A Conformational Study of 2-Oxanol: Insight into the Role of Ring Distortion on Enzyme-Catalyzed Glycosidic Bond Cleavage

Abstract

Ab initio molecular orbital theory at the G2(MP2,SVP) level has been used to study several conformations, defining part of the pseudorotational itinerary, of equatorial 2-oxanol. Half-chair (3H4) and boat (B1,4) transition states lie 23.7 and 14.3 kJ mol-1 above the chair conformation (1C4), respectively, while the twist-boat conformers (3S1 and 5S1) lie 6.9 and 5.9 kJ mol-1 above the chair, respectively. Protonation of the glycosidic oxygen of the chair conformer yields an oxonium ion in the chair conformation. All other conformations collapse to give an oxocarbonium ion−water complex upon protonation. The axial anomer in the chair conformation lies 12.0 kJ mol-1 lower than the equatorial anomer. Protonation of the axial anomer in the chair conformation does not yield a chair, but collapses to the oxocarbonium ion. A clear role is shown for ring distortion in enzymes which perform acid-catalyzed hydrolysis of equatorial glycosides. In addition to avoiding high-energy oxonium ion intermediates, distortion of the ring also reduces the glycosidic bond-stretch energy which delays the transition state and reduces the reaction barrier. Enzymes which hydrolyze the axial anomer do not require ring distortion to achieve a concerted pathway to the oxocarbonium ion. These results are discussed in relation to three enzymes, lysozyme, neuraminidase, and β-amylase.