Conformational equilibria of α-L-iduronate residues in disaccharides derived from heparin

Abstract

The disaccharides IdoA(2SO3)-anManOH(6SO3) and IdoA-anManOH (where IdoA represents alpha-L-iduronate, anManOH represents 2,5-anhydro-D-mannitol and SO3 represents sulphate ester) were prepared from bovine lung heparin using HNO2 depolymerization, borohydride reduction and desulphation, and were examined by 400 MHz 1H-n.m.r. spectroscopy. Three-bond proton-proton coupling constants around the IdoA ring were determined under a range of experimental conditions. For unsulphated IdoA all four proton-proton coupling constants varied markedly as a function of temperature, pH and solvent, providing clear evidence for a rapid conformational equilibrium. These data were analysed in terms of the three most energetically stable IdoA conformers: 1C4, 4C1, and 2S0. Predicted coupling constants for these conformers were determined using a modified Karplus-type relationship. For unsulphated IdoA in dimethyl sulphoxide the equilibrium was provoked strongly in favour of a slightly distorted 4C1 'chair' IdoA conformer for which coupling constants have not previously been reported. For sulphated IdoA in aqueous conditions and at low pH the equilibrium is strongly in favour of the alternative 1C4 chair conformer. Under many conditions, however, significant contributions from all three conformers occur for the non-reducing terminal IdoA in these disaccharides.

Interactions of Multiple Heparin Binding Growth Factors with Neuropilin-1 and Potentiation of the Activity of Fibroblast Growth Factor-2

“…HGF/SF binds to a similar subclass of sequences in HS, requiring 6-O-sulfate and iduronate (44), with a tetrasaccharide representing the minimal length of saccharide (27), whereas PrP c shows a strong preference for 2-O-sulfated iduronate (45). Iduronate residues contribute significantly to these interactions, which probably reflects the role of the flexibility of this sugar ring (46,47) in mediating protein interactions. Indeed, HGF/SF also interacts with dermatan sulfate but not chondroitin sulfate (48), including a dermatan sulfate, which probably contains just one iduronate per chain (49).…”

Pharmacology of Heparin and Related Drugs

“…Investigations of the dynamic aspects of the iduronate ring conformation used NMR data ( 1 H-1 H coupling constants) for both sulfated and unsulfated iduronate (Sanderson et al, 1987;Ferro et al, 1990). A force-field study provided a rationalization of these data in terms of a conformation equilibrium between 1 C 4 chair and skew-boat forms for iduronate, whether sulfated or not, in heparin/HS sequences (Ferro et al, 1990).…”

Conformation, dynamics, solvation and relative stabilities of selected β-hexopyranoses in water: a molecular dynamics study with the gromos 45A4 force field

“…However, a 1 C 4 conformation appears to be significantly populated for the a-and (to a lesser extent) b-anomers of D D-idose (populations $80% and $25% for the a-and b-anomers, respectively 30 ), as well as D D-altrose and (possibly) D D-gulose (population ratios unknown). This alternative chair conformation may become dominant for some D D-monosaccharide derivatives (e.g., of glucose, 194,325 idose, 59,83,326 xylose 327 and iduronates 48,51,54,57,58,60,328 ). Most (empirical or theoretical) estimates suggest a stability difference comprised between 25 and 45 kJ mol À1 between the two chair conformations of Glc in the gas-phase.…”

“…Skewboat forms may also be of relevance for some systems. 48,[54][55][56][57][58][59][60][61][62][63][64][65] For a given monosaccharide stereochemistry, the relative free energies of the different pyranose ring conformations in aqueous solution may be estimated using empirical additive schemes (e.g., HasselOttar, 66 Reeves-Kelly, 38,41 Angyal 18,67 and CoreyFeiner 68,69 schemes). These schemes were derived from experimental complexation 38,39,41,70,71 and NMR 18,67,72 measurements on model six-membered ring compounds.…”