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- Title
Influence of substitution pattern and cation binding on conformation and activity in heparin derivatives.
- Authors
Timothy R Rudd; Scott E Guimond; Mark A Skidmore; Laurence Duchesne; Marco Guerrini; Giangiacomo Torri; Cesare Cosentino; Alan Brown; David T Clarke; Jeremy E Turnbull; David G Fernig; Edwin A Yates
- Abstract
As model compounds for the biologically important heparan sulfate, eight systematically modified heparin derivatives were studied by synchrotron radiation circular dichroism (SRCD), which is sensitive to uronic acid confor- mation. Substitution pattern altered uronic acid conformation, even when structural changes were made in adjacent glucosamine residues (e.g. 6-O-desulfation) and did not involve a chromophore. SRCD spectra of these derivatives following conversion to the Na, K, Mg2, Ca2, Mn2, Cu2 and Fe3 cation forms revealed that almost all substitution/cation combinations resulted in unique spectra, showing that each was structurally distinct. The detailed effects that binding Na, K, Mg2 and Ca2 ions had on a 2-de-O-sulfated derivative was also studied by NMR, revealing that subtle changes in conformation (by NOE) and flexibility (by T2 measurements) resulted. Conversion to the K and Cu2 ion forms also drastically modified biological activity, from inactive to active, in a cell-based assay of fibroblast growth factor-receptor (FGF2/FGFR1c) signalling and this effect was not reproduced by free cations. These observations could explain the often-contradictory data concerning structureâactivity relationships for these derivatives in the literature and, furthermore, argue strongly against the established trend of considering sequence as a complete structural definition. It also provides additional means of modifying the activity of these polysaccharides and suggests a possible additional level of control in biological systems. There are also obvious potential applications for these findings in the biotechnology sphere.
- Subjects
CATIONS; DICHROISM; URONIC acids; GLUCOSAMINE
- Publication
Glycobiology, 2007, Vol 17, Issue 9, p983
- ISSN
0959-6658
- Publication type
Article
- DOI
10.1093/glycob/cwm062