Department of Chemical and Biological Engineering, Northwestern University , Evanston, Illinois 60208, United States.
J Am Chem Soc. 2014 Jan 22;136(3):1008-22. doi: 10.1021/ja410264d. Epub 2014 Jan 10.
Glycoside hydrolases (GHs) distort carbohydrate ring geometry along particular "catalytic itineraries" during the cleavage of glycosidic bonds, illustrating the relationship between substrate conformation and reactivity. Previous theoretical studies of thermodynamics of isolated monosaccharides offer insights into the catalytic itineraries of particular sugars. However, kinetic accessibility of carbohydrate puckering conformations and the role of exocyclic groups have not yet been thoroughly addressed. Here we present the first complete library of low-energy local minima and puckering interconversion transition states for five biologically relevant pyranose sugars: β-xylose, β-mannose, α-glucose, β-glucose, and β-N-acetylglucosamine. These were obtained by a thorough theoretical investigation each of the 38 IUPAC designated puckering geometries and all possible conformations of the exocyclic groups. These calculations demonstrate that exocyclic groups must be explicitly considered when examining these interconversion pathways. Furthermore, these data enable evaluation of previous hypotheses of why enzymes perturb ring geometries from the low-energy equatorial chair ((4)C1) conformation. They show that the relative thermodynamics alone do not universally correlate with GH catalytic itineraries. For some sugars, particular puckers offer both catalytically favorable electronic structure properties, such as anomeric carbon partial charge, and low kinetic barriers to achieve a given puckering conformation. However, different factors correlate with catalytic itineraries for other sugars; for β-N-acetylglucosamine, the key N-acetyl arm confounds the puckering landscape and appears to be the crucial factor. Overall, this study reveals a more comprehensive understanding of why particular puckering geometries are favored in carbohydrate catalysis concomitant with the complexity of glycobiology.
糖苷水解酶（GHs）在糖苷键的断裂过程中沿着特定的“催化轨迹”扭曲碳水化合物环的几何形状，说明了底物构象与反应性之间的关系。先前对孤立单糖热力学的理论研究为特定糖的催化轨迹提供了深入的了解。然而，碳水化合物构象的动力学可及性和外环基团的作用尚未得到彻底解决。在这里，我们首次提供了五个生物相关吡喃糖：β-木糖、β-甘露糖、α-葡萄糖、β-葡萄糖和β-N-乙酰葡萄糖胺的低能局部极小值和构象转换过渡态的完整库。这些都是通过对 IUPAC 指定的 38 种构象和外环基团的所有可能构象进行彻底的理论研究得到的。这些计算表明，在外环基团参与的情况下，必须明确考虑这些构象转换途径。此外，这些数据使我们能够评估先前关于酶为何从低能赤道椅（(4)C1）构象扭曲环几何形状的假设。它们表明，相对热力学本身并不普遍与 GH 催化轨迹相关。对于某些糖，特定的构象具有有利的电子结构特性，例如端基碳原子的部分电荷，并且达到给定构象的动力学障碍较低。然而，对于其他糖，不同的因素与催化轨迹相关；对于β-N-乙酰葡萄糖胺，关键的 N-乙酰臂使构象变化复杂化，似乎是关键因素。总体而言，这项研究揭示了为什么特定构象在碳水化合物催化中受到青睐的更全面的理解，同时也揭示了糖生物学的复杂性。
