Inhibition of iduronic acid biosynthesis by ebselen reduces glycosaminoglycan accumulation in mucopolysaccharidosis type I fibroblasts
(2021) In Glycobiology 31(10). p.1319-1329- Abstract
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... (More)
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.
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- author
- Maccarana, Marco LU ; Tykesson, Emil LU ; Pera, Edgar M. LU ; Gouignard, Nadège LU ; Fang, Jianping ; Malmström, Anders LU ; Ghiselli, Giancarlo LU and Li, Jin Ping
- organization
- publishing date
- 2021-10-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- chondroitin dermatan sulfate, ebselen, epimerases, mucopolysaccharidosis type I, substrate reduction therapy
- in
- Glycobiology
- volume
- 31
- issue
- 10
- pages
- 11 pages
- publisher
- Oxford University Press
- external identifiers
-
- pmid:34192316
- scopus:85121130273
- ISSN
- 0959-6658
- DOI
- 10.1093/glycob/cwab066
- language
- English
- LU publication?
- yes
- id
- ec98dc64-fe51-4530-be67-073763101673
- date added to LUP
- 2022-02-03 11:56:05
- date last changed
- 2024-08-27 13:11:36
@article{ec98dc64-fe51-4530-be67-073763101673, abstract = {{<p>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. </p>}}, author = {{Maccarana, Marco and Tykesson, Emil and Pera, Edgar M. and Gouignard, Nadège and Fang, Jianping and Malmström, Anders and Ghiselli, Giancarlo and Li, Jin Ping}}, issn = {{0959-6658}}, keywords = {{chondroitin dermatan sulfate; ebselen; epimerases; mucopolysaccharidosis type I; substrate reduction therapy}}, language = {{eng}}, month = {{10}}, number = {{10}}, pages = {{1319--1329}}, publisher = {{Oxford University Press}}, series = {{Glycobiology}}, title = {{Inhibition of iduronic acid biosynthesis by ebselen reduces glycosaminoglycan accumulation in mucopolysaccharidosis type I fibroblasts}}, url = {{http://dx.doi.org/10.1093/glycob/cwab066}}, doi = {{10.1093/glycob/cwab066}}, volume = {{31}}, year = {{2021}}, }