The structure of human dermatan sulfate epimerase 1 emphasizes the importance of C5-epimerization of glucuronic acid in higher organisms.
| Type | Information |
|---|---|
| Nr | 72 (Research article) |
| Authors | Hasan, Mahmudul; Khakzad, Hamed; Happonen, Lotta; Sundin, Anders; Unge, Johan; Mueller, Uwe; Malmström, Johan; Westergren-Thorsson, Gunilla; Malmström, Lars; Ellervik, Ulf; Malmström, Anders; Tykesson, Emil |
| Title | The structure of human dermatan sulfate epimerase 1 emphasizes the importance of C5-epimerization of glucuronic acid in higher organisms. |
| Journal | Chem Sci (2021) 12 1869-1885 |
| DOI | 10.1039/d0sc05971d |
| Citations | 6 citations (journal impact: 9.35) |
| 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 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 Hisdouble-Tyr motif. Our work uncovers detailed information about the domain architecture active site metal-coordinating center and pattern of -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. |