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

Hasan M, Khakzad H, Happonen L, Sundin A, Unge J, Mueller U, Malmström J, Westergren-Thorsson G, Malmström L, Ellervik U, Malmström A, Tykesson E

Chem. Sci. 12 (5) 1869-1885 [2021-02-07; online 2020-12-08]

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.

Structural Proteomics [Collaborative]

PubMed 33815739

DOI 10.1039/d0sc05971d

Crossref 10.1039/d0sc05971d

pii: d0sc05971d
pmc: PMC8006597