The ~2S_O Skew-Boat Conformation in L-Iduronic Acid

摘要

L-Iduronic acid (l-MoA), an essential component of the glycosaminoglycans heparin, heparan sulfate, and dermatan sulfate, is biosynthesized in the polymeric form through a single epimerization at the C5-position of D-glucuronic acid. This locally controlled epimerization confers unique properties to L-IdoA-containing biomolecules, and the presence of L-IdoA in glycosaminoglycans explains their unique ability to control the activity of proteins such as growth factors, chemokines, blood coagulation enzymes, etc. This unique ability of the highly flexible L-IdoA ring is related to its ability to adopt several conformations of comparable energies. The iduronate ring conformation, initially thought to be restricted to an equilibrium between the ~1C4 and ~4C1 chair conformations, was further complicated when it was discovered that the ~2S0 skew-boat geometry could play a critical role in the control of blood coagulation. Over the past decades, extensive solution NMR experiments as well as theoretical computations'61 have been carried out, mostly using heparin fragments comprising up to 6 pyranose rings, to gain insight into the geometries of L-IdoA. Several macromolecular X-ray diffraction studies have also been performed, and a skew-boat conformation has been suggested based on studies of L-IdoA-containing polysaccharides complexed with their protein receptors.'7' Even though all these ingenious studies have given a convincing picture of L-IdoA with the ~2S_O geometry, an atomic-resolution model (d≈1 A) is still required, especially as such a highly flexible ring may present a quasicon-tinuous distribution of conformations. This model is presented herein through the study of the crystal structure of an L-idopyranosyluronic methyl ester, in the synthetic disacchar-ide 1 (Scheme 1).