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The structure of human dermatan sulfate epimerase 1 emphasizes the importance of C5-epimerization of glucuronic acid in higher organisms

Hasan, Mahmudul LU ; Khakzad, Hamed ; Happonen, Lotta LU ; Sundin, Anders LU ; Unge, Johan LU ; Mueller, Uwe ; Malmström, Johan LU orcid ; Westergren-Thorsson, Gunilla LU orcid ; Malmström, Lars LU and Ellervik, Ulf LU orcid , et al. (2021) In Chemical Science 12(5). p.1869-1885
Abstract

Dermatan sulfate epimerase 1 (DS-epi1, EC 5.1.3.19) catalyzes the conversion of d-glucuronic acid to l-iduronic acid on the polymer level, a key step in the biosynthesis of the glycosaminoglycan dermatan sulfate. Here, we present the first crystal structure of the catalytic domains of DS-epi1, solved at 2.4 Å resolution, as well as a model of the full-length luminal protein obtained by a combination of macromolecular crystallography and targeted cross-linking mass spectrometry. Based on docking studies and molecular dynamics simulations of the protein structure and a chondroitin substrate, we suggest a novel mechanism of DS-epi1, involving a His/double-Tyr motif. Our work uncovers detailed information about the domain architecture,... (More)

Dermatan sulfate epimerase 1 (DS-epi1, EC 5.1.3.19) catalyzes the conversion of d-glucuronic acid to l-iduronic acid on the polymer level, a key step in the biosynthesis of the glycosaminoglycan dermatan sulfate. Here, we present the first crystal structure of the catalytic domains of DS-epi1, solved at 2.4 Å resolution, as well as a model of the full-length luminal protein obtained by a combination of macromolecular crystallography and targeted cross-linking mass spectrometry. Based on docking studies and molecular dynamics simulations of the protein structure and a chondroitin substrate, we suggest a novel mechanism of DS-epi1, involving a His/double-Tyr motif. Our work uncovers detailed information about the domain architecture, active site, metal-coordinating center and pattern of N-glycosylation of the protein. Additionally, the structure of DS-epi1 reveals a high structural similarity to proteins from several families of bacterial polysaccharide lyases. DS-epi1 is of great importance in a range of diseases, and the structure provides a necessary starting point for design of active site inhibitors.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Chemical Science
volume
12
issue
5
pages
17 pages
publisher
Royal Society of Chemistry
external identifiers
  • scopus:85101166678
  • pmid:33815739
ISSN
2041-6520
DOI
10.1039/d0sc05971d
project
Small molecules that interfere with the biosynthesis of dermatan sulfate for exploration of cell surface carbohydrates and use as cancer therapy
language
English
LU publication?
yes
id
7f5e95b2-2227-428e-9353-e25b4e07f4f0
date added to LUP
2021-03-10 17:07:54
date last changed
2025-10-18 16:47:50
@article{7f5e95b2-2227-428e-9353-e25b4e07f4f0,
  abstract     = {{<p>Dermatan sulfate epimerase 1 (DS-epi1, EC 5.1.3.19) catalyzes the conversion of d-glucuronic acid to l-iduronic acid on the polymer level, a key step in the biosynthesis of the glycosaminoglycan dermatan sulfate. Here, we present the first crystal structure of the catalytic domains of DS-epi1, solved at 2.4 Å resolution, as well as a model of the full-length luminal protein obtained by a combination of macromolecular crystallography and targeted cross-linking mass spectrometry. Based on docking studies and molecular dynamics simulations of the protein structure and a chondroitin substrate, we suggest a novel mechanism of DS-epi1, involving a His/double-Tyr motif. Our work uncovers detailed information about the domain architecture, active site, metal-coordinating center and pattern of N-glycosylation of the protein. Additionally, the structure of DS-epi1 reveals a high structural similarity to proteins from several families of bacterial polysaccharide lyases. DS-epi1 is of great importance in a range of diseases, and the structure provides a necessary starting point for design of active site inhibitors.</p>}},
  author       = {{Hasan, Mahmudul and Khakzad, Hamed and Happonen, Lotta and Sundin, Anders and Unge, Johan and Mueller, Uwe and Malmström, Johan and Westergren-Thorsson, Gunilla and Malmström, Lars and Ellervik, Ulf and Malmström, Anders and Tykesson, Emil}},
  issn         = {{2041-6520}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{5}},
  pages        = {{1869--1885}},
  publisher    = {{Royal Society of Chemistry}},
  series       = {{Chemical Science}},
  title        = {{The structure of human dermatan sulfate epimerase 1 emphasizes the importance of C5-epimerization of glucuronic acid in higher organisms}},
  url          = {{http://dx.doi.org/10.1039/d0sc05971d}},
  doi          = {{10.1039/d0sc05971d}},
  volume       = {{12}},
  year         = {{2021}},
}