The structure of human dermatan sulfate epimerase 1 emphasizes the importance of C5-epimerization of glucuronic acid in higher organisms.
|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|
|Citations||3 citations (journal impact: 9.35)|
|Abstract||Dermatan sulfate epimerase 1 DS-epi1 EC 18.104.22.168 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.|