Introduction to the Molecules Special Edition Entitled ‘Heparan Sulfate and Heparin: Challenges and Controversies’: Some Outstanding Questions in Heparan Sulfate and Heparin Research

Abstract

The scope of this article is to provide a brief general introduction to heparan sulfate (HS) and heparin, and attempt to identify some of the central challenges regarding research into the chemistry and biology of glycosaminoglycans (GAGs), some of which are the subject of contributions to the special issue of Molecules (published in volume 23, 2018) entitled ‘Heparan Sulfate and Heparin: Challenges and Controversies’ [...]

Structural Insights Into How Proteoglycans Determine Chemokine-CXCR1/CXCR2 Interactions: Progress and Challenges

“…Heparin is preferred for structural and biophysical studies as it is more uniformly sulfated and because of the availability of size-defined oligosaccharides. Heparin is assumed to be a good surrogate for describing HS interactions; this could be an oversimplification considering that their solution structures are different, and the fine structure of HS due to differential sulfation cannot be captured by heparin (76)(77)(78). We recently characterized the binding of heparin and HS polymers to CXCL1 and CXCL5 using NMR spectroscopy (79).…”

High sensitivity (zeptomole) detection of BODIPY-labelled heparan sulfate (HS) disaccharides by ion-paired RP-HPLC and LIF detection enables analysis of HS from mosquito midguts

“…Following synthesis, removal of 6-O-sulfate groups from the HS polysaccharide by sulfatases (Sulf 1 and 2) may also provide an additional means of control. [14][15][16] Owing to the relatively poor detection sensitivity inherent to carbohydrates, heterogeneous HS chains are typically isolated from a comparatively large number of cells (typically 10 3 to 10 5 cells) or mass of tissue (at least milligrams of starting material). To advance understanding of HS structure and metabolic control mechanisms linking HS biosynthesis and expression with activity, extraction and subsequent detection of much smaller HS samples will be required to enable differences in HS structure to be detected and correlated with activity.…”

“…Following synthesis, removal of 6- O -sulfate groups from the HS polysaccharide by sulfatases (Sulf 1 and 2) may also provide an additional means of control. 14–16…”

Hydrolytic Degradation of Heparin in Acidic Environments: Nuclear Magnetic Resonance Reveals Details of Selective Desulfation

“…It has been established that a major contribution to the biological activity of heparin follows from electrostatic interactions between the negatively charged sulfate groups densely populated throughout the polymer chain, brought into appropriate geometric proximity with basic amino acid residues (arginine, lysine, and, at appropriate pH values, also histidine) of heparin-binding proteins. ,, The selectivity of the binding is further adapted to control numerous important biological processes, among which the blood coagulation has been examined with the greatest attention. ,, The ability of heparin to modulate blood clotting arises principally from its interactions with two proteins: antithrombin (ATIII) and thrombin (factor IIa), but, importantly, the nature of these interactions at the molecular level differs considerably. While interactions with thrombin require an extended stretch of heparin with little requirement for particular heparin sequences, those between heparin and ATIII involve higher affinity interactions, conditional upon pentasaccharide sequences containing the low-abundance tri-sulfated glucosamine residue, for subsequent action on factor Xa.…”