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Exploration of the active site of β4GalT7: modifications of the aglycon of aromatic xylosides.

In English

Författare

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Summary, in English

Proteoglycans (PGs) are macromolecules that consist of long linear polysaccharides, glycosaminoglycan (GAG) chains, covalently attached to a core protein by the carbohydrate xylose. The biosynthesis of GAG chains is initiated by xylosylation of the core protein followed by galactosylation by the galactosyltransferase β4GalT7. Some β-d-xylosides, such as 2-naphthyl β-d-xylopyranoside, can induce GAG synthesis by serving as acceptor substrates for β4GalT7 and by that also compete with the GAG synthesis on core proteins. Here we present structure-activity relationships for β4GalT7 and xylosides with modifications of the aromatic aglycon, using enzymatic assays, cell studies, and molecular docking simulations. The results show that the aglycons reside on the outside of the active site of the enzyme and that quite bulky aglycons are accepted. By separating the aromatic aglycon from the xylose moiety by linkers, a trend towards increased galactosylation with increased linker length is observed. The galactosylation is influenced by the identity and position of substituents in the aromatic framework, and generally, only xylosides with β-glycosidic linkages function as good substrates for β4GalT7. We also show that the galactosylation ability of a xyloside is increased by replacing the anomeric oxygen with sulfur, but decreased by replacing it with carbon. Finally, we propose that reaction kinetics of galactosylation by β4GalT7 is dependent on subtle differences in orientation of the xylose moiety.

Avdelning/ar

Publiceringsår

2015

Språk

Engelska

Sidor

3351-3362

Publikation/Tidskrift/Serie

Organic and Biomolecular Chemistry

Volym

13

Issue

11

Dokumenttyp

Artikel i tidskrift

Förlag

Royal Society of Chemistry

Ämne

  • Medicinal Chemistry
  • Cell and Molecular Biology

Status

Published

Forskningsgrupp

  • Glycobiology
  • Lung Biology

ISBN/ISSN/Övrigt

  • ISSN: 1477-0539