1992;1(4):333-9. PMID:1301941 doi:http://dx.doi.org/10.1002/humu.1380010412
- ↑ Bunge S, Kleijer WJ, Steglich C, Beck M, Zuther C, Morris CP, Schwinger E, Hopwood JJ, Scott HS, Gal A. Mucopolysaccharidosis type I: identification of 8 novel mutations and determination of the frequency of the two common alpha-L-iduronidase mutations (W402X and Q70X) among European patients. Hum Mol Genet. 1994 Jun;3(6):861-6. PMID:7951228
- ↑ Tieu PT, Bach G, Matynia A, Hwang M, Neufeld EF. Four novel mutations underlying mild or intermediate forms of alpha-L-iduronidase deficiency (MPS IS and MPS IH/S). Hum Mutat. 1995;6(1):55-9. PMID:7550232 doi:http://dx.doi.org/10.1002/humu.1380060111
- ↑ Bunge S, Kleijer WJ, Steglich C, Beck M, Schwinger E, Gal A. Mucopolysaccharidosis type I: identification of 13 novel mutations of the alpha-L-iduronidase gene. Hum Mutat. 1995;6(1):91-4. PMID:7550242 doi:http://dx.doi.org/10.1002/humu.1380060119
- ↑ Scott HS, Anson DS, Orsborn AM, Nelson PV, Clements PR, Morris CP, Hopwood JJ. Human alpha-L-iduronidase: cDNA isolation and expression. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9695-9. PMID:1946389
- ↑ Lee-Chen GJ, Lin SP, Tang YF, Chin YW. Mucopolysaccharidosis type I: characterization of novel mutations affecting alpha-L-iduronidase activity. Clin Genet. 1999 Jul;56(1):66-70. PMID:10466419
- ↑ Teng YN, Wang TR, Hwu WL, Lin SP, Lee-Chen GJ. Identification and characterization of -3c-g acceptor splice site mutation in human alpha-L-iduronidase associated with mucopolysaccharidosis type IH/S. Clin Genet. 2000 Feb;57(2):131-6. PMID:10735634
- ↑ Matte U, Yogalingam G, Brooks D, Leistner S, Schwartz I, Lima L, Norato DY, Brum JM, Beesley C, Winchester B, Giugliani R, Hopwood JJ. Identification and characterization of 13 new mutations in mucopolysaccharidosis type I patients. Mol Genet Metab. 2003 Jan;78(1):37-43. PMID:12559846
- ↑ Yogalingam G, Guo XH, Muller VJ, Brooks DA, Clements PR, Kakkis ED, Hopwood JJ. Identification and molecular characterization of alpha-L-iduronidase mutations present in mucopolysaccharidosis type I patients undergoing enzyme replacement therapy. Hum Mutat. 2004 Sep;24(3):199-207. PMID:15300847 doi:http://dx.doi.org/10.1002/humu.20081
- ↑ Bertola F, Filocamo M, Casati G, Mort M, Rosano C, Tylki-Szymanska A, Tuysuz B, Gabrielli O, Grossi S, Scarpa M, Parenti G, Antuzzi D, Dalmau J, Di Rocco M, Vici CD, Okur I, Rosell J, Rovelli A, Furlan F, Rigoldi M, Biondi A, Cooper DN, Parini R. IDUA mutational profiling of a cohort of 102 European patients with mucopolysaccharidosis type I: identification and characterization of 35 novel alpha-L-iduronidase (IDUA) alleles. Hum Mutat. 2011 Jun;32(6):E2189-210. doi: 10.1002/humu.21479. Epub 2011 Mar 10. PMID:21394825 doi:http://dx.doi.org/10.1002/humu.21479
- ↑ Artola M, Kuo CL, McMahon SA, Oehler V, Hansen T, van der Lienden M, He X, van den Elst H, Florea BI, Kermode AR, van der Marel GA, Gloster TM, Codee JDC, Overkleeft HS, Aerts JMFG. New Irreversible alpha-l-Iduronidase Inhibitors and Activity-Based Probes. Chemistry. 2018 Oct 11. doi: 10.1002/chem.201804662. PMID:30307091 doi:http://dx.doi.org/10.1002/chem.201804662
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