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Inhibition of iduro...
Inhibition of iduronic acid biosynthesis by ebselen reduces glycosaminoglycan accumulation in mucopolysaccharidosis type I fibroblasts
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- Maccarana, Marco (författare)
- Uppsala University,Lund University,Lunds universitet,Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Uppsala Univ, Dept Med Biochem & Microbiol, BMC B11,Husargatan 3 Box 582, S-75123 Uppsala, Sweden.;Lund Univ, Dept Expt Med Sci, BMC C12,BMC H11, S-22184 Lund, Sweden.,Matrixbiologi,Forskargrupper vid Lunds universitet,Matrix Biology,Lund University Research Groups,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine
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- Tykesson, Emil (författare)
- Lund University,Lunds universitet,Lungbiologi,Forskargrupper vid Lunds universitet,Lung Biology,Lund University Research Groups
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- Pera, Edgar M. (författare)
- Lund Univ, Lund Stem Cell Ctr, Dept Lab Med, BMC H11, S-22184 Lund, Sweden.
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- Gouignard, Nadège (författare)
- Lund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine
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- Fang, Jianping (författare)
- GlycoNovo Technol Co Ltd, Shanghai 201203, Peoples R China.,GlycoNovo Technologies Co., Ltd.
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- Malmström, Anders (författare)
- Lund University,Lunds universitet,Matrixbiologi,Forskargrupper vid Lunds universitet,Matrix Biology,Lund University Research Groups
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- Ghiselli, Giancarlo (författare)
- Glyconova Srl, Parco Sci Silvano Fumero, I-10010 Colleretto Giacosa, TO, Italy.
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- Li, Jin-Ping (författare)
- Uppsala University,Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- 2021-06-29
- 2021
- Engelska.
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Ingår i: Glycobiology. - : Oxford University Press. - 0959-6658 .- 1460-2423. ; 31:10, s. 1319-1329
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Mucopolysaccharidosis type I (MPS-I) is a rare lysosomal storage disorder caused by deficiency of the enzyme alpha-L-iduronidase, which removes iduronic acid in both chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) and thereby contributes to the catabolism of glycosaminoglycans (GAGs). To ameliorate this genetic defect, the patients are currently treated by enzyme replacement and bone marrow transplantation, which have a number of drawbacks. This study was designed to develop an alternative treatment by inhibition of iduronic acid formation. By screening the Prestwick drug library, we identified ebselen as a potent inhibitor of enzymes that produce iduronic acid in CS/DS and HS. Ebselen efficiently inhibited iduronic acid formation during CS/DS synthesis in cultured fibroblasts. Treatment of MPS-I fibroblasts with ebselen not only reduced accumulation of CS/DS but also promoted GAG degradation. In early Xenopus embryos, this drug phenocopied the effect of downregulation of DS-epimerase 1, the main enzyme responsible for iduronic production in CS/DS, suggesting that ebselen inhibits iduronic acid production in vivo. However, ebselen failed to ameliorate the CS/DS and GAG burden in MPS-I mice. Nevertheless, the results propose a potential of iduronic acid substrate reduction therapy for MPS-I patients.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Nyckelord
- chondroitin dermatan sulfate
- ebselen
- epimerases
- mucopolysaccharidosis type I
- substrate reduction therapy
- chondroitin dermatan sulfate
- ebselen
- epimerases
- mucopolysaccharidosis type I
- substrate reduction therapy
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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